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Shalaby MS, Abdel-Reheim ES, Almanaa TN, Alhaber LA, Nabil A, Ahmed OM, Elwan M, Abdel-Moneim A. Therapeutic effects of mesenchymal stem cell conditioned media on streptozotocin-induced diabetes in Wistar rats. Regen Ther 2025; 28:1-11. [PMID: 39678398 PMCID: PMC11638607 DOI: 10.1016/j.reth.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 07/02/2024] [Accepted: 11/08/2024] [Indexed: 12/17/2024] Open
Abstract
Cell-based therapy is a new direction of treatment of diseases such as type 1 diabetes mellitus (T1DM); but unfortunately, its severe side effects include immunogenicity and tumor development. Using Mesenchymal stem cells conditioned medium (MSCs-CM) may be an alternative therapy to avoid stem cell risks, preserving effectiveness and demonstrating noticeably increased levels of cytokines, angiogenic factors, and growth factors that encourage and support regenerative processes. In the current work, we examined the effects of MSCs-CM injected in tail vein and pancreas directly compared with the standard antidiabetic drug, glimepiride in streptozotocin-induced type 1 diabetic rats. Fifty adults Male Wistar rats were allocated equally into five groups: normal, diabetic control and three diabetic groups treated respectively with glimepiride, MSCs-CM injected daily into tail vein (MSCs-CMT) and MSCs-CM injected directly in pancreas (MSCs-CMP); all treatments continued for 28 days. The treatments produced a significant improvement in blood glucose level and glycosylated hemoglobin A1c (HbA1c), serum insulin level and lipid panel, and pancreas apoptosis-related markers including B cell lymphoma-2 (Bcl-2) and vimentin. In addition, the treatments resulted in suppression in the oxidation stress and enhancement in the antioxidant, which were manifested by the suppressed lipid peroxidation and the increased antioxidant markers (glutathione, catalase and superoxide dismutase) in the pancreas. In association with the significant decrease in tumour necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) and a significant increase in interleukin-10 (IL-10) levels, the inflammatory mediator nuclear factor-kappa B (NF-κB) expression was significantly decreased by MSCs-CMT and MSCs-CMP. The histological amelioration of the pancreatic islet cells assured our study especially in MSCs-CMP group than MSCs-CMT which supports islet regeneration and elevated circulating insulin. These results imply that MSCs-CM infusion has therapeutic benefits in T1DM rats and may be a viable novel therapeutic approach; MSCs-CMP was shown to be more effective than glimepiride and MSCs-CMT. The mechanisms of antidiabtic actions may be mediated via the antioxidant, anti-apoptotic and anti-inflammatory effects.
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Affiliation(s)
- Marwa S. Shalaby
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef, Egypt
| | - Eman S. Abdel-Reheim
- Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Taghreed N. Almanaa
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Lama Abdulaziz Alhaber
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ahmed Nabil
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef, Egypt
| | - Osama M. Ahmed
- Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Mariam Elwan
- Heath Affairs Directorate, Egyptian Ministry of Health, Mansoura, Egypt
| | - Adel Abdel-Moneim
- Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
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2
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Kaokaen P, Pangjantuk A, Kunhorm P, Promjantuek W, Chaicharoenaudomrung N, Noisa P. Conditioned medium of human umbilical cord-mesenchymal stem cells cultivated with human cord blood serum enhances stem cell stemness and secretome profiles. Toxicol In Vitro 2025; 103:105973. [PMID: 39561911 DOI: 10.1016/j.tiv.2024.105973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 11/10/2024] [Accepted: 11/14/2024] [Indexed: 11/21/2024]
Abstract
The proteins secreted by human umbilical cord mesenchymal stem cells (hUC-MSCs) may enhance tissue regeneration and wound healing. Traditional hUC-MSC cultures may not be enough since they undergo recurrent cellular senescence during large-scale production. This decreases the therapeutic ability of hUC-MSCs by altering genes and proteins that control stemness, proliferation, and protein release. Human cord blood serum (CBS) and the middle-density technique were used to evaluate hUC-MSC regeneration ability. To evaluate early-passage hMSCs for secretome-based therapies, they were expanded and secreted in vitro. After 4 days, hUC-MSCs cultivated at 3000 cells/cm2 and supplemented with 1 ng/ml CBS showed increased growth, cell proliferation, and a much lower population doubling time. CBS treatment reduced CD34, CD45, and HLA-DR levels in human umbilical cord mesenchymal stem cells (hUC-MSCs) by less than 2 %. Positive markers such CD73, CD90, and CD105 were found at >97 %, like control hUC-MSCs. Over extended culture, this combination culture can increase survival, proliferation, and stemness and postpone cell death and hUC-MSC senescence. The protein profile and hUC-MSC secretion were improved to make MSC secretion protein therapeutic. This improves cell-free treatment, proliferation, and wound healing in human skin cells. To improve cell-based transplantation or cosmeceutical manufacturing, this technique can boost hUC-MSC regeneration capacity.
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Affiliation(s)
- Palakorn Kaokaen
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, 111 University Avenue, Nakhon Ratchasima 30000, Thailand
| | - Amorn Pangjantuk
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, 111 University Avenue, Nakhon Ratchasima 30000, Thailand
| | - Phongsakorn Kunhorm
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, 111 University Avenue, Nakhon Ratchasima 30000, Thailand
| | - Wilasinee Promjantuek
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, 111 University Avenue, Nakhon Ratchasima 30000, Thailand
| | - Nipha Chaicharoenaudomrung
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, 111 University Avenue, Nakhon Ratchasima 30000, Thailand
| | - Parinya Noisa
- Laboratory of Cell-Based Assays and Innovations, School of Biotechnology, Institute of Agricultural Technology, Suranaree University of Technology, 111 University Avenue, Nakhon Ratchasima 30000, Thailand.
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Yoon JY, Quang BD, Shin JS, Kim JB, Lee JH, Kim HW, Lee JH. Establishing Minimum Criteria for Stem Cells from Human Exfoliated Deciduous Teeth (SHEDs) Cultured in Human Platelet Lysate (hPL)-Contained Media as Cell Therapy Candidates: Characterization and Predictive Analysis of Secretome Effects. Cells 2025; 14:316. [PMID: 39996787 PMCID: PMC11854447 DOI: 10.3390/cells14040316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/14/2025] [Accepted: 02/18/2025] [Indexed: 02/26/2025] Open
Abstract
SHEDs have demonstrated significant potential in cell therapy due to their superior proliferation rate, self-renewal and differentiation capacity (particularly neurogenesis attributed to their neural crest origin), and the less invasive procedure required for tissue collection compared to other stem cells. However, there is no established criterion to verify the minimum qualification to select one from numerous candidates, especially for SHEDs' cultured FBS-free medium for clinic application. For that, we performed a characteristic analysis containing the growth rate, colony-forming unit (CFU) number, average colony size, and migration capacity with hPL-cultured SHEDs from 21 different donors, and we suggest the result as a minimum standard to filter out unqualified candidates. In addition, in the secretome analysis to predict the paracrine effect, it was found that upregulated proteins compared to the control were related to angiogenesis, immune response, and BMP signaling, and this was found to have a strong correlation only with protein concentration. This study presents a minimum standard for selecting cell therapy candidates and suggests the protein concentration of a conditioned medium as a cost-effective tool to expect the paracrine effect of SHEDs.
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Affiliation(s)
- Ji-Young Yoon
- Research Institute for Stem Cell & Matters, Cell & Matter Corporation, Cheonan 31116, Republic of Korea; (J.-Y.Y.); (B.D.Q.)
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea; (J.H.L.); (H.-W.K.)
| | - Bình Do Quang
- Research Institute for Stem Cell & Matters, Cell & Matter Corporation, Cheonan 31116, Republic of Korea; (J.-Y.Y.); (B.D.Q.)
| | - Ji-Sun Shin
- Department of Pediatric Dentistry, College of Dentistry, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea; (J.-S.S.); (J.-B.K.)
| | - Jong-Bin Kim
- Department of Pediatric Dentistry, College of Dentistry, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea; (J.-S.S.); (J.-B.K.)
| | - Jun Hee Lee
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea; (J.H.L.); (H.-W.K.)
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea
- Mechanobiology Dental Medicine Research Center, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea
- Cell & Matter Institute, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea
- Department of Biomaterials Science, School of Dentistry, Dankook University, Cheonan 31116, Republic of Korea
| | - Hae-Won Kim
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea; (J.H.L.); (H.-W.K.)
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea
- Mechanobiology Dental Medicine Research Center, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea
- Cell & Matter Institute, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea
- Department of Biomaterials Science, School of Dentistry, Dankook University, Cheonan 31116, Republic of Korea
| | - Jung-Hwan Lee
- Research Institute for Stem Cell & Matters, Cell & Matter Corporation, Cheonan 31116, Republic of Korea; (J.-Y.Y.); (B.D.Q.)
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea; (J.H.L.); (H.-W.K.)
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea
- Mechanobiology Dental Medicine Research Center, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea
- Cell & Matter Institute, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea
- Department of Biomaterials Science, School of Dentistry, Dankook University, Cheonan 31116, Republic of Korea
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4
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Ladner YD, Menzel U, Thompson K, Armiento AR, Stoddart MJ. Phenotypic alterations in articulating joint cells: Role of mechanically loaded MSC secretome. Heliyon 2025; 11:e42234. [PMID: 39975836 PMCID: PMC11835575 DOI: 10.1016/j.heliyon.2025.e42234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 01/15/2025] [Accepted: 01/22/2025] [Indexed: 02/21/2025] Open
Abstract
Improvements in the treatment of cartilage require insights into the secretory profile of mesenchymal stem cells (MSCs). Apart from their differentiation potential, MSCs secrete a multitude of molecules with therapeutic properties that benefit chondrogenesis and immunomodulation. Previously, we employed a small-panel microarray to demonstrate differences within conditioned medium (CM) of MSCs that were mechanically stimulated within a joint-mimicking bioreactor and their unloaded controls. This study analyzed the proteomic content within CM from 4 week mechanically loaded MSCs with a larger protein microarray. We examined the chondrogenic effect of CM by administration to MSC and chondrocyte pellet cultures, as well as functional changes in T cell proliferation. CM from mechanically loaded samples shows a promising push towards chondrogenic phenotypes within both pellet cultures. Inhibition of T cell proliferation was also observed. This in vitro model could enhance our understanding how mechanical load induces changes in MSC secretome benefitting cartilage healing.
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Affiliation(s)
- Yann D. Ladner
- AO Research Institute Davos, Clavadelerstrasse 8, 7270, Davos Platz, Switzerland
- Institute for Biomechanics, ETH Zurich, Lengghalde 5, CH-8008, Zurich, Switzerland
| | - Ursula Menzel
- AO Research Institute Davos, Clavadelerstrasse 8, 7270, Davos Platz, Switzerland
| | | | | | - Martin J. Stoddart
- AO Research Institute Davos, Clavadelerstrasse 8, 7270, Davos Platz, Switzerland
- Department of Orthopedics and Trauma Surgery, Medical Center-Albert-Ludwigs-University of Freiburg, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, 79106, Freiburg, Germany
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5
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Pacilio S, Lombardi S, Costa R, Paris F, Petrocelli G, Marrazzo P, Cenacchi G, Alviano F. Role of Perinatal Stem Cell Secretome as Potential Therapy for Muscular Dystrophies. Biomedicines 2025; 13:458. [PMID: 40002871 DOI: 10.3390/biomedicines13020458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/02/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
Inflammation mechanisms play a critical role in muscle homeostasis, and in Muscular Dystrophies (MDs), the myofiber damage triggers chronic inflammation which significantly controls the disease progression. Immunomodulatory strategies able to target inflammatory pathways and mitigate the immune-mediated damage in MDs may provide new therapeutic options. Owing to its capacity of influencing the immune response and enhancing tissue repair, stem cells' secretome has been proposed as an adjunct or standalone treatment for MDs. In this review study, we discuss the challenging points related to the inflammation condition characterizing MD pathology and provide a concise summary of the literature supporting the potential of perinatal stem cells in targeting and modulating the MD inflammation.
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Affiliation(s)
- Serafina Pacilio
- Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Sara Lombardi
- Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Roberta Costa
- Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Francesca Paris
- Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Giovannamaria Petrocelli
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Pasquale Marrazzo
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Giovanna Cenacchi
- Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
| | - Francesco Alviano
- Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
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6
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Cadelano F, Giannasi C, Gualerzi A, Gerli M, Niada S, Della Morte E, Brini AT. Pre-Concentration Freezing Alters the Composition of Mesenchymal Stem/Stromal Cell-Conditioned Medium. BIOLOGY 2025; 14:181. [PMID: 40001949 DOI: 10.3390/biology14020181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/07/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025]
Abstract
Batch-to-batch reproducibility and robust quality assessment are crucial for producing cell-free biologics, such as conditioned medium (CM) derived from mesenchymal stem/stromal cells (MSCs). This study investigated the effects of freezing CM at -80 °C prior to concentration, a step that could occur in large scale pipelines, compared to freshly processed CM. Quality assessment included total protein quantification; extracellular vesicle evaluation using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and cytofluorimetry; and biochemical analysis using Raman spectroscopy. The freezing process resulted in a 34% reduction in total protein content, as confirmed for selected bioactive mediators, and significant depletion of specific particle types, particularly larger ones. Interestingly, the total particle concentration and polydispersity remained stable. Alterations in Raman spectra highlighted changes in protein, lipid, and nucleic acid content. These findings demonstrate that even routine steps like freezing can alter CM composition, likely due to temperature-induced structural changes in biological molecules. Careful consideration of pre- and intra-processing handling temperatures is critical for preserving the integrity of CM and ensuring consistent quality. This study emphasizes the importance of refining manufacturing protocols in the production of cell-free biologics.
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Affiliation(s)
- Francesca Cadelano
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20100 Milan, Italy
- Laboratory of Biotechnological Applications, IRCCS Istituto Ortopedico Galeazzi, 20157 Milan, Italy
| | - Chiara Giannasi
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20100 Milan, Italy
- Laboratory of Biotechnological Applications, IRCCS Istituto Ortopedico Galeazzi, 20157 Milan, Italy
| | | | - Martina Gerli
- IRCCS Fondazione Don Gnocchi Onlus, 20148 Milan, Italy
| | - Stefania Niada
- Laboratory of Biotechnological Applications, IRCCS Istituto Ortopedico Galeazzi, 20157 Milan, Italy
| | - Elena Della Morte
- Laboratory of Biotechnological Applications, IRCCS Istituto Ortopedico Galeazzi, 20157 Milan, Italy
| | - Anna Teresa Brini
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20100 Milan, Italy
- Laboratory of Biotechnological Applications, IRCCS Istituto Ortopedico Galeazzi, 20157 Milan, Italy
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Chen M, Liu Y, Cao Y, Zhao C, Liu Q, Li N, Liu Y, Cui X, Liu P, Liang J, Fan Y, Wang Q, Zhang X. Remodeling the Proinflammatory Microenvironment in Osteoarthritis through Interleukin-1 Beta Tailored Exosome Cargo for Inflammatory Regulation and Cartilage Regeneration. ACS NANO 2025; 19:4924-4941. [PMID: 39848926 DOI: 10.1021/acsnano.4c16785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2025]
Abstract
Osteoarthritis (OA) presents a significant therapeutic challenge, with few options for preserving joint cartilage and repairing associated tissue damage. Inflammation is a pivotal factor in OA-induced cartilage deterioration and synovial inflammation. Recently, exosomes derived from human umbilical cord mesenchymal stem cells (HucMSCs) have gained recognition as a promising noncellular therapeutic modality, but their use is hindered by the challenge of harvesting a sufficient number of exosomes with effective therapeutic efficacy. Given that HucMSCs are highly sensitive to microenvironmental signals, we hypothesized that priming HucMSCs within a proinflammatory environment would increase the number of exosomes secreted with enhanced anti-inflammatory properties. Subsequent miRNA profiling and pathway analysis confirmed that interleukin-1 beta (IL-1β)-induced exosomes (C-Exos) exert positive effects through miRNA regulation and signaling pathway modulation. In vitro experiments revealed that C-Exos enhance chondrocyte functionality and cartilage matrix production, as well as macrophage polarization, thereby enhancing cartilage repair. C-Exos were encapsulated in hyaluronic acid hydrogel microspheres (HMs) to ensure sustained release, leading to substantial improvements in the inflammatory microenvironment and cartilage regeneration in a rat OA model. This study outlines a strategy to tailor exosome cargo for anti-inflammatory and cartilage regenerative purposes, with the functionalized HMs demonstrating potential for OA treatment.
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Affiliation(s)
- Manyu Chen
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China
| | - Yuhan Liu
- The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, China
| | - Yi Cao
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China
| | - Chengkun Zhao
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China
| | - Quanying Liu
- Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Na Li
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China
- Sichuan Testing Center for Biomaterials and Medical Devices, Sichuan University, 29 Wangjiang Road, Chengdu 610000, China
| | - Yuan Liu
- Orthopedics Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, P. R. China
| | - Xiaolin Cui
- Cardiac and Osteochondral Tissue Engineering (COTE) Group, School of medicine, the Chinese University of Hong Kong, Shenzhen 518172, China
- Department of Orthopedic Surgery & Musculoskeletal Medicine, Centre for Bioengineering & Nanomedicine, University of Otago, Christchurch 8011, New Zealand
| | - Pengcheng Liu
- Chengdu Xiangyakanglin Biotechnology Co., Ltd, Chengdu 610213, China
| | - Jie Liang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China
- Sichuan Testing Center for Biomaterials and Medical Devices, Sichuan University, 29 Wangjiang Road, Chengdu 610000, China
| | - Yujiang Fan
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China
| | - Qiguang Wang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China
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Sheikhi K, Ghaderi S, Firouzi H, Rahimibarghani S, Shabani E, Afkhami H, Yarahmadi A. Recent advances in mesenchymal stem cell therapy for multiple sclerosis: clinical applications and challenges. Front Cell Dev Biol 2025; 13:1517369. [PMID: 39963155 PMCID: PMC11830822 DOI: 10.3389/fcell.2025.1517369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 01/09/2025] [Indexed: 02/20/2025] Open
Abstract
Multiple sclerosis (MS), a chronic autoimmune disorder of the central nervous system (CNS), is characterized by inflammation, demyelination, and neurodegeneration, leading to diverse clinical manifestations such as fatigue, sensory impairment, and cognitive dysfunction. Current pharmacological treatments primarily target immune modulation but fail to arrest disease progression or entirely reverse CNS damage. Mesenchymal stem cell (MSC) therapy offers a promising alternative, leveraging its immunomodulatory, neuroprotective, and regenerative capabilities. This review provides an in-depth analysis of MSC mechanisms of action, including immune system regulation, promotion of remyelination, and neuroregeneration. It examines preclinical studies and clinical trials evaluating the efficacy, safety, and limitations of MSC therapy in various MS phenotypes. Special attention is given to challenges such as delivery routes, dosing regimens, and integrating MSCs with conventional therapies. By highlighting advancements and ongoing challenges, this review underscores the potential of MSCs to revolutionize MS treatment, paving the way for personalized and combinatory therapeutic approaches.
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Affiliation(s)
- Kamran Sheikhi
- Kurdistan University of Medical Sciences, Kurdistan, Iran
| | | | - Hassan Firouzi
- Department of Medical Laboratory, Faculty of Medicine, Sari Branch, Islamic Azad University, Sari, Iran
| | - Sarvenaz Rahimibarghani
- Department of Physical Medicine and Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran
| | - Ehsan Shabani
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
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9
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Jiang N, Yang S, Sun Y, Zhang C, Liu K, Huang Y, Li F. The effect of exosomes from canine bone mesenchymal stem cells on IL-1β-mediated inflammatory responses in chondrocytes. Cytotechnology 2025; 77:27. [PMID: 39736844 PMCID: PMC11682030 DOI: 10.1007/s10616-024-00685-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 12/16/2024] [Indexed: 01/01/2025] Open
Abstract
Osteoarthritis is a degenerative disease of cartilage, and exosome derived from mesenchymal stem cells (MSCs) are considered promising for treating inflammatory musculoskeletal disorders, although their mechanisms are not fully understood. This study aimed to investigate the effects of exosomes derived from canine bone marrow mesenchymal stem cells (cBMSCs-Exos) on the expression of inflammatory factors and genes related cartilage matrix metabolism in IL-1β-induced canine chondrocytes. Canine BMSCs were isolated and characterized for surface markers and trilineage differentiation. Exosomes were then extracted and performed surface labeling detection. Canine chondrocytes were exposed to IL-1β to mimic osteoarthritis in vitro. Subsequently, the chondrocytes were treated with exosomes from BMSCs, and the expression levels of related genes and IL-6 protein were assessed. The mesenchymal stem cells isolated from bone marrow and cultured exhibited positive CD44 and CD90, negative expression of CD45 and HLA, and demonstrated potential to differentiate into adipocytes, osteoblasts and chondrocytes. Exosomes from BMSCs exhibited positivity expression of CD9, CD63 and CD81. Treatment with exosomes significantly reduced IL-6 and TNF-α mRNA levels induced by IL-1β, as well as IL-6 protein expression. Additionally, a significant decrease was observed in the mRNA levels catabolic marker genes MMP-13, ADAMTS-5, and COX2. Conversely, there was a significant increase in the mRNA levels of anti-inflammatory cytokines IL-4, IL-10, and anabolic marker genes, such as COL2A1, ACAN, and SOX9. cBMSCs-Exos play a vital role in cartilage protection by suppressing the expression of pro-inflammatory and anabolic genes while simultaneously enhancing the expression of genes involved in synthesis metabolism.
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Affiliation(s)
- Nan Jiang
- College of Veterinary Medicine, Qingdao Agricultural University, No. 700 Changcheng Road, Chengyang, Qingdao, 266109 China
| | - Shuna Yang
- College of Veterinary Medicine, Qingdao Agricultural University, No. 700 Changcheng Road, Chengyang, Qingdao, 266109 China
| | - Yunfei Sun
- College of Veterinary Medicine, Qingdao Agricultural University, No. 700 Changcheng Road, Chengyang, Qingdao, 266109 China
| | - Chao Zhang
- Scholl of Biotechnology, Jiuquan Vocational Technical College, Jiuquan, 735000 China
| | - Kaicheng Liu
- Qingdao Kangdi’en Animal Pharmaceutical Co., Ltd, Qingdao, 266041 China
| | - Yufeng Huang
- College of Veterinary Medicine, Qingdao Agricultural University, No. 700 Changcheng Road, Chengyang, Qingdao, 266109 China
| | - Fangzheng Li
- College of Veterinary Medicine, Qingdao Agricultural University, No. 700 Changcheng Road, Chengyang, Qingdao, 266109 China
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10
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Marzookian K, Aliakbari F, Hourfar H, Sabouni F, Otzen DE, Morshedi D. The neuroprotective effect of human umbilical cord MSCs-derived secretome against α-synuclein aggregates on the blood-brain barrier. Int J Biol Macromol 2025; 304:140387. [PMID: 39880228 DOI: 10.1016/j.ijbiomac.2025.140387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 01/22/2025] [Accepted: 01/26/2025] [Indexed: 01/31/2025]
Abstract
The blood-brain barrier (BBB) is a specialized network that maintains central nervous system homeostasis. Disruption of the BBB can lead to neuronal damage and contribute to neurodegenerative diseases like Parkinson's disease (PD), characterized by alpha-synuclein (αSN) aggregation, which forms intracellular inclusions. Mesenchymal stem cells (MSCs) have shown promise in alleviating the severity of neurological diseases through their paracrine secretions. However, the impact of MSCs secretome on the BBB remains largely unclear. In this study, we investigated the effect of human umbilical cord-derived MSCs (hUC-MSCs) secretome on the BBB in the presence of toxic αSN-aggregates (αSN-AGs). Using in vitro BBB models established through mono- and co-culture systems of hCMEC/D3 cells, we assessed the influence of the secretome on the cytotoxicity and inflammatory responses induced by αSN-AGs. Our results demonstrate that the hUC-MSCs secretome exerts protective effects by mitigating the toxic effects of αSN-AGs on the BBB. Specifically, this study shows a notable reduction in cytotoxicity and inflammation. Our findings highlight the potential of hUC-MSCs secretome as a promising candidate for innovative, cell-free therapies in PD treatment. Furthermore, we propose an optimized method for isolating MSCs from umbilical cord tissue, aimed at facilitating future research on the therapeutic applications of these cells.
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Affiliation(s)
- Kimia Marzookian
- Department of Bioprocess Engineering, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Farhang Aliakbari
- Department of Bioprocess Engineering, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran; Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Hamdam Hourfar
- Department of Bioprocess Engineering, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Farzaneh Sabouni
- Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Daniel E Otzen
- Interdisciplinary Nanoscience Centre (iNANO), Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 14, Aarhus C DK-8000, Denmark
| | - Dina Morshedi
- Department of Bioprocess Engineering, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.
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11
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Jiu J, Liu H, Li D, Li X, Zhang J, Yan L, Fan Z, Li S, Du G, Li JJ, Wu A, Liu W, Du Y, Zhao B, Wang B. 3D Mechanical Response Stem Cell Complex Repairs Spinal Cord Injury by Promoting Neurogenesis and Regulating Tissue Homeostasis. Adv Healthc Mater 2025:e2404925. [PMID: 39853962 DOI: 10.1002/adhm.202404925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Indexed: 01/26/2025]
Abstract
Spinal cord injury (SCI) leads to acute tissue damage that disrupts the microenvironmental homeostasis of the spinal cord, inhibiting cell survival and function, and thereby undermining treatment efficacy. Traditional stem cell therapies have limited success in SCI, due to the difficulties in maintaining cell survival and inducing sustained differentiation into neural lineages. A new solution may arise from controlling the fate of stem cells by creating an appropriate mechanical microenvironment. In this study, mechanical response stem cell complex (MRSCC) is created as an innovative therapeutic strategy for SCI, utilizing 3D bioprinting technology and gelatin microcarriers (GM) loaded with mesenchymal stem cells (MSCs). GM creates an optimal microenvironment for MSCs growth and paracrine activity. Meanwhile, 3D bioprinting allows accurate control of spatial pore architecture and mechanical characteristics of the cell construct to encourage neuroregeneration. The mechanical microenvironment created by MRSCC is found to activate the Piezo1 channel and prevent excessive nuclear translocation of YAP, thereby increasing neural-related gene expression in MSCs. Transplanting MRSCC in rats with spinal cord injuries boosts sensory and motor recovery, reduces inflammation, and stimulates the regeneration of neurons and glial cells. The MRSCC offers a new tissue engineering solution that can promote spinal cord repair.
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Affiliation(s)
- Jingwei Jiu
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
- Department of Orthopedics, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China
| | - Haifeng Liu
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
- Department of Orthopedics, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China
| | - Dijun Li
- Department of Orthopedics, Affiliated Renhe Hospital of China Three Gorges University, Yichang, 443000, China
| | - Xiaoke Li
- Department of Orthopedics, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China
| | - Jing Zhang
- Department of Emergency Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, China
| | - Lei Yan
- Department of Orthopedics, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China
| | - Zijuan Fan
- Department of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, 030001, China
| | - Songyan Li
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Guangyuan Du
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Jiao Jiao Li
- School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Sydney, NSW, 2007, Australia
| | - Aimin Wu
- Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Wei Liu
- Development of Research, Beijing Hua Niche Biotechnology Co., LTD, Beijing, 100084, China
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Bin Zhao
- Department of Orthopedics, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China
| | - Bin Wang
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
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12
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Montagnino J, Kaufman MW, Shetty M, Centeno C, Fredericson M. Optimizing orthobiologic therapies with exercise, diet, and supplements. PM R 2025. [PMID: 39853939 DOI: 10.1002/pmrj.13320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 10/09/2024] [Accepted: 11/22/2024] [Indexed: 01/26/2025]
Abstract
Orthobiologic injections including platelet-rich plasma (PRP) and cell-based injections are becoming increasingly popular. Evidence suggests that these therapies can be effective in certain situations. The efficacy of these injections may be more dependent on the quality of the injectate, which given their autologous nature, may be dependent on lifestyle choices like exercise, diet, and supplements. The literature describing PRP injections shows that the number and activity of platelets can improve their efficacy. A multitude of lifestyle modifications can affect those factors. Exercise intensity appears to increase platelet count and increases adhesion as well as release of growth factors. Low inflammatory diets increase platelet counts and activity overall. Stress, some supplements, high cholesterol, or processed sugar diets can increase inflammation and potentially decrease platelet counts as well as quality of PRP injectate. Similarly, cell-based therapies can be affected by mesenchymal stromal cell (MSC) number and quality. Cell-based therapy is based upon limiting cellular senescence and increasing replication and differentiation. Exercise may limit senescence and improve replication and differentiation of these cell-based therapies, especially in older adult populations. There are a multitude of supplements that may potentiate these types of injections and patients should discuss the potential benefits and concerns when starting a supplement regimen. Certain foods as well as changes in oxygenation may limit cellular senescence and lower calorie intake may affect MSC viability and function as well. Overall, the current state of literature describes biologic plausibility of how exercise, diet and supplements might affect orthobiologic injection efficacy. Further translational research needs to be completed to describe the effect size and improve recommendations for clinical implementation.
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Affiliation(s)
- Jami Montagnino
- Department of Orthopaedic Surgery, Stanford University, Redwood City, California, USA
- Department of Orthopedics, Tulane University, Tulane Institute of Sports Medicine, New Orleans, Louisiana, USA
| | - Matthew W Kaufman
- Department of Orthopaedic Surgery, Stanford University, Redwood City, California, USA
- Stanford Research and Prevention Center, Stanford Lifestyle Medicine, Redwood City, California, USA
| | - Maya Shetty
- Department of Orthopaedic Surgery, Stanford University, Redwood City, California, USA
- Stanford Research and Prevention Center, Stanford Lifestyle Medicine, Redwood City, California, USA
| | | | - Michael Fredericson
- Department of Orthopaedic Surgery, Stanford University, Redwood City, California, USA
- Stanford Research and Prevention Center, Stanford Lifestyle Medicine, Redwood City, California, USA
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13
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Dong DL, Jin GZ. Targeting Chondrocyte Hypertrophy as Strategies for the Treatment of Osteoarthritis. Bioengineering (Basel) 2025; 12:77. [PMID: 39851351 PMCID: PMC11760869 DOI: 10.3390/bioengineering12010077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/08/2025] [Accepted: 01/14/2025] [Indexed: 01/26/2025] Open
Abstract
Osteoarthritis (OA) is a common joint disease characterized by pain and functional impairment, which severely impacts the quality of life of middle-aged and elderly individuals. During normal bone development, chondrocyte hypertrophy is a natural physiological process. However, in the progression of OA, chondrocyte hypertrophy becomes one of its key pathological features. Although there is no definitive evidence to date confirming that chondrocyte hypertrophy is the direct cause of OA, substantial experimental data indicate that it plays an important role in the disease's pathogenesis. In this review, we first explore the mechanisms underlying chondrocyte hypertrophy in OA and offer new insights. We then propose strategies for inhibiting chondrocyte hypertrophy from the perspectives of targeting signaling pathways and tissue engineering, ultimately envisioning the future prospects of OA treatment.
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Affiliation(s)
- Da-Long Dong
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Republic of Korea;
- Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea
| | - Guang-Zhen Jin
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Republic of Korea;
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14
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Irfan M, Kim JH, Sreekumar S, Chung S. RNA sequencing reveals key factors modulating TNFα-stimulated odontoblast-like differentiation of dental pulp stem cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.09.632294. [PMID: 39868289 PMCID: PMC11761799 DOI: 10.1101/2025.01.09.632294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Inflammation is a complex host response to harmful infections or injuries, playing both beneficial and detrimental roles in tissue regeneration. Notably, clinical dentinogenesis associated with caries development occurs within an inflammatory environment. Reparative dentinogenesis is closely linked to intense inflammation, which triggers the recruitment and differentiation of dental pulp stem cells (DPSCs) into the dentin lineage. Understanding how inflammatory responses influence DPSCs is essential for elucidating the mechanisms underlying dentin and pulp regeneration. Given the limited data on this process, a broad approach is employed here to gain a deeper understanding of the complex mechanisms involved and to identify downstream signaling targets. This study aims to investigate the role of inflammation and the complement receptor C5L2 in the odontoblastic differentiation of DPSCs and the associated transcriptomic changes using poly-A RNA sequencing (RNA-seq). RNA-seq techniques provide insight into the transcriptome of a cell, offering higher coverage and greater resolution of its dynamic nature. Following inflammatory stimulation, DPSCs exhibit significantly altered gene profiles, including marked upregulation of key odontogenic genes, highlighting the critical role of inflammation in dentinogenesis. We demonstrate that TNFα-treated odontoblast-like differentiating DPSCs, under C5L2 modulation, exhibit significant differential gene expression and transcriptomic changes. The data presented may provide new avenues for experimental approaches to uncover pathways in dentinogenesis by identifying specific transcription factors and gene profiles.
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Affiliation(s)
- Muhammad Irfan
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago 60612, IL, USA
| | - Ji Hyun Kim
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago 60612, IL, USA
| | - Sreelekshmi Sreekumar
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago 60612, IL, USA
| | - Seung Chung
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago 60612, IL, USA
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15
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Cong M, Hu JJ, Yu Y, Li XL, Sun XT, Wang LT, Wu X, Zhu LJ, Yang XJ, He QR, Ding F, Shi HY. miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells. Neural Regen Res 2025; 20:277-290. [PMID: 38767492 PMCID: PMC11246143 DOI: 10.4103/1673-5374.390956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 08/06/2023] [Accepted: 09/26/2023] [Indexed: 05/22/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.
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Affiliation(s)
- Meng Cong
- School of Medicine, Nantong University, Nantong, Jiangsu Province, China
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Jing-Jing Hu
- School of Medicine, Nantong University, Nantong, Jiangsu Province, China
- Department of Physiology, Jiangsu Health Vocational College, Nanjing, Jiangsu Province, China
| | - Yan Yu
- School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Xiao-Li Li
- School of Medicine, Nantong University, Nantong, Jiangsu Province, China
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Xiao-Ting Sun
- School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Li-Ting Wang
- School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Xia Wu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Ling-Jie Zhu
- School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Xiao-Jia Yang
- School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Qian-Ru He
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Fei Ding
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
- Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Hai-Yan Shi
- School of Medicine, Nantong University, Nantong, Jiangsu Province, China
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
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16
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Da Silva K, Kumar P, Choonara YE. The paradigm of stem cell secretome in tissue repair and regeneration: Present and future perspectives. Wound Repair Regen 2025; 33:e13251. [PMID: 39780313 PMCID: PMC11711308 DOI: 10.1111/wrr.13251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 12/04/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025]
Abstract
As the number of patients requiring organ transplants continues to rise exponentially, there is a dire need for therapeutics, with repair and regenerative properties, to assist in alleviating this medical crisis. Over the past decade, there has been a shift from conventional stem cell treatments towards the use of the secretome, the protein and factor secretions from cells. These components may possess novel druggable targets and hold the key to profoundly altering the field of regenerative medicine. Despite the progress in this field, clinical translation of secretome-containing products is limited by several challenges including but not limited to ensuring batch-to-batch consistency, the prevention of further heterogeneity, production of sufficient secretome quantities, product registration, good manufacturing practice protocols and the pharmacokinetic/pharmacodynamic profiles of all the components. Despite this, the secretome may hold the key to unlocking the regenerative blockage scientists have encountered for years. This review critically analyses the secretome derived from different cell sources and used in several tissues for tissue regeneration. Furthermore, it provides an overview of the current delivery strategies and the future perspectives for the secretome as a potential therapeutic. The success and possible shortcomings of the secretome are evaluated.
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Affiliation(s)
- Kate Da Silva
- Wits Advanced Drug Delivery Platform (WADDP) Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health SciencesUniversity of the WitwatersrandJohannesburgSouth Africa
| | - Pradeep Kumar
- Wits Advanced Drug Delivery Platform (WADDP) Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health SciencesUniversity of the WitwatersrandJohannesburgSouth Africa
| | - Yahya E. Choonara
- Wits Advanced Drug Delivery Platform (WADDP) Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health SciencesUniversity of the WitwatersrandJohannesburgSouth Africa
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17
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Guo X, Wang J, Su R, Luo D, Zhao K, Li Y. Repair effect analysis of mesenchymal stem cell conditioned media from multiple sources on HUVECs damaged by high glucose. Clin Proteomics 2024; 21:69. [PMID: 39734192 DOI: 10.1186/s12014-024-09521-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 12/16/2024] [Indexed: 12/31/2024] Open
Abstract
BACKGROUND The therapeutic potential of mesenchymal stem cells (MSCs) may be partly attributed to their secretion growth factors, cytokines and chemokines. In various preclinical studies, the use of MSC-conditioned media (CM) has demonstrated promising potential for promoting vascular repair. METHODS To gain a comprehensive understanding of the variations in conditioned media derived from different sources of mesenchymal stem cells (MSCs) including umbilical cord, adipose and bone marrow, we investigated their reparative effects on human umbilical vein endothelial cells (HUVECs) subjected to damage induced by high glucose. Initially, the secreted proteins from the three types of MSCs were assessed using the bicinchoninic acid (BCA) method. Subsequently, we examined the influence of different type of MSC secreted proteins on the proliferation of HUVECs under high glucose conditions. Following this, transwell migration experiments were conducted to evaluate the impact of MSC source on the migration of HUVECs damaged by high glucose. We further compared the effects of adding secreted proteins from the three types of MSCs on the tube formation ability of HUVECs subjected to high glucose damage. Finally, tandem mass tag (TMT) labeling quantitative proteomics was performed to analyze differently expressed proteins in the secreted proteins of three type MSC by using LC-MS/MS. RESULTS In this study, we observed a significantly higher secretion of proteins from umbilical cord mesenchymal stem cells (UMSCs) compared to adipose-derived stem cells (ADSCs). Subsequently, we found that the of proliferation HUVECs was significantly improved with supplementing the three MSCs secreted proteins under high glucose medium. Notably, the reparative effects of bone marrow mesenchymal stem cells (BMSCs) and UMSCs were superior to those of ADSCs. Afterwards, UMSCs exhibited the strongest ability to repair cell migration when HUVECs damaged by high glucose. Moreover, all three MSCs' secreted proteins exhibited the ability to enhance tube formation. Importantly, the UMSCs' secretome showed the most pronounced improvement in tube formation, as evidenced by the evaluation of parameters such as the number of nodes, the number of branches, and total length. These findings suggest that the UMSCs' secretome plays a crucial role in biological processes such as vasculature development, cell adhesion, and tissue remodeling. Additionally, the BMSCs' secretome was found to promote vascular development. The results collectively indicate the diverse therapeutic potential of MSC secretomes in influencing various aspects of cellular function and tissue repair. CONCLUSION In conclusion, this study offers a valuable reference for the selection of more suitable sources of mesenchymal stem cells (MSCs) in the treatment of diabetic cardiovascular disease.
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Affiliation(s)
- Xueyan Guo
- Department of Laboratory Medicine, Foshan Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Foshan, 528000, China
| | - Junyan Wang
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Rong Su
- Department of Laboratory Medicine, Foshan Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Foshan, 528000, China
| | - Dan Luo
- Western Institute of Health Data Science, Chongqing, 401329, China
| | - Keli Zhao
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- Western Institute of Health Data Science, Chongqing, 401329, China.
- Intervention and Cell Therapy Center, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, China.
- Children's Hospital of Chongqing Medical University, 400014, Chongqing, China.
| | - Yan Li
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- Western Institute of Health Data Science, Chongqing, 401329, China.
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
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18
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Doherty DF, Roets LE, Dougan CM, Brown RR, Hawthorne IJ, O'Kane C, Krasnodembskaya AD, Mall MA, Taggart CC, Weldon S. Mesenchymal stromal cells reduce inflammation and improve lung function in a mouse model of cystic fibrosis lung disease. Sci Rep 2024; 14:30899. [PMID: 39730509 DOI: 10.1038/s41598-024-81276-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 11/25/2024] [Indexed: 12/29/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) are multipotent adult stem cells which possess immunomodulatory and repair capabilities. In this study, we investigated whether MSC therapy could modulate inflammation and lung damage in the lungs of Scnn1b-transgenic mice overexpressing the β-subunit of the epithelial sodium channel (β-ENaC), a model with features of Cystic Fibrosis lung disease. Human bone marrow derived MSC cells were intravenously delivered to mice, prior to collection of bronchoalveolar lavage (BALF) and tissue. BALF analysis revealed a significant reduction in inflammatory cells after MSC administration, with both monocytic cells and neutrophils significantly reduced. Pro-inflammatory cytokines keratinocyte-derived chemokine (KC) and osteopontin were also significantly reduced. Histological tissue analysis revealed a reduction in emphysema in Scnn1b-TG mice treated with MSCs and consistent with these findings, improvements in lung function after MSC therapy were observed. Furthermore, MSCs enhanced Ki67 staining in alveolar cells, which may indicate regeneration of the destroyed parenchyma. Mechanistically, restoration of peroxisome proliferator-activated receptor-γ (PPARγ) expression and its transcriptional program were identified after MSC treatment. Our data demonstrate that MSC therapy can reduce inflammation, damage, and lung function decline in the chronically inflamed lung of Scnn1b-Tg mice, suggesting that MSCs may provide an effective tool in the treatment of muco-obstructive diseases such as cystic fibrosis.
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Affiliation(s)
- Declan F Doherty
- Airway Innate Immunity Research Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK
| | - Lydia E Roets
- Airway Innate Immunity Research Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK
| | - Caoifa M Dougan
- Airway Innate Immunity Research Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK
| | - Ryan R Brown
- Airway Innate Immunity Research Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK
| | - Ian J Hawthorne
- Airway Innate Immunity Research Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK
| | - Cecilia O'Kane
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - Anna D Krasnodembskaya
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - Marcus A Mall
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
- German Center for Lung Research (DZL), Associated Partner Site, Berlin, Germany
- BerlinInstitute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Clifford C Taggart
- Airway Innate Immunity Research Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK.
- Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson, Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.
| | - Sinéad Weldon
- Airway Innate Immunity Research Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University, Belfast, UK
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19
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Souza KBDS, Hochberger LC, Castrignano Camargo FE, Silva GS, Camargo GC, Mello JPL, Alcantara Dos Santos FC, Giachini FR, Lobato NDS, Souto PCDS. Umbilical vein remodeling is associated with pregestational maternal overweight. Front Endocrinol (Lausanne) 2024; 15:1483364. [PMID: 39758349 PMCID: PMC11695124 DOI: 10.3389/fendo.2024.1483364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/29/2024] [Indexed: 01/07/2025] Open
Abstract
Introduction Excess weight during pregnancy is a condition that can affect both mother and fetus, through the maternal-fetal interface, which is constituted by the placenta and umbilical cord. The umbilical vein is responsible for transporting oxygen and nutrients to the fetus, and its proper functioning depends on the integrity of its structure. The remodeling of the umbilical vein represents one of the causes of inadequate transport of nutrients to the fetus, being potentially harmful. This study aims to evaluate whether maternal overweight alters the structural characteristics of the umbilical vein. Methods Umbilical cords were collected from eutrophic and overweight pregnant women and were processed according to histological routine. We analyzed morphometry parameters, collagen and elastin fibers deposition, glycosaminoglycan level, and cell proliferation. Results Veins from overweight pregnant women were found to have greater total area, wall area, wall thickness, and diameter. There was higher collagen labeling in the perivascular region of the overweight group and a higher amount of type III collagen in the vascular smooth muscle. The proliferation of muscle and perivascular cells was higher in overweight pregnant women. A positive, although weak, correlation was observed between BMI and vessel thickness and with type III collagen deposition in vascular smooth muscle. Discussion With this study, we show that being overweight can structurally alter the umbilical vein, causing vascular remodeling of the vessel, through hypertrophy and hyperplasia.
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Affiliation(s)
| | | | | | - Gabriely Santos Silva
- Institute of Health and Biological Science, Federal University of Mato Grosso, Barra do Garças, Brazil
| | | | | | | | - Fernanda Regina Giachini
- Institute of Health and Biological Science, Federal University of Mato Grosso, Barra do Garças, Brazil
- Araguaia Multi-User Research Center, Federal University of Mato Grosso, Barra do Garças, Brazil
- Red Iberoamericana de Alteraciones Vasculares Asociadas a Transtornos del Embarazo (RIVATREM), Chillán, Chile
| | | | - Paula Cristina de Souza Souto
- Institute of Health and Biological Science, Federal University of Mato Grosso, Barra do Garças, Brazil
- Araguaia Multi-User Research Center, Federal University of Mato Grosso, Barra do Garças, Brazil
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20
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Sousa P, Lopes B, Sousa AC, Coelho A, de Sousa Moreira A, Rêma A, Gonçalves-Maia M, Amorim I, Alvites R, Alves N, Geuna S, Maurício AC. Isolation, Expansion, and Characterization of Rat Hair Follicle Stem Cells and Their Secretome: Insights into Wound Healing Potential. Biomedicines 2024; 12:2854. [PMID: 39767760 PMCID: PMC11672956 DOI: 10.3390/biomedicines12122854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/23/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Stem cells are capable of self-renewal and differentiation into various specialized cells, making them a potential therapeutic option in regenerative medicine. This study establishes a comprehensive methodology for isolating, culturing, and characterizing rat hair follicle stem cells. Methods and Results: Hair follicles were harvested from Sprague-Dawley rats and subjected to two different isolation techniques. Immunohistochemical analysis and real-time PCR confirm the expression of specific surface markers and genes, validating the cells' identity. Growth kinetics, colony formation units (CFU), and tri-differentiation capacity were also assessed. Additionally, the cells' secretome was analyzed, regarding its content in biofactors with wound healing properties. Conclusions: These findings highlight the potential of these cells as a valuable cell source for skin regeneration applications. They contribute to advancing our understanding of stem cell applications in regenerative medicine and hold promise for therapeutic interventions in various clinical contexts, aligning with broader research on the diverse capabilities of hair follicle stem cells.
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Affiliation(s)
- Patrícia Sousa
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Bruna Lopes
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Ana Catarina Sousa
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - André Coelho
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Alícia de Sousa Moreira
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Alexandra Rêma
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Maria Gonçalves-Maia
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Maia & Muller-Biotech, Rua Alfredo Allen, 455/461, 4200-135 Porto, Portugal
| | - Irina Amorim
- Departamento de Patologia e Imunologia Molecular, ICBAS—School of Medicine and Biomedical Sciences, University of Porto (UP), Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal;
- Institute for Research and Innovation in Health (i3S), Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
| | - Rui Alvites
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
- Instituto Universitário de Ciências da Saúde (CESPU), Avenida Central de Gandra 1317, 4585-116 Paredes, Portugal
| | - Nuno Alves
- Centre for Rapid and Sustainable Product Development, Polytechnic of Leiria, 2430-028 Marinha Grande, Portugal;
| | - Stefano Geuna
- Department of Clinical and Biological Sciences, Cavalieri Ottolenghi Neuroscience Institute, University of Turin, Ospedale San Luigi, 10043 Turin, Italy;
| | - Ana Colette Maurício
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal; (P.S.); (B.L.); (A.C.S.); (A.C.); (A.d.S.M.); (A.R.); (R.A.)
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal;
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
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21
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Yordanova A, Ivanova M, Tumangelova-Yuzeir K, Angelov A, Kyurkchiev S, Belemezova K, Kurteva E, Kyurkchiev D, Ivanova-Todorova E. Umbilical Cord Mesenchymal Stem Cell Secretome: A Potential Regulator of B Cells in Systemic Lupus Erythematosus. Int J Mol Sci 2024; 25:12515. [PMID: 39684227 DOI: 10.3390/ijms252312515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 11/13/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
Autoimmune diseases represent a severe personal and healthcare problem that seeks novel therapeutic solutions. Mesenchymal stem cells (MSCs) are multipotent cells with interesting cell biology and promising therapeutic potential. The immunoregulatory effects of secretory factors produced by umbilical cord mesenchymal stem cells (UC-MSCs) were assessed on B lymphocytes from 17 patients with systemic lupus erythematosus (SLE), as defined by the 2019 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE, and 10 healthy volunteers (HVs). Peripheral blood mononuclear cells (PBMCs) from patients and HVs were cultured in a UC-MSC-conditioned medium (UC-MSCcm) and a control medium. Flow cytometry was used to detect the surface expression of CD80, CD86, BR3, CD40, PD-1, and HLA-DR on CD19+ B cells and assess the percentage of B cells in early and late apoptosis. An enzyme-linked immunosorbent assay (ELISA) quantified the production of BAFF, IDO, and PGE2 in PBMCs and UC-MSCs. Under UC-MSCcm influence, the percentage and mean fluorescence intensity (MFI) of CD19+BR3+ cells were reduced in both SLE patients and HVs. Regarding the effects of the MSC secretome on B cells in lupus patients, we observed a decrease in CD40 MFI and a reduced percentage of CD19+PD-1+ and CD19+HLA-DR+ cells. In contrast, in the B cells of healthy participants, we found an increased percentage of CD19+CD80+ cells and decreased CD80 MFI, along with a decrease in CD40 MFI and the percentage of CD19+PD-1+ cells. The UC-MSCcm had a minimal effect on B-cell apoptosis. The incubation of patients' PBMCs with the UC-MSCcm increased PGE2 levels compared to the control medium. This study provides new insights into the impact of the MSC secretome on the key molecules involved in B-cell activation and antigen presentation and survival, potentially guiding the development of future SLE treatments.
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Affiliation(s)
- Adelina Yordanova
- University Hospital St. Ivan Rilski, Laboratory of Clinical Immunology, Department of Clinical Immunology, Medical Faculty, Medical University of Sofia, 15 Akademik Iv. E. Geshov Blvd., 1431 Sofia, Bulgaria
| | - Mariana Ivanova
- University Hospital St. Ivan Rilski, Clinic of Rheumatology, Department of Rheumatology, Medical Faculty, Medical University of Sofia, 13 Urvich St., 1612 Sofia, Bulgaria
| | - Kalina Tumangelova-Yuzeir
- University Hospital St. Ivan Rilski, Laboratory of Clinical Immunology, Department of Clinical Immunology, Medical Faculty, Medical University of Sofia, 15 Akademik Iv. E. Geshov Blvd., 1431 Sofia, Bulgaria
| | - Alexander Angelov
- University Hospital St. Ivan Rilski, Clinic of Rheumatology, Department of Rheumatology, Medical Faculty, Medical University of Sofia, 13 Urvich St., 1612 Sofia, Bulgaria
| | | | | | - Ekaterina Kurteva
- University Hospital St. Ivan Rilski, Laboratory of Clinical Immunology, Department of Clinical Immunology, Medical Faculty, Medical University of Sofia, 15 Akademik Iv. E. Geshov Blvd., 1431 Sofia, Bulgaria
| | - Dobroslav Kyurkchiev
- University Hospital St. Ivan Rilski, Laboratory of Clinical Immunology, Department of Clinical Immunology, Medical Faculty, Medical University of Sofia, 15 Akademik Iv. E. Geshov Blvd., 1431 Sofia, Bulgaria
| | - Ekaterina Ivanova-Todorova
- University Hospital St. Ivan Rilski, Laboratory of Clinical Immunology, Department of Clinical Immunology, Medical Faculty, Medical University of Sofia, 15 Akademik Iv. E. Geshov Blvd., 1431 Sofia, Bulgaria
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22
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Athiel Y, Cariot L, Jouannic JM, Maillet C, Mauffré V, Adam C, Huet H, Larghero J, Nasone J, Guilbaud L. Safety and efficacy of human umbilical cord-derived mesenchymal stromal cells in fetal ovine myelomeningocele repair. Stem Cell Res Ther 2024; 15:444. [PMID: 39568021 PMCID: PMC11580231 DOI: 10.1186/s13287-024-03991-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 10/09/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND The aim of this study was to assess the safety and efficacy of human umbilical cord mesenchymal stromal cells (hUC-MSCs) patch used as an adjuvant therapy in fetal myelomeningocele (MMC) surgery in the ovine model. METHODS hUC-MSCs were isolated from human umbilical cords (UC) using the explant method, cultured and characterized. hUC-MSCs were then embedded in a fibrin patch. MMC were surgically created at 75 days of gestation and repaired at 89 days of gestation in sheep fetuses. Two groups were compared: the hUC-MSCs group in which MMC was repaired using a cellular patch and the control group, in which MMC was repaired using an acellular patch. Safety was evaluated by clinical ewes' monitoring during gestation, and clinical and histological examinations of lambs after birth. Efficacy was assessed by clinical neurological evaluation at 2 and 24 h of life using the sheep locomotor rating scale and by histological analyses. RESULTS Among the 17 operated lambs, nine were born alive: six in the hUC-MSCs group and three in the control group. Overall fetal loss was 47% (8/17) without differences between the two groups. No fever was reported in ewes. No tumors were detected in clinical and histological examinations in the lambs. At 24 h of life, mean Sheep Locomotor Rating score was higher in the hUC-MSCs group than in the control group: 15.0 versus 2.0 (p = 0.07). Histological analyses showed a higher large neurons density in the hUC-MSCs group in comparison with the control group: 9.9 versus 6.3/mm2 of gray matter (p = 0.04). Lambs in the hUC-MSCs group had lower fibrosis around the spinal cord and at the level of the MMC scar: 70.9 versus 253.7 μm (p = 0.10) and 691.3 versus 1684.4 μm (p = 0,18), respectively. CONCLUSIONS Ovine fetal repair of MMC using human UC-MSCs seems to be an effective and safe procedure.
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Affiliation(s)
- Yoann Athiel
- Service de médecine foetale, DMU ORIGYN, APHP, Hôpital Trousseau, Sorbonne Université, Paris, France
- Unité de Thérapie Cellulaire, Université Paris Cité, AP-HP, Hôpital Saint-Louis, U976 et CIC de Biothérapies, INSERM, Paris, France
| | - Laura Cariot
- Service de médecine foetale, DMU ORIGYN, APHP, Hôpital Trousseau, Sorbonne Université, Paris, France
- Unité de Thérapie Cellulaire, Université Paris Cité, AP-HP, Hôpital Saint-Louis, U976 et CIC de Biothérapies, INSERM, Paris, France
| | - Jean-Marie Jouannic
- Service de médecine foetale, DMU ORIGYN, APHP, Hôpital Trousseau, Sorbonne Université, Paris, France
- Working Group Spina Bifida and Other Dysraphisms, European Reference Network ITHACA, Paris, France
| | - Corentin Maillet
- Service de médecine foetale, DMU ORIGYN, APHP, Hôpital Trousseau, Sorbonne Université, Paris, France
- Unité de Thérapie Cellulaire, Université Paris Cité, AP-HP, Hôpital Saint-Louis, U976 et CIC de Biothérapies, INSERM, Paris, France
| | - Vincent Mauffré
- École Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Clovis Adam
- Service d'anatomopathologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Hélène Huet
- École Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Jérôme Larghero
- Unité de Thérapie Cellulaire, Université Paris Cité, AP-HP, Hôpital Saint-Louis, U976 et CIC de Biothérapies, INSERM, Paris, France
| | - Justine Nasone
- Unité de Thérapie Cellulaire, Université Paris Cité, AP-HP, Hôpital Saint-Louis, U976 et CIC de Biothérapies, INSERM, Paris, France
| | - Lucie Guilbaud
- Service de médecine foetale, DMU ORIGYN, APHP, Hôpital Trousseau, Sorbonne Université, Paris, France.
- Unité de Thérapie Cellulaire, Université Paris Cité, AP-HP, Hôpital Saint-Louis, U976 et CIC de Biothérapies, INSERM, Paris, France.
- Working Group Spina Bifida and Other Dysraphisms, European Reference Network ITHACA, Paris, France.
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23
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Najafipour H, Rostamzadeh F, Jafarinejad-Farsangi S, Bagheri-Hosseinabadi Z, Jafari E, Farsinejad A, Bagheri MM. Human platelet lysate combined with mesenchymal stem cells pretreated with platelet lysate improved cardiac function in rats with myocardial infarction. Sci Rep 2024; 14:27701. [PMID: 39533052 PMCID: PMC11557824 DOI: 10.1038/s41598-024-79050-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024] Open
Abstract
Myocardial infarction (MI) is a leading cause of heart failure, disability and mortality worldwide. In this study, the effects of intramyocardial injection of human platelet lysate (HPL), bone marrow mesenchymal stem cells pretreated with HPL (PMSCs), and PMSC lysate (lys), alone and in combination were investigated on MI-induced by LAD ligation in male Wistar rats. The experiment was carried out on sham, vehicle (Veh), HPL, PMSCs, PMSC lysate (PMSC lys), HPL + PMSCs, and HPL + PMSC lys groups. SBP, DBP, and ± dp/dt max were monitored by the PowerLab physiograph. The MSC characteristics and CD31, NKX2.5, and cardiac troponin I (cTnI) contents were determined by flow cytometry, immunohistochemistry, and immunofluorescence, respectively. SBP, DBP, and ± dp/dt max that decreased in the MI group were recovered by HPL, PMSC, PMSC lys, HPL + PMSC, and HPL + PMSC lys treatments. CD31 density was higher in all treated groups compared to the Veh group. CD31 density in the HPL + PMSCs and HPL + PMSC lys groups was higher than in the PMSCs group. The number of Dil+/NKX2.5 + and Dil+/cTnI + cells was higher in the HPL + PMSCs group compared to the PMSCs group. The HPL and PMSCs mitigates heart injuries and cardiac dysfunction after MI. HPL provides an appropriate environment for cardiomyocyte differentiation from PMSCs.
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Affiliation(s)
- Hamid Najafipour
- Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Farzaneh Rostamzadeh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Boulevard Jihad, Ebne-Sina Avenue, 7619813159, Kerman, Iran.
| | - Seedieh Jafarinejad-Farsangi
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Bagheri-Hosseinabadi
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, and Department of Clinical Biochemistry, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Elham Jafari
- Pathology and Stem Cell Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Alireza Farsinejad
- Stem Cell and Regenerative Medicine Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohmmad Mehdi Bagheri
- Gastroenterology and Hepatology Research Center, Kerman University of Medical Sciences, Kerman, Iran
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24
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Kasahara N, Teratani T, Doi J, Yokota S, Shimodaira K, Kaneko Y, Ohzawa H, Sakuma Y, Sasanuma H, Fujimoto Y, Urahashi T, Yoshitomi H, Yamaguchi H, Kitayama J, Sata N. Controlled release of hydrogel-encapsulated mesenchymal stem cells-conditioned medium promotes functional liver regeneration after hepatectomy in metabolic dysfunction-associated steatotic liver disease. Stem Cell Res Ther 2024; 15:395. [PMID: 39497124 PMCID: PMC11536549 DOI: 10.1186/s13287-024-03993-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 10/10/2024] [Indexed: 11/06/2024] Open
Abstract
BACKGROUND Globally, prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing, and there is an urgent need to develop innovative therapies that promote liver regeneration following hepatectomy for this disease. Surgical excision is a key therapeutic approach with curative potential for liver tumors. However, hepatic steatosis can lead to delayed liver regeneration and higher post-operative complication risk. Mesenchymal stem cells-conditioned medium (MSC-CM) is considered a rich source of paracrine factors that can repair tissues and restore function of damaged organs. Meanwhile, hydrogels have been widely recognized to load MSC secretome and achieve sustained release. This study aimed to evaluate the therapeutic effect of hydrogel-encapsulated MSC-CM on liver regeneration following partial hepatectomy (PHx) in a rodent model of diet-induced hepatic steatosis. METHODS Male Lewis rats were fed with a methionine and choline-deficient diet. After 3 weeks of feeding, PHx was performed and rats were randomly allocated into two groups that received hydrogel-encapsulated MSC-CM or vehicle via the intra-mesenteric space of the superior mesenteric vein (SMV). RESULTS The regeneration of the remnant liver at 30 and 168 h after PHx was significantly accelerated, and the expressions of proliferating cell nuclear antigen were significantly enhanced in the MSC-CM group. MSC-CM treatment significantly increased hepatic ATP and β-hydroxybutyrate content at 168 h after PHx, indicating that MSC-CM fosters regeneration not only in volume but also in functionality. The number of each TUNEL- and cleaved caspase-3 positive nuclei in hepatocytes at 9 h after PHx were significantly decreased in the MSC-CM group, suggesting that MSC-CM suppressed apoptosis. MSC-CM increased serum immunoregulatory cytokine interleukin-10 and interleukin-13 at 30 h after PHx. Additionally, mitotic figures and cyclin D1 expression decreased and hepatocyte size increased in the MSC-CM group, implying that this mode of regeneration was mainly through cell hypertrophy rather than cell division. CONCLUSIONS MSC-CM represents a novel therapeutic approach for patients with MASLD requiring PHx.
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Affiliation(s)
- Naoya Kasahara
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Takumi Teratani
- Division of Translational Research, Jichi Medical University, Shimotsuke, Japan.
| | - Junshi Doi
- Department of Surgery, Japanese Red Cross Otsu Hospital, Otsu, Japan
| | | | | | - Yuki Kaneko
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hideyuki Ohzawa
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Yasunaru Sakuma
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hideki Sasanuma
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Yasuhiro Fujimoto
- Department of Transplant Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Taizen Urahashi
- Department of Surgery, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan
| | - Hideyuki Yoshitomi
- Department of Surgery, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan
| | | | - Joji Kitayama
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Naohiro Sata
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
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25
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Wei S, Cheng RJ, Li S, Lu C, Zhang Q, Wu Q, Zhao X, Tian X, Zeng X, Liu Y. MSC-microvesicles protect cartilage from degradation in early rheumatoid arthritis via immunoregulation. J Nanobiotechnology 2024; 22:673. [PMID: 39497131 PMCID: PMC11536868 DOI: 10.1186/s12951-024-02922-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 10/10/2024] [Indexed: 11/06/2024] Open
Abstract
OBJECTIVE As research into preclinical rheumatoid arthritis (pre-RA) has advanced, a growing body of evidence suggests that abnormalities in RA-affected joint cartilage precede the onset of arthritis. Thus, early prevention and treatment strategies are imperative. In this study, we aimed to explore the protective effects of mesenchymal stem cell (MSC)-derived microvesicles (MVs) on cartilage degradation in a collagen-induced arthritis (CIA) mouse model. METHODS A CIA mouse model was established to observe early pathological changes in cartilage (days 21-25) through histological and radiological examinations. On day 22, MSCs-MVs were intravenously injected into the mice with CIA. Radiological, histological, and flow cytometric examinations were conducted to observe inflammation and cartilage changes in these mice compared to the mice with CIA and the control mice. In vitro, chondrocytes were cultured with inflammatory factors such as IL-1β and TNFα to simulate inflammatory damage to cartilage. After the addition of MVs, changes in inflammatory levels and collagen expression were measured via Western blotting, immunofluorescence, enzyme-linked immunosorbent assays (ELISAs), and quantitative PCR to determine the role of MVs in maintaining chondrocytes. RESULTS MSC-MVs expressed vesicular membrane proteins (CD63 and Annexin V) and surface markers characteristic of MSCs (CD44, CD73, CD90, and CD105). In the early stages of CIA in mice, a notable decrease in collagen content was observed in the joint cartilage. In mice with CIA, injection of MSCs-MVs resulted in a significant reduction in the peripheral blood levels of IL-1β, TNFα, and IL-6, along with a decrease in the ratio of proinflammatory T and B cells. Additionally, MSC-MVs downregulated the expression of IL-1β, TNFα, MMP-13, and ADAMTS-5 in cartilage while maintaining the stability of type I and type II collagen. These MVs also attenuated the destruction of cartilage, which was evident on imaging. In vitro experiments demonstrated that MSC-MVs effectively suppressed the secretion of the inflammatory factors IL-1β, TNFα, and IL-6 in stimulated peripheral blood mononuclear cells (PBMCs). CONCLUSIONS MSCs-MVs can inhibit the decomposition of the inflammation-induced cartilage matrix by regulating immune cell inflammatory factors to attenuate cartilage destruction. MSC-MVs are promising effective treatments for the early stages of RA.
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Affiliation(s)
- Shixiong Wei
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College. National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology. State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital. Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Rui-Juan Cheng
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Sujia Li
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Chenyang Lu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Qiuping Zhang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Qiuhong Wu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xueting Zhao
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xinping Tian
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College. National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology. State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital. Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
| | - Xiaofeng Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College. National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology. State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital. Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
| | - Yi Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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Lee GB, Park SM, Jung UJ, Kim SR. The Potential of Mesenchymal Stem Cells in Treating Spinocerebellar Ataxia: Advances and Future Directions. Biomedicines 2024; 12:2507. [PMID: 39595073 PMCID: PMC11591855 DOI: 10.3390/biomedicines12112507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/28/2024] [Accepted: 10/31/2024] [Indexed: 11/28/2024] Open
Abstract
Spinocerebellar ataxia (SCA) is a heterogeneous disorder characterized by impaired balance and coordination caused by cerebellar dysfunction. The absence of treatments approved by the U.S. Food and Drug Administration for SCA has driven the investigation of alternative therapeutic strategies, including stem cell therapy. Mesenchymal stem cells (MSCs), known for their multipotent capabilities, have demonstrated significant potential in treating SCA. This review examines how MSCs may promote neuronal growth, enhance synaptic connectivity, and modulate brain inflammation. Recent findings from preclinical and clinical studies are also reviewed, emphasizing the promise of MSC therapy in addressing the unmet needs of SCA patients. Furthermore, ongoing clinical trials and future directions are proposed to address the limitations of the current approaches.
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Affiliation(s)
- Gi Beom Lee
- School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; (G.B.L.); (S.M.P.)
| | - Se Min Park
- School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; (G.B.L.); (S.M.P.)
| | - Un Ju Jung
- Department of Food Science and Nutrition, Pukyong National University, Busan 48513, Republic of Korea;
| | - Sang Ryong Kim
- School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; (G.B.L.); (S.M.P.)
- Brain Science and Engineering Institute, Kyungpook National University, Daegu 41404, Republic of Korea
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27
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Nainggolan ADC, Hartrianti P, Anjani QK, Donnelly RF, Putra ABN, Kho K, Kurniawan A, Andranilla RK, Rattu SA, Ramadon D. Double-layer dissolving microneedles for delivery of mesenchymal stem cell Secretome: Formulation, characterisation and skin irritation study. Eur J Pharm Biopharm 2024; 204:114495. [PMID: 39277118 DOI: 10.1016/j.ejpb.2024.114495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 08/31/2024] [Accepted: 09/08/2024] [Indexed: 09/17/2024]
Abstract
Regenerative therapy based on stem cells have been developed, focusing on either stem cell or secretome delivery. Most marketed cellular and gene therapy products are available as injectable dosage forms, leading to several limitations requiring alternative routes, such as the intradermal route. Microneedles, capable of penetratingthe stratum corneumbarrier, offer a potential alternative for intradermal delivery. This present study aimed to develop double-layer dissolving microneedles (DMN) for the delivery of freeze-dried mesenchymal stem cell secretome. DMNs were fabricated using a two-step casting method and composed of two polymer combinations: poly(vinyl pyrrolidone) (PVP) with poly(vinyl alcohol) (PVA) or PVP with sodium hyaluronate (SH). The manufactured DMNs underwent assessments for morphology, mechanical strength, in skin dissolution, protein content, in vitro permeation, in vivo skin irritation, and physical stability. Based on evaluations of morphology and mechanical strength, two formulas (F5 and F12) met acceptance criteria. Evaluation of protein content revealed that F12 (PVP-SH combination) had a higher protein content than F5 (PVP-PVA combination), 99.02 ± 3.24 μg and 78.36 ± 3.75 μg respectively. In vitro permeation studies showed that F5 delivered secretome protein by 100.84 ± 0.88%, while F12 delivered 99.63 ± 9.21% in 24 h. After four days of observation onSprague-Dawleyrat's skin, no signs of irritation, such as oedema and redness, was observed after applying both formulations. The safety of using PVP-PVA and PVP-SH combinations as excipients for DMN secretome delivery has been confirmed, promising significant advancements in biotherapeutic development in the future.
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Affiliation(s)
| | - Pietradewi Hartrianti
- Department of Pharmacy, School of Life Sciences, Indonesia International Institute of Life Sciences, Jakarta 13210, Indonesia
| | - Qonita Kurnia Anjani
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Ryan F Donnelly
- School of Pharmacy, Medical Biology Centre, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
| | - Agus Budiawan Naro Putra
- Research Centre for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), Cibinong, Bogor 16911, Indonesia
| | - Katherine Kho
- Department of Biotechnology, School of Life Sciences, Indonesia International Institute of Life Sciences, Jakarta 13210, Indonesia
| | - Arief Kurniawan
- Faculty of Pharmacy, Universitas Indonesia, Depok 16424, Indonesia
| | | | - Shereen Angelina Rattu
- Department of Biomedicine, School of Life Sciences, Indonesia International Institute of Life Sciences, Jakarta 13210, Indonesia
| | - Delly Ramadon
- Faculty of Pharmacy, Universitas Indonesia, Depok 16424, Indonesia.
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González-Cubero E, González-Fernández ML, Esteban-Blanco M, Pérez-Castrillo S, Pérez-Fernández E, Navasa N, Aransay AM, Anguita J, Villar-Suárez V. The Therapeutic Potential of Adipose-Derived Mesenchymal Stem Cell Secretome in Osteoarthritis: A Comprehensive Study. Int J Mol Sci 2024; 25:11287. [PMID: 39457070 PMCID: PMC11508730 DOI: 10.3390/ijms252011287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/06/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. This study investigates the therapeutic potential of secretome derived from adipose tissue mesenchymal stem cells (ASCs) in mitigating inflammation and promoting cartilage repair in an in vitro model of OA. Our in vitro model comprised chondrocytes inflamed with TNF. To assess the therapeutic potential of secretome, inflamed chondrocytes were treated with it and concentrations of pro-inflammatory cytokines, metalloproteinases (MMPs) and extracellular matrix markers were measured. In addition, secretome-treated chondrocytes were subject to a microarray analysis to determine which genes were upregulated and which were downregulated. Treating TNF-inflamed chondrocytes with secretome in vitro inhibits the NF-κB pathway, thereby mediating anti-inflammatory and anti-catabolic effects. Additional protective effects of secretome on cartilage are revealed in the inhibition of hypertrophy markers such as RUNX2 and COL10A1, increased production of COL2A1 and ACAN and upregulation of SOX9. These findings suggest that ASC-derived secretome can effectively reduce inflammation, promote cartilage repair, and maintain chondrocyte phenotype. This study highlights the potential of ASC-derived secretome as a novel, non-cell-based therapeutic approach for OA, offering a promising alternative to current treatments by targeting inflammation and cartilage repair mechanisms.
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Affiliation(s)
- Elsa González-Cubero
- Department of Neurosurgery, Stanford School of Medicine, Stanford University, Palo Alto, CA 94304, USA;
- Department of Anatomy, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain; (M.L.G.-F.); (M.E.-B.); (S.P.-C.); (E.P.-F.)
| | - Maria Luisa González-Fernández
- Department of Anatomy, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain; (M.L.G.-F.); (M.E.-B.); (S.P.-C.); (E.P.-F.)
| | - Marta Esteban-Blanco
- Department of Anatomy, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain; (M.L.G.-F.); (M.E.-B.); (S.P.-C.); (E.P.-F.)
| | - Saúl Pérez-Castrillo
- Department of Anatomy, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain; (M.L.G.-F.); (M.E.-B.); (S.P.-C.); (E.P.-F.)
| | - Esther Pérez-Fernández
- Department of Anatomy, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain; (M.L.G.-F.); (M.E.-B.); (S.P.-C.); (E.P.-F.)
| | - Nicolás Navasa
- Department of Molecular Biology, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain;
- Center for Cooperative Research in Biosciences (CIC bioGUNE)-Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Building 801-A, 48160 Derio, Spain; (A.M.A.); (J.A.)
| | - Ana M. Aransay
- Center for Cooperative Research in Biosciences (CIC bioGUNE)-Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Building 801-A, 48160 Derio, Spain; (A.M.A.); (J.A.)
- CIBERehd, ISCIII, 28029 Madrid, Spain
| | - Juan Anguita
- Center for Cooperative Research in Biosciences (CIC bioGUNE)-Basque Research and Technology Alliance (BRTA), Parque Tecnológico de Bizkaia, Building 801-A, 48160 Derio, Spain; (A.M.A.); (J.A.)
- IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
| | - Vega Villar-Suárez
- Department of Anatomy, Faculty of Veterinary Sciences, Campus de Vegazana, University of Léon-Universidad de León, 24071 León, Spain; (M.L.G.-F.); (M.E.-B.); (S.P.-C.); (E.P.-F.)
- Institute of Biomedicine (IBIOMED), Faculty of Veterinary Sciences, Campus de Vegazana, University of León-Universidad de León, 24071 León, Spain
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Liu KF, Ramachandran S, Chang CW, Chen RF, Huang CH, Huang HT, Lee CC, Li YT, Kuo YR. The Synergistic Effect of Full-Spectrum Light Therapy and Transient Immunosuppressants Prolonged Allotransplant Survival. Plast Reconstr Surg 2024; 154:775-783. [PMID: 37815307 DOI: 10.1097/prs.0000000000011135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/11/2023]
Abstract
BACKGROUND The lifelong administration of immunosuppressants remains the largest drawback in vascularized composite allotransplantation (VCA). Therefore, developing alternative strategies to minimize the long-term use of immunosuppressive agents is crucial. This study investigated whether full-spectrum bright light therapy (FBLT) combined with short-term immunosuppressant therapy could prolong VCA survival in a rodent hindlimb model. METHODS Hindlimb allotransplantation was conducted from Brown-Norway to Lewis rats, and the rats were divided into 4 groups. Group 1 did not receive treatment as a rejection control. Group 2 received FBLT alone. Group 3 was treated with short-term antilymphocyte serum (ALS) and cyclosporine A (CsA). Group 4 was administered short-term ALS/CsA combined with FBLT for 8 weeks. Peripheral blood and transplanted tissues were collected for analysis. RESULTS The results revealed median survival time of FBLT alone (group 2) did not increase allograft survival compared with the control (group 1). However, in group 4, FBLT combined with short-term ALS/CsA, median composite tissue allograft survival time (266 days) was significantly prolonged compared with groups 1 (11 days), 2 (10 days), and 3 (41 days) ( P < 0.01). Group 4 also showed a significant increase in regulatory T cells ( P = 0.04) and transforming growth factor-β1 levels ( P = 0.02), and a trend toward a decrease in interleukin-1β levels ( P = 0.03) at 16 weeks after transplantation as compared with control (group 1). CONCLUSIONS FBLT combined with short-term immunosuppressants prolonged allotransplant survival by modulating T-cell regulatory functions and antiinflammatory cytokine expression. This approach could be a potential strategy to increase VCA survival. CLINICAL RELEVANCE STATEMENT Full-spectrum light therapy could be a potential strategy to increase vascularized composite allotransplant survival.
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Affiliation(s)
- Keng-Fan Liu
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital
- Faculty of Medicine, College of Medicine, Orthopaedic Research Center, Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University
| | | | - Chao-Wei Chang
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital
| | - Rong-Fu Chen
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital
| | - Chao-Hsin Huang
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital
| | - Han-Ting Huang
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital
| | - Chia-Chun Lee
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital
| | - Yun-Ting Li
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital
| | - Yur-Ren Kuo
- From the Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital
- Faculty of Medicine, College of Medicine, Orthopaedic Research Center, Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University
- Department of Plastic and Reconstructive Surgery, Singapore General Hospital
- Department of Biological Sciences, National Sun Yat-sen University
- Academic Clinical Programme for Musculoskeletal Sciences, Duke-National University of Singapore Graduate Medical School
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30
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Mozaffari N, Mohammadi R, Delirezh N, Hobbenaghi R, Mohammadi V. Effect of macrophages combined with supernatant of mesenchymal stem cell culture and macrophage culture on wound healing in rats. Tissue Cell 2024; 90:102474. [PMID: 39079451 DOI: 10.1016/j.tice.2024.102474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/22/2024] [Accepted: 07/11/2024] [Indexed: 09/03/2024]
Abstract
Wound healing is an orderly sequence of events restoring the integrity of the damaged tissue. It consists of inflammatory, proliferation, and remodeling phases. The objective of the current study was to investigate the effect of local transplantation of cultured macrophage loaded with mesenchymal stem cell/macrophage culture supernatants on wound healing. Sixty-four healthy adult male Wistar rats were randomized into 4 groups of sixteen animals each: 1) SHAM group. 2) MAC-MSC/SN group: One-milliliter application of a mixture comprising mesenchymal stem cell and macrophage culture supernatants in a 1:1 ratio was administered locally to the wound bed. 3) MAC group: Local transplantation of macrophage cells cultured in the wound bed. 4) MAC + MAC-MSC/SN group: Local transplantation of cultured macrophage in combination with mesenchymal stem cell/ macrophage culture supernatants in the wound bed. An incisional wound model was used for biomechanical studies, while an excisional wound model was used for biochemical, histopathological, and planimetric assessments. The wound area was significantly reduced in the MAC + MAC-MSC/SN group compared to other groups (P < 0.05). Biomechanical measurements from the MAC + MAC-MSC/SN group were significantly higher compared to other experimental groups (P < 0.05). Biochemical and quantitative histopathological analyses revealed a significant difference between MAC + MAC-MSC/SN and other groups (P < 0.05). MAC + MAC-MSC/SN showed the potential to improve wound healing significantly. This appears to work by angiogenesis stimulation, fibroblast proliferation, inflammation reduction, and granulation tissue formation during the initial stages of the healing process. This accelerated healing leads to earlier wound area reduction and enhanced tensile strength of the damaged area due to the reorganization of granulation tissue and collagen fibers.
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Affiliation(s)
- Nima Mozaffari
- Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Rahim Mohammadi
- Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.
| | - Nowruz Delirezh
- Department of Microbiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Rahim Hobbenaghi
- Department of Pathobiology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Vahid Mohammadi
- Department of Internal Medicine and Clinical Pathology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
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Deng Y, Xiao J, Xie J, Sun J, Liu H, Huang X, Cao Z. VDAC1-enriched apoptotic extracellular vesicles emerge as an autophagy activator orchestrating PDLSC-based bone regeneration. CHEMICAL ENGINEERING JOURNAL 2024; 497:154625. [DOI: 10.1016/j.cej.2024.154625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2025]
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Chow SKH, Gao Q, Pius A, Morita M, Ergul Y, Murayama M, Shinohara I, Cekuc MS, Ma C, Susuki Y, Goodman SB. The Advantages and Shortcomings of Stem Cell Therapy for Enhanced Bone Healing. Tissue Eng Part C Methods 2024; 30:415-430. [PMID: 39311464 DOI: 10.1089/ten.tec.2024.0252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/05/2024] Open
Abstract
This review explores the regenerative potential of key progenitor cell types and therapeutic strategies to improve healing of complex fractures and bone defects. We define, summarize, and discuss the differentiation potential of totipotent, pluripotent, and multipotent stem cells, emphasizing the advantages and shortcomings of cell therapy for bone repair and regeneration. The fundamental role of mesenchymal stem cells is highlighted due to their multipotency to differentiate into the key lineage cells including osteoblasts, osteocytes, and chondrocytes, which are crucial for bone formation and remodeling. Hematopoietic stem cells (HSCs) also play a significant role; immune cells such as macrophages and T-cells modulate inflammation and tissue repair. Osteoclasts are multinucleated cells that are important to bone remodeling. Vascular progenitor (VP) cells are critical to oxygen and nutrient supply. The dynamic interplay among these lineages and their microenvironment is essential for effective bone restoration. Therapies involving cells that are more than "minimally manipulated" are controversial and include embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). ESCs, derived from early-stage embryos, possess pluripotent capabilities and have shown promise in preclinical studies for bone healing. iPSCs, reprogrammed from somatic cells, offer personalized medicine applications and can differentiate into various tissue-specific cell lines. Minimally manipulative cell therapy approaches such as the use of bone marrow aspirate concentrate (BMAC), exosomes, and various biomaterials for local delivery are explored for their effectiveness in bone regeneration. BMAC, which contains mostly immune cells but few mesenchymal and VPs, probably improves bone healing by facilitating paracrine-mediated intercellular communication. Exosome isolation harnesses the biological signals and cellular by-products that are a primary source for cell crosstalk and activation. Safe, efficacious, and cost-effective strategies to enhance bone healing using novel cellular therapies are part of a changing paradigm to modulate the inflammatory, repair, and regenerative pathways to achieve earlier more robust tissue healing and improved physical function. Impact Statement Stem cell therapy holds immense potential for bone healing due to its ability to regenerate damaged tissue. Nonmanipulated bone marrow aspirate contains mesenchymal stem cells that promote bone repair and reduce healing time. Induced pluripotent stem cells offer the advantage of creating patient-specific cells that can differentiate into osteoblasts, aiding in bone regeneration. Other delivery methods, such as scaffold-based techniques, enhance stem cell integration and function. Collectively, these approaches can improve treatment outcomes, reduce recovery periods, and advance our understanding of bone healing mechanisms, making them pivotal in orthopedic research and regenerative medicine.
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Affiliation(s)
- Simon Kwoon-Ho Chow
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Qi Gao
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Alexa Pius
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Mayu Morita
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Yasemin Ergul
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Masatoshi Murayama
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Issei Shinohara
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Mehmet Sertac Cekuc
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Chao Ma
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Yosuke Susuki
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
| | - Stuart B Goodman
- Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA
- Department of Bioengineering, Stanford University, Stanford, California, USA
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Kråkenes T, Sandvik CE, Ytterdal M, Gavasso S, Evjenth EC, Bø L, Kvistad CE. The Therapeutic Potential of Exosomes from Mesenchymal Stem Cells in Multiple Sclerosis. Int J Mol Sci 2024; 25:10292. [PMID: 39408622 PMCID: PMC11477223 DOI: 10.3390/ijms251910292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/17/2024] [Accepted: 09/23/2024] [Indexed: 10/20/2024] Open
Abstract
Although treatment for multiple sclerosis (MS) has undergone a revolution in the last decades, at least two important barriers remain: alleviation of innate inflammation driving disease progression and promotion of remyelination and neural regeneration. Mesenchymal stem cells (MSCs) possess immunomodulatory properties and promote remyelination in murine MS models. The main therapeutic mechanism has, however, been attributed to their potent paracrine capacity, and not to in vivo tissue implantation. Studies have demonstrated that exosomes released as part of the cells' secretome effectively encapsulate the beneficial properties of MSCs. These membrane-enclosed nanoparticles contain a variety of proteins and nucleic acids and serve as mediators of intercellular communication. In vitro studies have demonstrated that exosomes from MSCs modulate activated microglia from an inflammatory to an anti-inflammatory phenotype and thereby dampen the innate inflammation. Rodent studies have also demonstrated potent immunomodulation and remyelination with improved outcomes following exosome administration. Thus, exosomes from MSCs may represent a potential cell-free treatment modality to prevent disease progression and promote remyelination in MS. In this narrative review, we summarize the current knowledge of exosomes from MSCs as a potential treatment for MS and discuss the remaining issues before successful translation into clinical trials.
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Affiliation(s)
- Torbjørn Kråkenes
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway (L.B.); (C.E.K.)
| | - Casper Eugen Sandvik
- Department of Clinical Medicine, Faculty of Medicine, University of Bergen, 5021 Bergen, Norway
| | - Marie Ytterdal
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway (L.B.); (C.E.K.)
| | - Sonia Gavasso
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway (L.B.); (C.E.K.)
- Department of Clinical Medicine, Faculty of Medicine, University of Bergen, 5021 Bergen, Norway
| | - Elisabeth Claire Evjenth
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway (L.B.); (C.E.K.)
| | - Lars Bø
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway (L.B.); (C.E.K.)
- Department of Clinical Medicine, Faculty of Medicine, University of Bergen, 5021 Bergen, Norway
| | - Christopher Elnan Kvistad
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway (L.B.); (C.E.K.)
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Zorina A, Zorin V, Isaev A, Kudlay D, Manturova N, Ustugov A, Kopnin P. Current Status of Biomedical Products for Gene and Cell Therapy of Recessive Dystrophic Epidermolysis Bullosa. Int J Mol Sci 2024; 25:10270. [PMID: 39408598 PMCID: PMC11476579 DOI: 10.3390/ijms251910270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/22/2024] [Accepted: 08/27/2024] [Indexed: 10/20/2024] Open
Abstract
This detailed review describes innovative strategies and current products for gene and cell therapy at different stages of research and development to treat recessive dystrophic epidermolysis bullosa (RDEB) which is associated with the functional deficiency of collagen type VII alpha 1 (C7) caused by defects in the COL7A1 gene. The use of allogenic mesenchymal stem/stromal cells, which can be injected intradermally and intravenously, appears to be the most promising approach in the field of RDEB cell therapy. Injections of genetically modified autologous dermal fibroblasts are also worth mentioning under this framework. The most common methods of RDEB gene therapy are gene replacement using viral vectors and gene editing using programmable nucleases. Ex vivo epidermal transplants (ETs) based on autologous keratinocytes (Ks) have been developed using gene therapy methods; one such ET successively passed phase III clinical trials. Products based on the use of two-layer transplants have also been developed with both types of skin cells producing C7. Gene products have also been developed for local use. To date, significant progress has been achieved in the development of efficient biomedical products to treat RDEB, one of the most severe hereditary diseases.
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Affiliation(s)
- Alla Zorina
- Artgen Biotech, Moscow 119333, Russia; (A.Z.)
- Skincell LLC, Moscow 119333, Russia
| | - Vadim Zorin
- Artgen Biotech, Moscow 119333, Russia; (A.Z.)
- Skincell LLC, Moscow 119333, Russia
| | - Artur Isaev
- Artgen Biotech, Moscow 119333, Russia; (A.Z.)
| | - Dmitry Kudlay
- Department of Pharmacology, The I. M. Sechenov First Moscow State Medical University (The Sechenov University), Moscow 119991, Russia
- Department of Pharmacognosy and Industrial Pharmacy, Lomonosov Moscow State University, Moscow 119992, Russia
| | - Natalia Manturova
- Department of Plastic and Reconstructive surgery, Cosmetology and Cell Technologies, Pirogov Russian National Research Medical University, Moscow 117997, Russia
- JSC Plastic Surgery and Cosmetology Institute, Moscow 125047, Russia
| | - Andrei Ustugov
- Department of Plastic and Reconstructive surgery, Cosmetology and Cell Technologies, Pirogov Russian National Research Medical University, Moscow 117997, Russia
- JSC Plastic Surgery and Cosmetology Institute, Moscow 125047, Russia
| | - Pavel Kopnin
- Scientific Research Institute of Carcinogenesis, N. N. Blokhin National Medical Research Center of Oncology, Moscow 115522, Russia
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Teng M, Wu TJ, Jing X, Day BW, Pritchard KA, Naylor S, Teng RJ. Temporal Dynamics of Oxidative Stress and Inflammation in Bronchopulmonary Dysplasia. Int J Mol Sci 2024; 25:10145. [PMID: 39337630 PMCID: PMC11431892 DOI: 10.3390/ijms251810145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/04/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024] Open
Abstract
Bronchopulmonary dysplasia (BPD) is the most common lung complication of prematurity. Despite extensive research, our understanding of its pathophysiology remains limited, as reflected by the stable prevalence of BPD. Prematurity is the primary risk factor for BPD, with oxidative stress (OS) and inflammation playing significant roles and being closely linked to premature birth. Understanding the interplay and temporal relationship between OS and inflammation is crucial for developing new treatments for BPD. Animal studies suggest that OS and inflammation can exacerbate each other. Clinical trials focusing solely on antioxidants or anti-inflammatory therapies have been unsuccessful. In contrast, vitamin A and caffeine, with antioxidant and anti-inflammatory properties, have shown some efficacy, reducing BPD by about 10%. However, more than one-third of very preterm infants still suffer from BPD. New therapeutic agents are needed. A novel tripeptide, N-acetyl-lysyltyrosylcysteine amide (KYC), is a reversible myeloperoxidase inhibitor and a systems pharmacology agent. It reduces BPD severity by inhibiting MPO, enhancing antioxidative proteins, and alleviating endoplasmic reticulum stress and cellular senescence in a hyperoxia rat model. KYC represents a promising new approach to BPD treatment.
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Affiliation(s)
- Michelle Teng
- Department of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd Street, Milwaukee, WI 53226, USA; (M.T.); (T.-J.W.); (X.J.)
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
| | - Tzong-Jin Wu
- Department of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd Street, Milwaukee, WI 53226, USA; (M.T.); (T.-J.W.); (X.J.)
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
| | - Xigang Jing
- Department of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd Street, Milwaukee, WI 53226, USA; (M.T.); (T.-J.W.); (X.J.)
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
| | - Billy W. Day
- ReNeuroGen LLC, 2160 San Fernando Dr., Elm Grove, WI 53122, USA; (B.W.D.); (S.N.)
| | - Kirkwood A. Pritchard
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
- ReNeuroGen LLC, 2160 San Fernando Dr., Elm Grove, WI 53122, USA; (B.W.D.); (S.N.)
- Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA
| | - Stephen Naylor
- ReNeuroGen LLC, 2160 San Fernando Dr., Elm Grove, WI 53122, USA; (B.W.D.); (S.N.)
| | - Ru-Jeng Teng
- Department of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd Street, Milwaukee, WI 53226, USA; (M.T.); (T.-J.W.); (X.J.)
- Children’s Research Institute, Medical College of Wisconsin, 8701 W Watertown Plank Rd., Wauwatosa, WI 53226, USA;
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Wu S, Zhou Z, Li Y, Jiang J. Advancements in diabetic foot ulcer research: Focus on mesenchymal stem cells and their exosomes. Heliyon 2024; 10:e37031. [PMID: 39286219 PMCID: PMC11403009 DOI: 10.1016/j.heliyon.2024.e37031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/11/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024] Open
Abstract
Diabetes represents a widely acknowledged global public health concern. Diabetic foot ulcer (DFU) stands as one of the most severe complications of diabetes, its occurrence imposing a substantial economic burden on patients, profoundly impacting their quality of life. Despite the deepening comprehension regarding the pathophysiology and cellular as well as molecular responses of DFU, the current therapeutic arsenal falls short of efficacy, failing to offer a comprehensive remedy for deep-seated chronic wounds and microvascular occlusions. Conventional treatments merely afford symptomatic alleviation or retard the disease's advancement, devoid of the capacity to effectuate further restitution of compromised vasculature and nerves. An escalating body of research underscores the prominence of mesenchymal stem cells (MSCs) owing to their paracrine attributes and anti-inflammatory prowess, rendering them a focal point in the realm of chronic wound healing. Presently, MSCs have been validated as a highly promising cellular therapeutic approach for DFU, capable of effectuating cellular repair, epithelialization, granulation tissue formation, and neovascularization by means of targeted differentiation, angiogenesis promotion, immunomodulation, and paracrine activities, thereby fostering wound healing. The secretome of MSCs comprises cytokines, growth factors, chemokines, alongside exosomes harboring mRNA, proteins, and microRNAs, possessing immunomodulatory and regenerative properties. The present study provides a systematic exposition on the etiology of DFU and elucidates the intricate molecular mechanisms and diverse functionalities of MSCs in the context of DFU treatment, thereby furnishing pioneering perspectives aimed at harnessing the therapeutic potential of MSCs for DFU management and advancing wound healing processes.
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Affiliation(s)
- ShuHui Wu
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - ZhongSheng Zhou
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yang Li
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jinlan Jiang
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
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Shan Y, Zhang M, Tao E, Wang J, Wei N, Lu Y, Liu Q, Hao K, Zhou F, Wang G. Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges. Signal Transduct Target Ther 2024; 9:242. [PMID: 39271680 PMCID: PMC11399464 DOI: 10.1038/s41392-024-01936-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 07/04/2024] [Accepted: 07/23/2024] [Indexed: 09/15/2024] Open
Abstract
Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.
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Affiliation(s)
- Yunlong Shan
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Mengying Zhang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Enxiang Tao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Jing Wang
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Ning Wei
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Yi Lu
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Qing Liu
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Kun Hao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Fang Zhou
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Guangji Wang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
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38
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Wan X, Ni X, Xie Y, Chen L, Cai B, Lin Q, Ke R, Huang T, Shan X, Wang B. Research progress and application prospect of adipose-derived stem cell secretome in diabetes foot ulcers healing. Stem Cell Res Ther 2024; 15:279. [PMID: 39227906 PMCID: PMC11373215 DOI: 10.1186/s13287-024-03912-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 08/29/2024] [Indexed: 09/05/2024] Open
Abstract
Diabetic foot ulcers (DFUs) are chronic wounds and one of the most common complications of diabetes, imposing significant physical and mental burdens on patients due to their poor prognosis and treatment efficacy. Adipose-derived stem cells (ADSCs) have been proven to promote wound healing, with studies increasingly attributing these beneficial effects to their paracrine actions. Consequently, research on ADSC secretome as a novel and promising alternative for DFU treatment has been extensively conducted. This article provides a comprehensive review of the mechanisms underlying refractory DFU wounds, the secretome of ADSCs, and its role in promoting wound healing in diabetes foot ulcers. And the review aims to provide reliable evidence for the clinical application of ADSC secretome in the treatment of refractory DFU wounds.
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Affiliation(s)
- Xiaofen Wan
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Xuejun Ni
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Yunjia Xie
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Lu Chen
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Beichen Cai
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
- Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
| | - Qian Lin
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Ruonan Ke
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Tao Huang
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Xiuying Shan
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
- Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
| | - Biao Wang
- Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
- Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
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Selestin Raja I, Kim C, Oh N, Park JH, Hong SW, Kang MS, Mao C, Han DW. Tailoring photobiomodulation to enhance tissue regeneration. Biomaterials 2024; 309:122623. [PMID: 38797121 DOI: 10.1016/j.biomaterials.2024.122623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/25/2024] [Accepted: 05/19/2024] [Indexed: 05/29/2024]
Abstract
Photobiomodulation (PBM), the use of biocompatible tissue-penetrating light to interact with intracellular chromophores to modulate the fates of cells and tissues, has emerged as a promising non-invasive approach to enhancing tissue regeneration. Unlike photodynamic or photothermal therapies that require the use of photothermal agents or photosensitizers, PBM treatment does not need external agents. With its non-harmful nature, PBM has demonstrated efficacy in enhancing molecular secretions and cellular functions relevant to tissue regeneration. The utilization of low-level light from various sources in PBM targets cytochrome c oxidase, leading to increased synthesis of adenosine triphosphate, induction of growth factor secretion, activation of signaling pathways, and promotion of direct or indirect gene expression. When integrated with stem cell populations, bioactive molecules or nanoparticles, or biomaterial scaffolds, PBM proves effective in significantly improving tissue regeneration. This review consolidates findings from in vitro, in vivo, and human clinical outcomes of both PBM alone and PBM-combined therapies in tissue regeneration applications. It encompasses the background of PBM invention, optimization of PBM parameters (such as wavelength, irradiation, and exposure time), and understanding of the mechanisms for PBM to enhance tissue regeneration. The comprehensive exploration concludes with insights into future directions and perspectives for the tissue regeneration applications of PBM.
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Affiliation(s)
| | - Chuntae Kim
- Institute of Nano-Bio Convergence, Pusan National University, Busan, 46241, Republic of Korea; Center for Biomaterials Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
| | - Nuri Oh
- Department of Chemistry and Biology, Korea Science Academy of KAIST, Busan, 47162, Republic of Korea
| | - Ji-Ho Park
- Department of Bio and Brain Engineering and KAIST Institute for Health Science and Technology, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Suck Won Hong
- Department of Cogno-Mechatronics Engineering, College of Nanoscience & Nanotechnology, Pusan National University, Busan, 46241, Republic of Korea
| | - Moon Sung Kang
- Department of Cogno-Mechatronics Engineering, College of Nanoscience & Nanotechnology, Pusan National University, Busan, 46241, Republic of Korea
| | - Chuanbin Mao
- Department of Biomedical Engineering, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China.
| | - Dong-Wook Han
- Institute of Nano-Bio Convergence, Pusan National University, Busan, 46241, Republic of Korea; Department of Cogno-Mechatronics Engineering, College of Nanoscience & Nanotechnology, Pusan National University, Busan, 46241, Republic of Korea.
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40
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Mansoori M, Solhjoo S, Palmerini MG, Nematollahi-Mahani SN, Ezzatabadipour M. Granulosa cell insight: unraveling the potential of menstrual blood-derived stem cells and their exosomes on mitochondrial mechanisms in polycystic ovary syndrome (PCOS). J Ovarian Res 2024; 17:167. [PMID: 39153978 PMCID: PMC11330151 DOI: 10.1186/s13048-024-01484-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 07/23/2024] [Indexed: 08/19/2024] Open
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) presents a significant challenge in women's reproductive health, characterized by disrupted folliculogenesis and ovulatory dysfunction. Central to PCOS pathogenesis are granulosa cells, whose dysfunction contributes to aberrant steroid hormone production and oxidative stress. Mitochondrial dysfunction emerges as a key player, influencing cellular energetics, oxidative stress, and steroidogenesis. This study investigates the therapeutic potential of menstrual blood-derived stem cells (MenSCs) and their exosomes in mitigating mitochondrial dysfunction and oxidative stress in PCOS granulosa cells. METHODS Using a rat model of PCOS induced by letrozole, granulosa cells were harvested and cultured. MenSCs and their exosomes were employed to assess their effects on mitochondrial biogenesis, oxidative stress, and estrogen production in PCOS granulosa cells. RESULTS Results showed diminished mitochondrial biogenesis and increased oxidative stress in PCOS granulosa cells, alongside reduced estrogen production. Treatment with MenSCs and their exosomes demonstrated significant improvements in mitochondrial biogenesis, oxidative stress levels, and estrogen production in PCOS granulosa cells. Further analysis showed MenSCs' superior efficacy over exosomes, attributed to their sustained secretion of bioactive factors. Mechanistically, MenSCs and exosomes activated pathways related to mitochondrial biogenesis and antioxidative defense, highlighting their therapeutic potential for PCOS. CONCLUSIONS This study offers insights into granulosa cells mitochondria's role in PCOS pathogenesis and proposes MenSCs and exosomes as a potential strategy for mitigating mitochondrial dysfunction and oxidative stress in PCOS. Further research is needed to understand underlying mechanisms and validate clinical efficacy, presenting promising avenues for addressing PCOS complexity.
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Affiliation(s)
- Mahna Mansoori
- Anatomical Sciences Department, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Somayeh Solhjoo
- Anatomical Sciences Department, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Maria Grazia Palmerini
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | | | - Massood Ezzatabadipour
- Anatomical Sciences Department, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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Misra R, Sanjana Sharath N. Red blood cells based nanotheranostics: A smart biomimetic approach for fighting against cancer. Int J Pharm 2024; 661:124401. [PMID: 38986966 DOI: 10.1016/j.ijpharm.2024.124401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 07/12/2024]
Abstract
The technique of engineering drug delivery vehicles continues to develop, which bring enhancements in working more efficiently and minimizing side effects to make it more effective and safer. The intense capability of therapeutic agents to remain undamaged in a harsh extracellular environment is helpful to the success of drug development efforts. With this in mind, alterations of biopharmaceuticals with enhanced stability and decreased immunogenicity have been an increasingly active focus of such efforts. Red blood cells (RBCs), also known as erythrocytes have undergone extensive scrutiny as potential vehicles for drug delivery due to their remarkable attributes over the years of research. These include intrinsic biocompatibility, minimal immunogenicity, flexibility, and prolonged systemic circulation. Throughout the course of investigation, a diverse array of drug delivery platforms based on RBCs has emerged. These encompass genetically engineered RBCs, non-genetically modified RBCs, and RBC membrane-coated nanoparticles, each devised to cater to a range of biomedical objectives. Given their prevalence in the circulatory system, RBCs have gained significant attention for their potential to serve as biomimetic coatings for artificial nanocarriers. By virtue of their surface emulation capabilities and customizable core materials, nanocarriers mimicking these RBCs, hold considerable promise across a spectrum of applications, spanning drug delivery, imaging, phototherapy, immunomodulation, sensing, and detection. These multifaceted functionalities underscore the considerable therapeutic and diagnostic potential across various diseases. Our proposed review provides the synthesis of recent strides in the theranostic utilization of erythrocytes in the context of cancer. It also delves into the principal challenges and prospects intrinsic to this realm of research. The focal point of this review pertains to accentuating the significance of erythrocyte-based theranostic systems in combating cancer. Furthermore, it precisely records the latest and the most specific methodologies for tailoring the attributes of these biomimetic nanoscale formulations, attenuating various discoveries for the treatment and management of cancer.
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Affiliation(s)
- Ranjita Misra
- Department of Biotechnology, Centre for Research in Pure and Applied Sciences, School of Sciences, Jain (Deemed-to-be University), JC Road, Bengaluru 560027, Karnataka, India.
| | - Naomi Sanjana Sharath
- Department of Biotechnology, Centre for Research in Pure and Applied Sciences, School of Sciences, Jain (Deemed-to-be University), JC Road, Bengaluru 560027, Karnataka, India
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Kostecka A, Kalamon N, Skoniecka A, Koczkowska M, Skowron PM, Piotrowski A, Pikuła M. Adipose-derived mesenchymal stromal cells in clinical trials: Insights from single-cell studies. Life Sci 2024; 351:122761. [PMID: 38866216 DOI: 10.1016/j.lfs.2024.122761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/15/2024] [Accepted: 05/27/2024] [Indexed: 06/14/2024]
Abstract
Mesenchymal Stromal Cells (MSCs) offer tremendous potential for the treatment of various diseases and their healing properties have been explored in hundreds of clinical trials. These trails primarily focus on immunological and neurological disorders, as well as regenerative medicine. Adipose tissue is a rich source of mesenchymal stromal cells and methods to obtain and culture adipose-derived MSCs (AD-MSCs) have been well established. Promising results from pre-clinical testing of AD-MSCs activity prompted clinical trials that further led to the approval of AD-MSCs for the treatment of complex perianal fistulas in Crohn's disease and subcutaneous tissue defects. However, AD-MSC heterogeneity along with various manufacturing protocols or different strategies to boost their activity create the need for standardized quality control procedures and safety assessment of the intended cell product. High-resolution transcriptomic methods have been recently gaining attention, as they deliver insight into gene expression profiles of individual cells, helping to deconstruct cellular hierarchy and differentiation trajectories, and to understand cell-cell interactions within tissues. This article presents a comprehensive overview of completed clinical trials evaluating the safety and efficacy of AD-MSC treatment, together with current single-cell studies of human AD-MSC. Furthermore, our work emphasizes the increasing significance of single-cell research in elucidating the mechanisms of cellular action and predicting their therapeutic effects.
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Affiliation(s)
- Anna Kostecka
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland; 3P - Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland.
| | - Natalia Kalamon
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
| | - Aneta Skoniecka
- Laboratory of Tissue Engineering and Regenerative Medicine, Division of Embryology, Faculty of Medicine, Medical University of Gdansk, Dębinki 1, 80-211 Gdańsk, Poland.
| | - Magdalena Koczkowska
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland; 3P - Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland.
| | - Piotr M Skowron
- Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland.
| | - Arkadiusz Piotrowski
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland; 3P - Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland.
| | - Michał Pikuła
- Laboratory of Tissue Engineering and Regenerative Medicine, Division of Embryology, Faculty of Medicine, Medical University of Gdansk, Dębinki 1, 80-211 Gdańsk, Poland.
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Pharoun J, Berro J, Sobh J, Abou-Younes MM, Nasr L, Majed A, Khalil A, Joseph, Stephan, Faour WH. Mesenchymal stem cells biological and biotechnological advances: Implications for clinical applications. Eur J Pharmacol 2024; 977:176719. [PMID: 38849038 DOI: 10.1016/j.ejphar.2024.176719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/31/2024] [Accepted: 06/05/2024] [Indexed: 06/09/2024]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to differentiate into multiple lineages including bone, cartilage, muscle and fat. They hold immunomodulatory properties and therapeutic ability to treat multiple diseases, including autoimmune and chronic degenerative diseases. In this article, we reviewed the different biological properties, applications and clinical trials of MSCs. Also, we discussed the basics of manufacturing conditions, quality control, and challenges facing MSCs in the clinical setting. METHODS Extensive review of the literature was conducted through the databases PubMed, Google Scholar, and Cochrane. Papers published since 2015 and covering the clinical applications and research of MSC therapy were considered. Furthermore, older papers were considered when referring to pioneering studies in the field. RESULTS The most widely studied stem cells in cell therapy and tissue repair are bone marrow-derived mesenchymal stem cells. Adipose tissue-derived stem cells became more common and to a lesser extent other stem cell sources e.g., foreskin derived MSCs. MSCs therapy were also studied in the setting of COVID-19 infections, ischemic strokes, autoimmune diseases, tumor development and graft rejection. Multiple obstacles, still face the standardization and optimization of MSC therapy such as the survival and the immunophenotype and the efficiency of transplanted cells. MSCs used in clinical settings displayed heterogeneity in their function despite their extraction from healthy donors and expression of similar surface markers. CONCLUSION Mesenchymal stem cells offer a rising therapeutic promise in various diseases. However, their potential use in clinical applications requires further investigation.
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Affiliation(s)
- Jana Pharoun
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Jana Berro
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Jeanine Sobh
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | | | - Leah Nasr
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Ali Majed
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Alia Khalil
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Joseph
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Stephan
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Wissam H Faour
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36.
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Xue Z, Hu D, Tang H, Xue M, Zhu Y, Li Y, Liao Y. Mechanical force regulates the paracrine functions of ADSCs to assist skin expansion in rats. Stem Cell Res Ther 2024; 15:250. [PMID: 39135129 PMCID: PMC11321134 DOI: 10.1186/s13287-024-03822-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 06/30/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND In the repair of massive tissue defects using expanded large skin flaps, the incidence of complications increases with the size of the expanded area. Currently, stem cell therapy has limitations to solve this problem. We hypothesized that conditioned medium of adipose-derived stem cells (ADSC-CM) collected following mechanical pretreatment can assist skin expansion. METHODS Rat aortic endothelial cells and fibroblasts were cultured with ADSC-CM collected under 0%, 10%, 12%, and 15% stretching force. Ten-milliliter cylindrical soft tissue expanders were subcutaneously implanted into the backs of 36 Sprague-Dawley rats. The 0% and 10% stretch groups were injected with ADSC-CM collected under 0% and 10% stretching force, respectively, while the control group was not injected. After 3, 7, 14, and 30 days of expansion, expanded skin tissue was harvested for staining and qPCR analyses. RESULTS Endothelial cells had the best lumen formation and highest migration rate, and fibroblasts secreted the most collagen upon culture with ADSC-CM collected under 10% stretching force. The skin expansion rate was significantly increased in the 10% stretch group. After 7 days of expansion, the number of blood vessels in the expanded area, expression of the angiogenesis-associated proteins vascular endothelial growth factor, basic fibroblast growth factor, and hepatocyte growth factor, and collagen deposition were significantly increased in the 10% stretch group. CONCLUSIONS The optimal mechanical force upregulates specific paracrine proteins in ADSCs to increase angiogenesis and collagen secretion, and thereby promote skin regeneration and expansion. This study provides a new auxiliary method to expand large skin flaps.
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Grants
- 202312121015, S202312121094, 202312121227, 202312121313, 202312121314, 202312121317, 202312121321 College Students' Innovative Entrepreneurial Training Plan Program
- 82202474, 82360615 National Natural Science Foundation of China
- 2022CR007 Clinical Program of Nanfang Hospital, Southern Medical University
- KHYJ-2023-5-02,2023-KHRCBZ-B14 First People's Hospital of Yunnan Province
- 2021A1515110440 Basic and Applied Basic Research Foundation of Guangdong Province
- 2024A04J5192, 2023A04J2350, 2023A04J2349, 2023A04J2347, 2023A04J2271 Science and Technology Projects in Guangzhou
- College Students’ Innovative Entrepreneurial Training Plan Program
- First People’s Hospital of Yunnan Province
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Affiliation(s)
- Zhixin Xue
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, P. R. China
| | - Delin Hu
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, P. R. China
| | - Haojing Tang
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, P. R. China
| | - Mingheng Xue
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, P. R. China
| | - Yufan Zhu
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, P. R. China
| | - Ye Li
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, P. R. China.
| | - Yunjun Liao
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, P. R. China.
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Zhang Q, Liu T, Li Y, Fan Y, Shang H, Zhao H, Sun H, Yu Z, Han M, Wan C. Gelatin methacryloyl microneedle loaded with 3D-MSC-Exosomes for the protection of ischemia-reperfusion. Int J Biol Macromol 2024; 275:133336. [PMID: 38936568 DOI: 10.1016/j.ijbiomac.2024.133336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 06/12/2024] [Accepted: 06/19/2024] [Indexed: 06/29/2024]
Abstract
Exosomes (Exo) generated from mesenchymal stem cells (MSCs) have great therapeutic potential in ischemia-reperfusion treatment. For best therapeutic effect, high quality Exo product and effective delivery system are indispensable. In this study, we developed a new strategy for ischemia-reperfusion recovery by combining MSCs 3D (3D-MSC) culturing technology to generate Exo (3D-MSC-Exo) and microneedle for topical delivery. Firstly, primary MSCs from neonatal mice were isolated and 3D cultured with gelatin methacryloyl (GelMA) hydrogel to prepare 3D-MSC-Exo. The 3D-MSC showed better viability and 3D-MSC-Exo exhibited more effective effects of reducing neuroinflammation, inhibiting glial scarring, and promoting angiogenesis. Subsequently, the biocompatible GelMA was used to construct microneedles for 3D-Exo delivery (GelMA-MN@3D-Exo). The results demonstrated GelMA microneedles had excellent 3D-Exo loading capacity and enabled continuous 3D-Exo release to maintain effective therapeutic concentrations. Furthermore, the rat middle cerebral artery occlusion (MCAO) model was established to evaluate the therapeutic effect of GelMA-MN@3D-Exo in ischemia-reperfusion in vivo. Animal experiments showed that the GelMA-MN@3D-Exo system could effectively reduce the local neuroinflammatory reaction, promote angiogenesis and minimize glial scar proliferation in ischemia-reperfusion. The underlying reasons for the stronger neuroprotective effect of 3D-Exo was further studied using mass spectrometry and transcriptome assays, verifying their effects on immune regulation and cell proliferation. Taken together, our findings demonstrated that GelMA-MN@3D-Exo microneedle can effectively attenuate ischemia-reperfusion cell damage in the MCAO model, which provides a promising therapeutic strategy for ischemia-reperfusion recovery.
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Affiliation(s)
- Qiong Zhang
- Department of Physical Medicine and Rehabilitation, Tianjin Medical University General Hospital, 154 Anshan Rd, District Heping, Tianjin 300052, P. R. China; Department of Geriatrics, The Fifth People's Hospital of Jinan, No. 24297 Jingshi Rd, District Huaiyin, Jinan 250000, Shandong, P. R. China
| | - Tiangui Liu
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P. R. China
| | - Yuming Li
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P. R. China
| | - Yang Fan
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P. R. China
| | - Hao Shang
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P. R. China
| | - Huayang Zhao
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P. R. China
| | - Haohan Sun
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P. R. China
| | - Zaiyang Yu
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P. R. China
| | - Min Han
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P. R. China.
| | - Chunxiao Wan
- Department of Physical Medicine and Rehabilitation, Tianjin Medical University General Hospital, 154 Anshan Rd, District Heping, Tianjin 300052, P. R. China.
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Marvin JC, Liu EJ, Chen HH, Shiovitz DA, Andarawis-Puri N. Proteins Derived From MRL/MpJ Tendon Provisional Extracellular Matrix and Secretome Promote Pro-Regenerative Tenocyte Behavior. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.08.602500. [PMID: 39026846 PMCID: PMC11257490 DOI: 10.1101/2024.07.08.602500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Tendinopathies are prevalent musculoskeletal conditions that have no effective therapies to attenuate scar formation. In contrast to other adult mammals, the tendons of Murphy Roths Large (MRL/MpJ) mice possess a superior healing capacity following acute and overuse injuries. Here, we hypothesized that the application of biological cues derived from the local MRL/MpJ tendon environment would direct otherwise scar-mediated tenocytes towards a pro-regenerative MRL/MpJ-like phenotype. We identified soluble factors enriched in the secretome of MRL/MpJ tenocytes using bioreactor systems and quantitative proteomics. We then demonstrated that the combined administration of structural and soluble constituents isolated from decellularized MRL/MpJ tendon provisional ECM (dPECM) and the secretome stimulate scar-mediated rodent tenocytes towards enhanced mechanosensitivity, proliferation, intercellular communication, and ECM deposition associated with MRL/MpJ cell behavior. Our findings highlight key biological mechanisms that drive MRL/MpJ tenocyte activity and their interspecies utility to be harnessed for therapeutic strategies that promote pro-regenerative healing outcomes. Teaser Proteins enriched in a super-healer mouse strain elicit interspecies utility in promoting pro-regenerative tenocyte behavior.
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Shen R, Lu Y, Cai C, Wang Z, Zhao J, Wu Y, Zhang Y, Yang Y. Research progress and prospects of benefit-risk assessment methods for umbilical cord mesenchymal stem cell transplantation in the clinical treatment of spinal cord injury. Stem Cell Res Ther 2024; 15:196. [PMID: 38956734 PMCID: PMC11218107 DOI: 10.1186/s13287-024-03797-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 06/10/2024] [Indexed: 07/04/2024] Open
Abstract
Over the past decade, we have witnessed the development of cell transplantation as a new strategy for repairing spinal cord injury (SCI). However, due to the complexity of the central nervous system (CNS), achieving successful clinical translation remains a significant challenge. Human umbilical cord mesenchymal stem cells (hUMSCs) possess distinct advantages, such as easy collection, lack of ethical concerns, high self-renewal ability, multilineage differentiation potential, and immunomodulatory properties. hUMSCs are promising for regenerating the injured spinal cord to a significant extent. At the same time, for advancing SCI treatment, the appropriate benefit and risk evaluation methods play a pivotal role in determining the clinical applicability of treatment plans. Hence, this study discusses the advantages and risks of hUMSCs in SCI treatment across four dimensions-comprehensive evaluation of motor and sensory function, imaging, electrophysiology, and autonomic nervous system (ANS) function-aiming to improve the rationality of relevant clinical research and the feasibility of clinical translation.
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Affiliation(s)
- Ruoqi Shen
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
| | - Yubao Lu
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
| | - Chaoyang Cai
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
| | - Ziming Wang
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
| | - Jiayu Zhao
- Department of Neuro-Oncological Surgery, Neurosurgery Center, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Yingjie Wu
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
| | - Yinian Zhang
- Department of Neuro-Oncological Surgery, Neurosurgery Center, Zhujiang Hospital of Southern Medical University, Guangzhou, China.
| | - Yang Yang
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China.
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China.
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China.
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China.
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Sousa AR, Gonçalves DC, Neves BG, Santos‐Coquillat A, Oliveira MB, Mano JF. Encapsulated Mesenchymal Stromal Cells as Cyclic Providers of Immunomodulatory Secretomes: A Living on-Demand Delivery System. Adv Healthc Mater 2024; 13:e2304012. [PMID: 38545848 PMCID: PMC11468815 DOI: 10.1002/adhm.202304012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 02/28/2024] [Indexed: 04/09/2024]
Abstract
The stimulation of mesenchymal stromal cells (MSCs) with inflammatory molecules is often used to boost their therapeutic effect. Prolonged exposure to inflammatory molecules has been explored to improve their action because MSCs therapies seem to be improved transiently with such stimuli. However, the possibility of cyclically stimulating MSCs to recover their optimized therapeutic potential is still to be elucidated, although the efficacy of cell-based therapies may be dependent on the ability to readapt to the relapse pathological conditions. Here, the response of MSCs, encapsulated in alginate hydrogels and cultured for 22 d, is explored using three different regimes: single, continuous, and intermittent stimulation with IFNγ. Exposure to IFNγ leads to a decrease in the secretion of IL-10, which is cyclically countered by IFNγ weaning. Conditioned media collected at different stages of pulsatile stimulation show an immunomodulatory potential toward macrophages, which directly correlates with IL-10 concentration in media. To understand whether the correlation between cyclic stimulation of MSCs and other biological actions can be observed, the effect on endothelial cells is studied, showcasing an overall modest influence on tube formation. Overall, the results describe the response of encapsulated MSCs to unusual pulsatile simulation regimens, exploring encapsulated MSCs as a living on-demand release system of tailored secretomes with recoverable immunomodulatory action.
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Affiliation(s)
- Ana Rita Sousa
- Department of ChemistryCICECO – Aveiro Institute of MaterialsUniversity of AveiroAveiro3810‐193Portugal
| | - Diana C. Gonçalves
- Department of ChemistryCICECO – Aveiro Institute of MaterialsUniversity of AveiroAveiro3810‐193Portugal
| | - Beatriz Guapo Neves
- Department of ChemistryCICECO – Aveiro Institute of MaterialsUniversity of AveiroAveiro3810‐193Portugal
| | - Ana Santos‐Coquillat
- Department of ChemistryCICECO – Aveiro Institute of MaterialsUniversity of AveiroAveiro3810‐193Portugal
| | - Mariana B. Oliveira
- Department of ChemistryCICECO – Aveiro Institute of MaterialsUniversity of AveiroAveiro3810‐193Portugal
| | - João F. Mano
- Department of ChemistryCICECO – Aveiro Institute of MaterialsUniversity of AveiroAveiro3810‐193Portugal
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Guo Q, Chen J, Bu Q, Zhang J, Ruan M, Chen X, Zhao M, Tu X, Zhao C. Establishing stable and highly osteogenic hiPSC-derived MSCs for 3D-printed bone graft through microenvironment modulation by CHIR99021-treated osteocytes. Mater Today Bio 2024; 26:101111. [PMID: 38933413 PMCID: PMC11201125 DOI: 10.1016/j.mtbio.2024.101111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 05/17/2024] [Accepted: 05/31/2024] [Indexed: 06/28/2024] Open
Abstract
Human induced pluripotent stem cell (hiPSC)-derived mesenchymal stem cells (iMSCs) are ideal candidates for the production of standardised and scalable bioengineered bone grafts. However, stable induction and osteogenic differentiation of iMSCs pose challenges in the industry. We developed a precise differentiation method to produce homogeneous and fully differentiated iMSCs. In this study, we established a standardised system to prepare iMSCs with increased osteogenic potential and improved bioactivity by introducing a CHIR99021 (C91)-treated osteogenic microenvironment (COOME). COOME enhances the osteogenic differentiation and mineralisation of iMSCs via canonical Wnt signalling. Global transcriptome analysis and co-culturing experiments indicated that COOME increased the pro-angiogenesis/neurogenesis activity of iMSCs. The superior osteogenic differentiation and mineralisation abilities of COOME-treated iMSCs were also confirmed in a Bio3D module generated using a polycaprolactone (PCL) and cell-integrated 3D printing (PCI3D) system, which is the closest model to in vivo research. This COOME-treated iMSCs differentiation system offers a new perspective for generating highly osteogenic, bioactive, and anatomically matched grafts for clinical applications. Statement of significance Although human induced pluripotent stem cell-derived MSCs (iMSCs) are ideal seed cells for synthetic bone implants, the challenges of stable induction and osteogenic differentiation hinder their clinical application. This study established a standardised system for the scalable preparation of iMSCs with improved osteogenic potential by combining our precise iMSC differentiation method with the CHIR99021 (C91)-treated osteocyte osteogenic microenvironment (COOME) through the activation of canonical Wnt signalling. Moreover, COOME upregulated the pro-angiogenic and pro-neurogenic capacities of iMSCs, which are crucial for the integration of implanted bone grafts. The superior osteogenic ability of COOME-treated iMSCs was confirmed in Bio3D modules generated using PCL and cell-integrated 3D printing systems, highlighting their functional potential in vivo. This study contributes to tissue engineering by providing insights into the functional differentiation of iMSCs for bone regeneration.
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Affiliation(s)
- Qiuling Guo
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Jingjing Chen
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Qiqi Bu
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Jinling Zhang
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Minjie Ruan
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Xiaoyu Chen
- Center for Medical Epigenetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Mingming Zhao
- Center for Medical Epigenetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Xiaolin Tu
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
| | - Chengzhu Zhao
- Laboratory of Skeletal Development and Regeneration, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
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Zhang Y, Zouboulis CC, Xiao Z. Exosomes from adipose-derived stem cells activate sebocytes through the PI3K/AKT/SREBP-1 pathway to accelerate wound healing. Cell Tissue Res 2024; 396:329-342. [PMID: 38411945 PMCID: PMC11144157 DOI: 10.1007/s00441-024-03872-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 01/25/2024] [Indexed: 02/28/2024]
Abstract
Sebocyte regeneration after injury is considered a key element of functional skin repair. Exosomes from adipose-derived stem cells (ADSCs-EXO) accelerate wound healing by promoting the proliferation of fibroblasts. However, the effects of ADSCs-EXO on sebocytes are largely unknown. In this study, the effects of ADSCs-EXO on sebocyte proliferation and migration were evaluated. The levels of phosphorylated AKT (p-AKT), AKT, sterol regulatory-element binding protein (SREBP), and perilipin-1 (PLIN-1) were detected with immunofluorescence, quantitative PCR, and western blot analysis. RNA-Seq was used to analyze the differential gene expression between the ADSCs-EXO group and the control group under anaerobic conditions. Lipogenesis was assessed with Nile red staining. In animal studies, full-thickness skin wounds in BALB/c mice were treated with gelatin methacrylate (GelMA) hydrogel-loaded sebocytes alone or in combination with ADSCs-EXO. Histopathological assessments of the wound tissues were performed Masson Trichrome staining, Immunohistochemical staining and so on. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway blocker LY294002 inhibited the effects of ADSCs-EXO on p-AKT and sebocytes proliferation. ADSCs-EXO also regulated the expression of SREBP-1 and PLIN-1 through the PI3K/AKT pathway in an oxygen level-dependent manner. In BALB/c mice, ADSCs-EXO accelerated sebocyte-assisted wound healing and regeneration. These in vitro and in vivo results supported that ADSCs-EXO can promote the regeneration of fully functional skin after injury through the PI3K/AKT-dependent activation of sebocytes.
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Affiliation(s)
- Yingbo Zhang
- Department of Plastic and Aesthetic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, People's Republic of China
| | - Christos C Zouboulis
- Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany
| | - Zhibo Xiao
- Department of Plastic and Aesthetic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, People's Republic of China.
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