|
1
|
Zununi Vahed S, Hejazian SM, Bakari WN, Landon R, Gueguen V, Meddahi-Pellé A, Anagnostou F, Barzegari A, Pavon-Djavid G. Milking mesenchymal stem cells: Updated protocols for cell lysate, secretome, and exosome extraction, and comparative analysis of their therapeutic potential. Methods 2025; 238:40-60. [PMID: 40058715 DOI: 10.1016/j.ymeth.2025.03.004] [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: 11/05/2024] [Revised: 02/28/2025] [Accepted: 03/04/2025] [Indexed: 03/21/2025] Open
Abstract
The potential of the cell lysate, secretome, and extracellular vesicles (EVs) of mesenchymal stem cells (MSCs) to modulate the immune response and promote tissue regeneration has positioned them as a promising option for cell-free therapy. Currently, many clinical trials in stem cells-derived EVs and secretome are in progress various diseases and sometimes the results are failing. The major challenge on this roadmap is the lack of a standard extraction method for exosome, secretome, and lysate. The most optimal method for obtaining the secretome of MSCs for clinical utilization involves a comprehensive approach that includes non-destructive collection methods, time optimization, multiple collection rounds, optimization of culture conditions, and quality control measures. Further research and clinical studies are warranted to validate and refine these methods for safe and effective utilization of the MSC exosome, secretome, and lysate in various clinical applications. To address these challenges, it is imperative to establish a standardized and unified methodology to ensure reliable evaluation of these extractions in clinical trials. This review seeks to outline the pros and cons of methods for the preparation of MSCs-derived exosome, and secretome/lysate, and comparative analysis of their therapeutic potential.
Collapse
Affiliation(s)
| | | | - William Ndjidda Bakari
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, 99 Av. Jean-Baptiste Clément 93430 Villetaneuse, France; Université Paris Cité, CNRS UMR7052, INSERM U1271, ENVA, B3OA, F-75010 Paris, France
| | - Rebecca Landon
- Université Paris Cité, CNRS UMR7052, INSERM U1271, ENVA, B3OA, F-75010 Paris, France
| | - Virginie Gueguen
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, 99 Av. Jean-Baptiste Clément 93430 Villetaneuse, France
| | - Anne Meddahi-Pellé
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, 99 Av. Jean-Baptiste Clément 93430 Villetaneuse, France
| | - Fani Anagnostou
- Université Paris Cité, CNRS UMR7052, INSERM U1271, ENVA, B3OA, F-75010 Paris, France
| | - Abolfazl Barzegari
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center for Pharmaceutical Nanotechnology (RCPN), Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Graciela Pavon-Djavid
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Nanotechnologies for Vascular Medicine and Imaging Team, 99 Av. Jean-Baptiste Clément 93430 Villetaneuse, France.
| |
Collapse
|
|
2
|
Li XY, Ding DP, Zhan MY, Ma TQ, Zhao XY, Zheng L, Han N, Leng F, Mao YC, Li Z, Wei W, Tan Y, Tang JM, Li TF. Accelerated differentiation of photothermal effect-induced mesenchymal stem cells regulated by activating HSP90-autophagy boosts wound repair. Int J Pharm 2025; 676:125631. [PMID: 40268207 DOI: 10.1016/j.ijpharm.2025.125631] [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: 01/02/2025] [Revised: 04/09/2025] [Accepted: 04/19/2025] [Indexed: 04/25/2025]
Abstract
Mesenchymal Stem Cells (MSC) have the potential for pluripotent differentiation, transformation into stromal cells, and release of various cytokines to accelerate tissue healing as well as fight against inflammatory response. However, the differentiation and maturation of MSC require considerable time, which limits their clinical application. To tackle this difficulty, we herein propose a strategy of "selective accelerated activation of MSC by photothermal effect (PTE)" based on our previous work of "laser-controlled platelet activation". In vitro experiments presented that a photothermal agent (Indocyanine green, ICG) could be loaded by bone marrow-derived MSC (BMSC), which facilitated temperature increase under laser irradiation, leading to the speed differentiation and maturity of BMSC. Further findings revealed that PTE prevented BMSC from oxidative stress, thereby reducing inflammation and apoptosis. The ICG-loaded BMSC, which mixed with hydrogel, was further covered on the acute wounds in rats, promoting wound healing and blood vessel regeneration under laser irradiation. In-depth RNA-sequencing results indicated that PTE treatment led to the differentially expressed genes (DEGs) enriched in autophagy and PI3K signaling pathways, as confirmed by the increased expression of autophagy-associated biomarkers and observed autophagosome in BMSC. Furthermore, the HSP90 was activated in response to the PTE, which inhibited PI3K signaling. Finally, the silence of HSP90 abolished PTE-driven PI3K blockage, autophagy, and differentiation of BMSC. To summarize, PTE could facilitate the differentiation of MSC by triggering HSP90-mediated autophagy, which provides a novel approach for controlled MSC differentiation and the potential application of MSC cytopharmaceutics in wound repair.
Collapse
Affiliation(s)
- Xian-Yu Li
- Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China
| | - Da-Peng Ding
- Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China
| | - Meng-Yi Zhan
- Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China
| | - Tian-Qi Ma
- Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China
| | - Xiang-Yi Zhao
- Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China; Department of Burns and Plastic Surgery, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China
| | - Liang Zheng
- Department of Burns and Plastic Surgery, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China
| | - Ning Han
- Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China
| | - Fan Leng
- Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China
| | - Yu-Cheng Mao
- Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China
| | - Zhengyuan Li
- Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China
| | - Wei Wei
- Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China
| | - Yan Tan
- Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China.
| | - Jun-Ming Tang
- Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China.
| | - Tong-Fei Li
- Shiyan Key Laboratory of Natural Medicine Nanoformulation Research, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei 442000, China.
| |
Collapse
|
|
3
|
Hodgson-Garms M, Moore MJ, Martino MM, Kelly K, Frith JE. Proteomic profiling of iPSC and tissue-derived MSC secretomes reveal a global signature of inflammatory licensing. NPJ Regen Med 2025; 10:7. [PMID: 39905050 PMCID: PMC11794695 DOI: 10.1038/s41536-024-00382-y] [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: 03/09/2024] [Accepted: 12/03/2024] [Indexed: 02/06/2025] Open
Abstract
Much of the therapeutic potential of mesenchymal stromal cells (MSCs) is underpinned by their secretome which varies significantly with source, donor and microenvironmental cues. Understanding these differences is essential to define the mechanisms of MSC-based tissue repair and optimise cell therapies. This study analysed the secretomes of bone-marrow (BM.MSCs), umbilical-cord (UC.MSCs), adipose-tissue (AT.MSCs) and clinical/commercial-grade induced pluripotent stem cell-derived MSCs (iMSCs), under resting and inflammatory licenced conditions. iMSCs recapitulated the inflammatory licensing process, validating their comparability to tissue-derived MSCs. Overall, resting secretomes were defined by extracellular matrix (ECM) and pro-regenerative proteins, while licensed secretomes were enriched in chemotactic and immunomodulatory proteins. iMSC and UC.MSC secretomes contained proteins indicating proliferative potential and telomere maintenance, whereas adult tissue-derived secretomes contained fibrotic and ECM-related proteins. The data and findings from this study will inform the optimum MSC source for particular applications and underpin further development of MSC therapies.
Collapse
Affiliation(s)
- Margeaux Hodgson-Garms
- Department of Materials Science and Engineering, Monash University, Melbourne, VIC, Australia.
- Cynata Therapeutics, Melbourne, VIC, Australia.
| | - Matthew J Moore
- Department of Materials Science and Engineering, Monash University, Melbourne, VIC, Australia
| | - Mikaël M Martino
- Australian Regenerative Medicine Institute, Melbourne, VIC, Australia
- Victorian Heart Institute, Monash University, Melbourne, VIC, Australia
| | | | - Jessica E Frith
- Department of Materials Science and Engineering, Monash University, Melbourne, VIC, Australia.
- Australian Regenerative Medicine Institute, Melbourne, VIC, Australia.
| |
Collapse
|
|
4
|
Zhang M, Zhang R, Kong Y, Li J, Wang G, Wu D, Lan H, Wu M. Microplastics Exposure Causes the Growth Hormone Resistance on the Stem Cell. J Biochem Mol Toxicol 2025; 39:e70176. [PMID: 39959945 DOI: 10.1002/jbt.70176] [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: 04/06/2024] [Revised: 01/13/2025] [Accepted: 02/06/2025] [Indexed: 05/09/2025]
Abstract
With the large range of applications for plastic products, the potential hazards of polystyrene microplastics (PS-MPs) as a hazardous substance have been widely concerned. Mesenchymal stem cells (MSCs) are important cells in the body with high self-renewal ability, multidirectional differentiation potential and low immunogenicity. Growth hormone (GH) has important biological regulatory effects on MSCs. However, the toxicological effects of PS-MPs on the role of GH in hMSCs are unclear yet. In this work, we explored the effects of PS-MPs on the biological activity of GH in hMSCs. Initially, we conducted experiments to investigate the cellular behavior of GH in hMSCs. It is noteworthy that poststimulation with PS-MPs, there was a significant reduction in the quantity of GH entering the cytoplasm, with almost negligible distribution observed in the cell nucleus. Consequently, we proceeded to examine the GH/GHR-mediated signaling pathways. The data revealed that poststimulation with PS-MPs, the downstream signaling pathways, including JAK2-STATs1/3/5, were significantly downregulated. To elucidate this intriguing finding, we delved further into the molecular mechanisms underlying the desensitization of GH/GHR signaling induced by PS-MPs. Experimental data demonstrated that the entry of PS-MPs into the cells resulted in a significant increase in intracellular reactive oxygen species (ROS), leading to cellular senescence. In summary, PS-MPs may induce desensitization of GH signaling in hMSCs through the ROS-induced cellular senescence. This study provides crucial insights into the biological effects of PS-MPs on the GH bioactivity in hMSCs.
Collapse
Affiliation(s)
- Meng Zhang
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Ruoting Zhang
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Yuebing Kong
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Jiawen Li
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Guoxia Wang
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Deyi Wu
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Hainan Lan
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Min Wu
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| |
Collapse
|
|
5
|
Sen S, de Guimaraes TAC, Filho AG, Fabozzi L, Pearson RA, Michaelides M. Stem cell-based therapies for retinal diseases: focus on clinical trials and future prospects. Ophthalmic Genet 2024:1-14. [PMID: 39544140 DOI: 10.1080/13816810.2024.2423784] [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: 03/04/2024] [Revised: 10/09/2024] [Accepted: 10/26/2024] [Indexed: 11/17/2024]
Abstract
Stem cell-based therapy has gained importance over the past decades due to huge advances in science and technology behind the generation and directed differentiation of pluripotent cells from embryos and adult cells. Preclinical proof-of-concept studies have been followed by clinical trials showing efficacy and safety of transplantation of stem cell-based therapy, which are beginning to establish this as a modality of treatment. Disease candidates of interest are primarily conditions that may benefit from replacing dead or dying cells, including advanced inherited retinal dystrophies and age-related macular degeneration, and predominantly seek to transplant either RPE or photoreceptors, although neurotrophic approaches have also been trialed. Whilst a consensus has yet to be reached about the best stage/type of cells for transplantation (stem cells, progenitor cells, differentiated RPE and photoreceptors) and the methods of implantation (sheet, suspension), several CTs have shown safety. There remain potential concerns regarding tumorigenicity and immune rejection; however, with ongoing improvements in cell generation, selection, and delivery, these can be minimized. Earlier studies showed efficacy with immunosuppressive drugs to prevent rejection, and recent donor-matched transplants have avoided the need for immunosuppression. Retinal regenerative medicine is a challenging field and is in a nascent stage but holds tremendous promise. This narrative review delves into the current understanding of stem cells and the latest clinical trials of retinal cell transplantation.
Collapse
Affiliation(s)
- Sagnik Sen
- Deaprtment of Genetics, Moorfields Eye Hospital, London, UK
- UCL Institute of Ophthalmology, University College London, London, UK
| | | | | | | | - Rachael A Pearson
- Ocular Cell and Gene Therapy Group, Centre for Gene Therapy and Regenerative Medicine, King's College London, London, UK
| | - Michel Michaelides
- Deaprtment of Genetics, Moorfields Eye Hospital, London, UK
- UCL Institute of Ophthalmology, University College London, London, UK
| |
Collapse
|
|
6
|
Artamonov MY, Sokov EL. Intraosseous Delivery of Mesenchymal Stem Cells for the Treatment of Bone and Hematological Diseases. Curr Issues Mol Biol 2024; 46:12672-12693. [PMID: 39590346 PMCID: PMC11592824 DOI: 10.3390/cimb46110752] [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: 10/03/2024] [Revised: 10/31/2024] [Accepted: 11/04/2024] [Indexed: 11/28/2024] Open
Abstract
Mesenchymal stem cells are used most in regenerative medicine due to their capacities in differentiation and immune modulation. The intraosseous injection of MSC into the bone has been recommended because of expected outcomes for retention, bioavailability, and enhanced therapeutic efficacy, particularly in conditions involving the bone, such as osteoporosis and osteonecrosis. A review of the intraosseous delivery of mesenchymal stem cells in comparison with intravenous and intra-arterial delivery methods will be subjected to critical examination. This delivery mode fares better regarding paracrine signaling and immunomodulation attributes, which are the cornerstone of tissue regeneration and inflammation reduction. The local complications and technical challenges still apply with this method. This study was more focused on further research soon to be conducted to further elucidate long-term safety and efficacy of intraosseous mesenchymal stem cell therapy. Though much has been achieved with very impressive progress in this field, it is worth noting that more studies need to be put into place so that this technique can be established as a routine approach, especially with further research in biomaterials, gene therapy, and personalized medicine.
Collapse
Affiliation(s)
| | - Evgeniy L. Sokov
- Department of Algology and Rehabilitation, Peoples’ Friendship University, Moscow 117198, Russia;
| |
Collapse
|
|
7
|
Oh SJ, Nguyen TT, Seo Y, Park HJ, Ahn JS, Shin YY, Kang BJ, Jang M, Park J, Jeong JH, Kim HS. Sustained release of stem cell secretome from nano-villi chitosan microspheres for effective treatment of atopic dermatitis. Int J Biol Macromol 2024; 277:134344. [PMID: 39089545 DOI: 10.1016/j.ijbiomac.2024.134344] [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: 11/06/2023] [Revised: 07/01/2024] [Accepted: 07/29/2024] [Indexed: 08/04/2024]
Abstract
Canine atopic dermatitis (AD) arises from hypersensitive immune reactions. AD symptoms entail severe pruritus and skin inflammation, with frequent relapses. Consequently, AD patients require continuous management, imposing financial burdens and mental fatigue on pet owners. In this study, we aimed to investigate the therapeutic relevance of secretome from canine adipose tissue-derived mesenchymal stem cells (MSCs), especially after encapsulation in nano-villi chitosan microspheres (CS-MS) to expect improved efficacy. Conditioned media (CM) from MSCs significantly inhibited the proliferation of splenocytes, induced the generation of regulatory T cells, and decreased mast cell degranulation. We found that beneficial soluble factors known to reduce AD symptoms, including transforming growth factor-beta 1, were detectable after sequential concentration and lyophilization of CM. The CS-MS, developed by a phase inversion regeneration method, showed high loading and sustained release of the secretome. Local injection of secretome-loaded CS-MS (ST/SC-MS) effectively reduced clinical severity compared to groups treated with secretome. Histological analysis revealed that ST/SC-MS potently suppressed epidermal hyperplasia, immunocyte infiltration and mast cell activation in the lesion. Taken together, this study presents a novel therapeutic approach exhibiting more potent and prolonged immunoregulatory efficacy of MSC secretome for canine AD treatment.
Collapse
Affiliation(s)
- Su-Jeong Oh
- Department of Oral Biochemistry, Dental and Life Science Institute, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Tiep Tien Nguyen
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea; Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Yoojin Seo
- Department of Oral Biochemistry, Dental and Life Science Institute, Pusan National University, Yangsan 50612, Republic of Korea
| | - Hee-Jeong Park
- Department of Oral Biochemistry, Dental and Life Science Institute, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Ji-Su Ahn
- Department of Oral Biochemistry, Dental and Life Science Institute, Pusan National University, Yangsan 50612, Republic of Korea
| | - Ye Young Shin
- Stem Cell and Regenerative Bioengineering Institute, Global R&D Center, Kangstem Biotech Co. Ltd., Seoul 08590, Republic of Korea
| | - Byung-Jae Kang
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea; BK21 FOUR Future Veterinary Medicine Leading Education and Research Center, Seoul National University, Seoul, 08826, Republic of Korea
| | - Min Jang
- Department of Veterinary Surgery, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Junhyeung Park
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Jee-Heon Jeong
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea.
| | - Hyung-Sik Kim
- Department of Oral Biochemistry, Dental and Life Science Institute, Pusan National University, Yangsan 50612, Republic of Korea; Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea; Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan 50612, Republic of Korea.
| |
Collapse
|
|
8
|
Cyr-Depauw C, Cook DP, Mižik I, Lesage F, Vadivel A, Renesme L, Deng Y, Zhong S, Bardin P, Xu L, Möbius MA, Marzahn J, Freund D, Stewart DJ, Vanderhyden BC, Rüdiger M, Thébaud B. Single-Cell RNA Sequencing Reveals Repair Features of Human Umbilical Cord Mesenchymal Stromal Cells. Am J Respir Crit Care Med 2024; 210:814-827. [PMID: 38564376 DOI: 10.1164/rccm.202310-1975oc] [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: 10/31/2023] [Accepted: 04/01/2024] [Indexed: 04/04/2024] Open
Abstract
Rationale: The chronic lung disease bronchopulmonary dysplasia (BPD) is the most severe complication of extreme prematurity. BPD results in impaired lung alveolar and vascular development and long-term respiratory morbidity, for which only supportive therapies exist. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) improve lung structure and function in experimental BPD. Results of clinical trials with MSCs for many disorders do not yet match the promising preclinical studies. A lack of specific criteria to define functionally distinct MSCs persists. Objectives: To determine and correlate single-cell UC-MSC transcriptomic profiles with therapeutic potential. Methods: UC-MSCs from five term donors and human neonatal dermal fibroblasts (HNDFs; control cells of mesenchymal origin) transcriptomes were investigated using single-cell RNA sequencing (scRNA-seq) analysis. The lung-protective effect of UC-MSCs with a distinct transcriptome and control HNDFs was tested in vivo in hyperoxia-induced neonatal lung injury in rats. Measurements and Main Results: UC-MSCs showed limited transcriptomic heterogeneity but were different from HNDFs. Gene Ontology enrichment analysis revealed distinct (progenitor-like and fibroblast-like) UC-MSC subpopulations. Only treatment with progenitor-like UC-MSCs improved lung function and structure and attenuated pulmonary hypertension in hyperoxia-exposed rat pups. Moreover, scRNA-seq identified major histocompatibility complex class I as a molecular marker of nontherapeutic cells and associated with decreased lung retention. Conclusions: UC-MSCs with a progenitor-like transcriptome, but not with a fibroblast-like transcriptome, provide lung protection in experimental BPD. High expression of major histocompatibility complex class I is associated with reduced therapeutic benefit. scRNA-seq may be useful to identify subsets of MSCs with superior repair capacity for clinical application.
Collapse
Affiliation(s)
- Chanèle Cyr-Depauw
- Sinclair Centre for Regenerative Medicine and
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - David P Cook
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Ivana Mižik
- Sinclair Centre for Regenerative Medicine and
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Flore Lesage
- Sinclair Centre for Regenerative Medicine and
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | | | - Laurent Renesme
- Sinclair Centre for Regenerative Medicine and
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Yupu Deng
- Sinclair Centre for Regenerative Medicine and
| | | | - Pauline Bardin
- Sinclair Centre for Regenerative Medicine and
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Liqun Xu
- Sinclair Centre for Regenerative Medicine and
| | - Marius A Möbius
- Neonatology and Pediatric Critical Care Medicine, Department of Pediatrics, University Hospital Carl Gustav Carus, and
- Research Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany
| | - Jenny Marzahn
- Neonatology and Pediatric Critical Care Medicine, Department of Pediatrics, University Hospital Carl Gustav Carus, and
| | - Daniel Freund
- Research Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany
| | - Duncan J Stewart
- Sinclair Centre for Regenerative Medicine and
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Barbara C Vanderhyden
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Obstetrics and Gynecology, University of Ottawa/The Ottawa Hospital, Ottawa, Ontario, Canada; and
| | - Mario Rüdiger
- Neonatology and Pediatric Critical Care Medicine, Department of Pediatrics, University Hospital Carl Gustav Carus, and
| | - Bernard Thébaud
- Sinclair Centre for Regenerative Medicine and
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
| |
Collapse
|
|
9
|
Huang D, Shen H, Xie F, Hu D, Jin Q, Hu Y, Zhong T. Role of mesenchymal stem cell-derived exosomes in the regeneration of different tissues. J Biol Eng 2024; 18:36. [PMID: 38845032 PMCID: PMC11155050 DOI: 10.1186/s13036-024-00431-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 05/10/2024] [Indexed: 06/10/2024] Open
Abstract
Exosomes are nanovesicles with multiple components used in several applications. Mesenchymal stem cells (MSCs) are well known for their great potential in clinical applications. MSC-derived exosomes (MSC-Exos) have been shown to mediate tissue regeneration in various diseases, including neurological, autoimmune, and inflammatory diseases, cancer, ischemic heart disease, lung injury, and liver fibrosis. They can modulate the immune response by interacting with immune effector cells in the presence of anti-inflammatory compounds and are involved in intercellular communication through various types of cargo. This review summarizes the MSC-Exos-mediated tissue regeneration in various diseases, including neurological, cardiovascular, liver, kidney, articular cartilage, and oral tissue applications. In addition, we discuss the challenges and prospects of MSC-Exos in tissue regeneration.
Collapse
Affiliation(s)
- Defa Huang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Haibin Shen
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Fangfang Xie
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Die Hu
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Qing Jin
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yuexin Hu
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Tianyu Zhong
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
- Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
| |
Collapse
|
|
10
|
Aprile D, Patrone D, Peluso G, Galderisi U. Multipotent/pluripotent stem cell populations in stromal tissues and peripheral blood: exploring diversity, potential, and therapeutic applications. Stem Cell Res Ther 2024; 15:139. [PMID: 38735988 PMCID: PMC11089765 DOI: 10.1186/s13287-024-03752-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 05/02/2024] [Indexed: 05/14/2024] Open
Abstract
The concept of "stemness" incorporates the molecular mechanisms that regulate the unlimited self-regenerative potential typical of undifferentiated primitive cells. These cells possess the unique ability to navigate the cell cycle, transitioning in and out of the quiescent G0 phase, and hold the capacity to generate diverse cell phenotypes. Stem cells, as undifferentiated precursors endow with extraordinary regenerative capabilities, exhibit a heterogeneous and tissue-specific distribution throughout the human body. The identification and characterization of distinct stem cell populations across various tissues have revolutionized our understanding of tissue homeostasis and regeneration. From the hematopoietic to the nervous and musculoskeletal systems, the presence of tissue-specific stem cells underlines the complex adaptability of multicellular organisms. Recent investigations have revealed a diverse cohort of non-hematopoietic stem cells (non-HSC), primarily within bone marrow and other stromal tissue, alongside established hematopoietic stem cells (HSC). Among these non-HSC, a rare subset exhibits pluripotent characteristics. In vitro and in vivo studies have demonstrated the remarkable differentiation potential of these putative stem cells, known by various names including multipotent adult progenitor cells (MAPC), marrow-isolated adult multilineage inducible cells (MIAMI), small blood stem cells (SBSC), very small embryonic-like stem cells (VSELs), and multilineage differentiating stress enduring cells (MUSE). The diverse nomenclatures assigned to these primitive stem cell populations may arise from different origins or varied experimental methodologies. This review aims to present a comprehensive comparison of various subpopulations of multipotent/pluripotent stem cells derived from stromal tissues. By analysing isolation techniques and surface marker expression associated with these populations, we aim to delineate the similarities and distinctions among stromal tissue-derived stem cells. Understanding the nuances of these tissue-specific stem cells is critical for unlocking their therapeutic potential and advancing regenerative medicine. The future of stem cells research should prioritize the standardization of methodologies and collaborative investigations in shared laboratory environments. This approach could mitigate variability in research outcomes and foster scientific partnerships to fully exploit the therapeutic potential of pluripotent stem cells.
Collapse
Affiliation(s)
- Domenico Aprile
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
| | - Deanira Patrone
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
| | - Gianfranco Peluso
- Faculty of Medicine and Surgery, Saint Camillus International, University of Health Sciences, Rome, Italy
| | - Umberto Galderisi
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy.
- Genome and Stem Cell Center (GENKÖK), Erciyes University, Kayseri, Turkey.
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine Temple University, Philadelphia, PA, USA.
| |
Collapse
|
|
11
|
Zhang F, Wang Y. Safety and Efficacy of Bone Marrow Mesenchymal Stem Cells in the Treatment of Ischemic Stroke: A Meta-Analysis. Ann Indian Acad Neurol 2024; 27:131-139. [PMID: 38751928 PMCID: PMC11093161 DOI: 10.4103/aian.aian_736_23] [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: 08/17/2023] [Revised: 11/08/2023] [Accepted: 11/11/2023] [Indexed: 05/18/2024] Open
Abstract
Objective We aimed to systematically evaluate the efficacy and safety of bone marrow mesenchymal stem cells (BMMSCs) in the treatment of ischemic stroke. Methods Six Chinese and English databases were searched for related randomized controlled trials from the establishment of the databases to 28 February 2023. Two investigators performed screening and a comprehensive analysis and evaluated the quality of the studies. They extracted information from the included studies, and managed and analzsed the data using RevMan 5.4.1 software (The First College of Clinical Medical Science, China Three Gorges University). Finally, they performed meta and heterogeneity analyses and created a risk-of-bias map. Results A total of 13 high-quality articles were included. The National Institute of Health Stroke Scale (NIHSS) scores of the experimental group differed significantly from those of the control group at 3 months (I2 <50%, mean difference [MD] = -2.88, P < 0.001) after treatment. The Fugl-Meyer assessment (FMA) scores of the experimental group varied significantly from that of the control group at 1 month (I2 >50%, MD = 15.94, P < 0.001), 3 months (I2 >50%, MD = 12.71, P < 0.001), and 6 months (I2 >50%, MD = 13.76, P < 0.001) after treatment, and the overall difference (I2 >50%, MD = 14.38, P ≤ 0.001) was significant. The functional independence measure (FIM) scores were significantly different from that of the control group at 1 month (I2 >50%, MD = 20.04, P = 0.02), 3 months (I2 >50%, MD = 15.51, P < 0.001), and 6 months (I2 >50%, MD = 13.46, P = 0.03). There was no significant increase in adverse events compared with the traditional treatment regimen. Conclusion To some extent, BMMSC transplantation can improve the neurological deficit, motor function, and daily living ability of patients with ischemic stroke.
Collapse
Affiliation(s)
- Feng Zhang
- Department of Medicament, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei, China
| | - Yanyan Wang
- Department of Medicament, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei, China
| |
Collapse
|
|
12
|
Vassallo V, Di Meo C, Alessio N, La Gatta A, Ferraro GA, Nicoletti GF, Schiraldi C. Highly Concentrated Stabilized Hybrid Complexes of Hyaluronic Acid: Rheological and Biological Assessment of Compatibility with Adipose Tissue and Derived Stromal Cells towards Regenerative Medicine. Int J Mol Sci 2024; 25:2019. [PMID: 38396698 PMCID: PMC10888561 DOI: 10.3390/ijms25042019] [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: 01/09/2024] [Revised: 01/29/2024] [Accepted: 02/03/2024] [Indexed: 02/25/2024] Open
Abstract
Cells and extracts derived from adipose tissue are gaining increasing attention not only in plastic surgery and for aesthetic purposes but also in regenerative medicine. The ability of hyaluronan (HA) to support human adipose stromal cell (hASC) viability and differentiation has been investigated. However, the compatibility of adipose tissue with HA-based formulation in terms of biophysical and rheological properties has not been fully addressed, although it is a key feature for tissue integration and in vivo performance. In this study, the biophysical and biochemical properties of highly concentrated (45 mg/mL) high/low-molecular-weight HA hybrid cooperative complex were assessed with a further focus on the potential application in adipose tissue augmentation/regeneration. Specifically, HA hybrid complex rheological behavior was observed in combination with different adipose tissue ratios, and hyaluronidase-catalyzed degradation was compared to that of a high-molecular-weight HA (HHA). Moreover, the HA hybrid complex's ability to induce in vitro hASCs differentiation towards adipose phenotype was evaluated in comparison to HHA, performing Oil Red O staining and analyzing gene/protein expression of PPAR-γ, adiponectin, and leptin. Both treatments supported hASCs differentiation, with the HA hybrid complex showing better results. These outcomes may open new frontiers in regenerative medicine, supporting the injection of highly concentrated hybrid formulations in fat compartments, eventually enhancing residing staminal cell differentiation and improving cell/growth factor persistence towards tissue regeneration districts.
Collapse
Affiliation(s)
- Valentina Vassallo
- Department of Experimental Medicine, Section of Biotechnology, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (V.V.); (C.D.M.); (N.A.); (A.L.G.)
| | - Celeste Di Meo
- Department of Experimental Medicine, Section of Biotechnology, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (V.V.); (C.D.M.); (N.A.); (A.L.G.)
| | - Nicola Alessio
- Department of Experimental Medicine, Section of Biotechnology, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (V.V.); (C.D.M.); (N.A.); (A.L.G.)
| | - Annalisa La Gatta
- Department of Experimental Medicine, Section of Biotechnology, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (V.V.); (C.D.M.); (N.A.); (A.L.G.)
| | - Giuseppe Andrea Ferraro
- Plastic Surgery Unit, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.A.F.); (G.F.N.)
| | - Giovanni Francesco Nicoletti
- Plastic Surgery Unit, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (G.A.F.); (G.F.N.)
| | - Chiara Schiraldi
- Department of Experimental Medicine, Section of Biotechnology, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (V.V.); (C.D.M.); (N.A.); (A.L.G.)
| |
Collapse
|
|
13
|
Huang R, Chen J, Guo B, Jiang C, Sun W. Diabetes-induced male infertility: potential mechanisms and treatment options. Mol Med 2024; 30:11. [PMID: 38225568 PMCID: PMC10790413 DOI: 10.1186/s10020-023-00771-x] [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: 08/12/2023] [Accepted: 12/14/2023] [Indexed: 01/17/2024] Open
Abstract
Male infertility is a physiological phenomenon in which a man is unable to impregnate a fertile woman during a 12-month period of continuous, unprotected sexual intercourse. A growing body of clinical and epidemiological evidence indicates that the increasing incidence of male reproductive problems, especially infertility, shows a very similar trend to the incidence of diabetes within the same age range. In addition, a large number of previous in vivo and in vitro experiments have also suggested that the complex pathophysiological changes caused by diabetes may induce male infertility in multiple aspects, including hypothalamic-pituitary-gonadal axis dysfunction, spermatogenesis and maturation disorders, testicular interstitial cell damage erectile dysfunction. Based on the above related mechanisms, a large number of studies have focused on the potential therapeutic association between diabetes progression and infertility in patients with diabetes and infertility, providing important clues for the treatment of this population. In this paper, we summarized the research results of the effects of diabetes on male reproductive function in recent 5 years, elaborated the potential pathophysiological mechanisms of male infertility induced by diabetes, and reviewed and prospected the therapeutic measures.
Collapse
Affiliation(s)
- Runchun Huang
- The First Clinical Medical College, Lanzhou University, Lanzhou, People's Republic of China, 730000
| | - Jiawang Chen
- The First Clinical Medical College, Lanzhou University, Lanzhou, People's Republic of China, 730000
| | - Buyu Guo
- The First Clinical Medical College, Lanzhou University, Lanzhou, People's Republic of China, 730000
| | - Chenjun Jiang
- The First Clinical Medical College, Lanzhou University, Lanzhou, People's Republic of China, 730000
| | - Weiming Sun
- The First Clinical Medical College, Lanzhou University, Lanzhou, People's Republic of China, 730000.
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China.
| |
Collapse
|
|
14
|
Vassallo V, Di Meo C, Schiraldi C. Adult Mesenchymal Stem Cells in Presence of Glycosaminoglycans. Methods Mol Biol 2024; 2835:29-37. [PMID: 39105903 DOI: 10.1007/978-1-0716-3995-5_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] [Indexed: 08/07/2024]
Abstract
The application of adult mesenchymal stem cells (MSCs) in the field of tissue regeneration is of increasing interest to the scientific community. In particular, scaffolds and/or hydrogel based on glycosaminoglycans (GAGs) play a pivotal role due to their ability to support the in vitro growth and differentiation of MSCs toward a specific phenotype. Here, we describe different possible approaches to develop GAGs-based biomaterials, hydrogel, and polymeric viscous solutions in order to assess/develop a suitable biomimetic environment. To sustain MSCs viability and promote their differentiation for potential therapeutic applications.
Collapse
Affiliation(s)
- Valentina Vassallo
- Department of Experimental Medicine (DMS), Section of Biotechnology, Molecular Biology and Medical Histology, University of Campania "L. Vanvitelli", Naples, Italy
| | - Celeste Di Meo
- Department of Experimental Medicine (DMS), Section of Biotechnology, Molecular Biology and Medical Histology, University of Campania "L. Vanvitelli", Naples, Italy
| | - Chiara Schiraldi
- Department of Experimental Medicine (DMS), Section of Biotechnology, Molecular Biology and Medical Histology, University of Campania "L. Vanvitelli", Naples, Italy.
| |
Collapse
|
|
15
|
Miceli V, Zito G, Bulati M, Gallo A, Busà R, Iannolo G, Conaldi PG. Different priming strategies improve distinct therapeutic capabilities of mesenchymal stromal/stem cells: Potential implications for their clinical use. World J Stem Cells 2023; 15:400-420. [PMID: 37342218 PMCID: PMC10277962 DOI: 10.4252/wjsc.v15.i5.400] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/07/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have shown significant therapeutic potential, and have therefore been extensively investigated in preclinical studies of regenerative medicine. However, while MSCs have been shown to be safe as a cellular treatment, they have usually been therapeutically ineffective in human diseases. In fact, in many clinical trials it has been shown that MSCs have moderate or poor efficacy. This inefficacy appears to be ascribable primarily to the heterogeneity of MSCs. Recently, specific priming strategies have been used to improve the therapeutic properties of MSCs. In this review, we explore the literature on the principal priming approaches used to enhance the preclinical inefficacy of MSCs. We found that different priming strategies have been used to direct the therapeutic effects of MSCs toward specific pathological processes. Particularly, while hypoxic priming can be used primarily for the treatment of acute diseases, inflammatory cytokines can be used mainly to prime MSCs in order to treat chronic immune-related disorders. The shift in approach from regeneration to inflammation implies, in MSCs, a shift in the production of functional factors that stimulate regenerative or anti-inflammatory pathways. The opportunity to fine-tune the therapeutic properties of MSCs through different priming strategies could conceivably pave the way for optimizing their therapeutic potential.
Collapse
Affiliation(s)
- Vitale Miceli
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy.
| | - Giovanni Zito
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Matteo Bulati
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Alessia Gallo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Rosalia Busà
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Gioacchin Iannolo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Pier Giulio Conaldi
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| |
Collapse
|
|
16
|
Wang C, Zhao B, Zhai J, Wang A, Cao N, Liao T, Su R, He L, Li Y, Pei X, Jia Y, Yue W. Clinical-grade human umbilical cord-derived mesenchymal stem cells improved skeletal muscle dysfunction in age-associated sarcopenia mice. Cell Death Dis 2023; 14:321. [PMID: 37173309 PMCID: PMC10182022 DOI: 10.1038/s41419-023-05843-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 04/23/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023]
Abstract
With the expansion of the aging population, age-associated sarcopenia (AAS) has become a severe clinical disease of the elderly and a key challenge for healthy aging. Regrettably, no approved therapies currently exist for treating AAS. In this study, clinical-grade human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were administrated to two classic mouse models (SAMP8 mice and D-galactose-induced aging mice), and their effects on skeletal muscle mass and function were investigated by behavioral tests, immunostaining, and western blotting. Core data results showed that hUC-MSCs significantly restored skeletal muscle strength and performance in both mouse models via mechanisms including raising the expression of crucial extracellular matrix proteins, activating satellite cells, enhancing autophagy, and impeding cellular aging. For the first time, the study comprehensively evaluates and demonstrates the preclinical efficacy of clinical-grade hUC-MSCs for AAS in two mouse models, which not only provides a novel model for AAS, but also highlights a promising strategy to improve and treat AAS and other age-associated muscle diseases. This study comprehensively evaluates the preclinical efficacy of clinical-grade hUC-MSCs in treating age-associated sarcopenia (AAS), and demonstrates that hUC-MSCs restore skeletal muscle strength and performance in two AAS mouse models via raising the expression of extracellular matrix proteins, activating satellite cells, enhancing autophagy, and impeding cellular aging, which highlights a promising strategy for AAS and other age-associated muscle diseases.
Collapse
Affiliation(s)
- Chao Wang
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Bichun Zhao
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Jinglei Zhai
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Ailin Wang
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Ning Cao
- 920th Hospital of Joint Logistics Support Force, Kunming, 650032, China
| | - Tuling Liao
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Ruyu Su
- South China Institute of Biomedicine, Guangzhou, 510005, China
| | - Lijuan He
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, 100850, China
- South China Institute of Biomedicine, Guangzhou, 510005, China
| | - Yanhua Li
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, 100850, China
- South China Institute of Biomedicine, Guangzhou, 510005, China
| | - Xuetao Pei
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
- South China Institute of Biomedicine, Guangzhou, 510005, China.
| | - Yali Jia
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
- South China Institute of Biomedicine, Guangzhou, 510005, China.
| | - Wen Yue
- Stem Cell and Regenerative Medicine Lab, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
- South China Institute of Biomedicine, Guangzhou, 510005, China.
| |
Collapse
|
|
17
|
Siraj Y, Galderisi U, Alessio N. Senescence induces fundamental changes in the secretome of mesenchymal stromal cells (MSCs): implications for the therapeutic use of MSCs and their derivates. Front Bioeng Biotechnol 2023; 11:1148761. [PMID: 37229499 PMCID: PMC10203235 DOI: 10.3389/fbioe.2023.1148761] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 04/24/2023] [Indexed: 05/27/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are a heterogeneous population containing multipotent adult stem cells with a multi-lineage differentiation capacity, which differentiated into mesodermal derivatives. MSCs are employed for therapeutic purposes and several investigations have demonstrated that the positive effects of MSC transplants are due to the capacity of MSCs to modulate tissue homeostasis and repair via the activity of their secretome. Indeed, the MSC-derived secretomes are now an alternative strategy to cell transplantation due to their anti-inflammatory, anti-apoptotic, and regenerative effects. The cellular senescence is a dynamic process that leads to permanent cell cycle arrest, loss of healthy cells' physiological functions and acquiring new activities, which are mainly accrued through the release of many factors, indicated as senescence-associated secretory phenotype (SASP). The senescence occurring in stem cells, such as those present in MSCs, may have detrimental effects on health since it can undermine tissue homeostasis and repair. The analysis of MSC secretome is important either for the MSC transplants and for the therapeutic use of secretome. Indeed, the secretome of MSCs, which is the main mechanism of their therapeutic activity, loses its beneficial functions and acquire negative pro-inflammatory and pro-aging activities when MSCs become senescent. When MSCs or their derivatives are planned to be used for therapeutic purposes, great attention must be paid to these changes. In this review, we analyzed changes occurring in MSC secretome following the switch from healthy to senescence status.
Collapse
Affiliation(s)
- Yesuf Siraj
- Department of Experimental Medicine, University of Campania, Naples, Italy
- Department of Medical Laboratory Sciences, School of Health Sciences, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia
| | - Umberto Galderisi
- Department of Experimental Medicine, University of Campania, Naples, Italy
- Department of Biology, Faculty of Science, Erciyes University, Kayseri, Türkiye
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, United States
| | - Nicola Alessio
- Department of Experimental Medicine, University of Campania, Naples, Italy
| |
Collapse
|
|
18
|
Man K, Eisenstein NM, Hoey DA, Cox SC. Bioengineering extracellular vesicles: smart nanomaterials for bone regeneration. J Nanobiotechnology 2023; 21:137. [PMID: 37106449 PMCID: PMC10134574 DOI: 10.1186/s12951-023-01895-2] [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: 01/12/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
In the past decade, extracellular vesicles (EVs) have emerged as key regulators of bone development, homeostasis and repair. EV-based therapies have the potential to circumnavigate key issues hindering the translation of cell-based therapies including functional tissue engraftment, uncontrolled differentiation and immunogenicity issues. Due to EVs' innate biocompatibility, low immunogenicity, and high physiochemical stability, these naturally-derived nanoparticles have garnered growing interest as potential acellular nanoscale therapeutics for a variety of diseases. Our increasing knowledge of the roles these cell-derived nanoparticles play, has made them an exciting focus in the development of novel pro-regenerative therapies for bone repair. Although these nano-sized vesicles have shown promise, their clinical translation is hindered due to several challenges in the EV supply chain, ultimately impacting therapeutic efficacy and yield. From the biochemical and biophysical stimulation of parental cells to the transition to scalable manufacture or maximising vesicles therapeutic response in vivo, a multitude of techniques have been employed to improve the clinical efficacy of EVs. This review explores state of the art bioengineering strategies to promote the therapeutic utility of vesicles beyond their native capacity, thus maximising the clinical potential of these pro-regenerative nanoscale therapeutics for bone repair.
Collapse
Affiliation(s)
- Kenny Man
- School of Chemical Engineering, University of Birmingham, Birmingham, B15 2TT, UK
| | - Neil M Eisenstein
- Research and Clinical Innovation, Royal Centre for Defence Medicine, ICT Centre, Vincent Drive, Birmingham, B15 2SQ, UK
- Institute of Translational Medicine, University of Birmingham, Heritage Building, Mindelsohn Way, Birmingham, B15 2TH, UK
| | - David A Hoey
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College, Dublin, D02 R590, Ireland
- Dept. of Mechanical, Manufacturing, and Biomedical Engineering, School of Engineering, Trinity College, Dublin 2, D02 DK07, Dublin, Ireland
- Advanced Materials and Bioengineering Research Centre, Trinity College Dublin & RCSI, Dublin 2, D02 VN51, Dublin, Ireland
| | - Sophie C Cox
- School of Chemical Engineering, University of Birmingham, Birmingham, B15 2TT, UK.
| |
Collapse
|
|
19
|
Wei Q, Liu X, Su JL, Wang YX, Chu ZQ, Ma K, Huang QL, Li HH, Fu XB, Zhang CP. Small extracellular vesicles from mesenchymal stem cells: A potential Weapon for chronic non-healing wound treatment. Front Bioeng Biotechnol 2023; 10:1083459. [PMID: 36704302 PMCID: PMC9872203 DOI: 10.3389/fbioe.2022.1083459] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/28/2022] [Indexed: 01/11/2023] Open
Abstract
Chronic non-healing wounds have posed a severe threat to patients mentally and physically. Behavior dysregulation of remaining cells at wound sites is recognized as the chief culprit to destroy healing process and hinders wound healing. Therefore, regulating and restoring normal cellular behavior is the core of chronic non-healing wound treatment. In recent years, the therapy with mesenchymal stem cells (MSCs) has become a promising option for chronic wound healing and the efficacy has increasingly been attributed to their exocrine functions. Small extracellular vesicles derived from MSCs (MSC-sEVs) are reported to benefit almost all stages of wound healing by regulating the cellular behavior to participate in the process of inflammatory response, angiogenesis, re-epithelization, and scarless healing. Here, we describe the characteristics of MSC-sEVs and discuss their therapeutic potential in chronic wound treatment. Additionally, we also provide an overview of the application avenues of MSC-sEVs in wound treatment. Finally, we summarize strategies for large-scale production and engineering of MSC-sEVs. This review may possibly provide meaningful guidance for chronic wound treatment with MSC-sEVs.
Collapse
Affiliation(s)
- Qian Wei
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Xi Liu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Jian-Long Su
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Ya-Xi Wang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Zi-Qiang Chu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Kui Ma
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
- Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Research Unit of Trauma Care, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China
| | - Qi-Lin Huang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Hai-Hong Li
- Department of Wound Repair, Institute of Wound Repair and Regeneration Medicine, Southern University of Science and Technology Hospital, Southern University of Science and Technology School of Medicine, Shenzhen, China
| | - Xiao-Bing Fu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
- Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Research Unit of Trauma Care, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China
| | - Cui-Ping Zhang
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and the 4th Medical Center of Chinese, PLA General Hospital, Beijing, China
- Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, Research Unit of Trauma Care, Beijing, China
- PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China
| |
Collapse
|
|
20
|
Extracellular Vesicles and Cellular Ageing. Subcell Biochem 2023; 102:271-311. [PMID: 36600137 DOI: 10.1007/978-3-031-21410-3_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Ageing is a complex process characterized by deteriorated performance at multiple levels, starting from cellular dysfunction to organ degeneration. Stem cell-based therapies aim to administrate stem cells that eventually migrate to the injured site to replenish the damaged tissue and recover tissue functionality. Stem cells can be easily obtained and cultured in vitro, and display several qualities such as self-renewal, differentiation, and immunomodulation that make them suitable candidates for stem cell-based therapies. Current animal studies and clinical trials are being performed to assess the safety and beneficial effects of stem cell engraftments for regenerative medicine in ageing and age-related diseases.Since alterations in cell-cell communication have been associated with the development of pathophysiological processes, new research is focusing on the modulation of the microenvironment. Recent research has highlighted the important role of some microenvironment components that modulate cell-cell communication, thus spreading signals from damaged ageing cells to neighbor healthy cells, thereby promoting systemic ageing. Extracellular vesicles (EVs) are small-rounded vesicles released by almost every cell type. EVs cargo includes several bioactive molecules, such as lipids, proteins, and genetic material. Once internalized by target cells, their specific cargo can induce epigenetic modifications and alter the fate of the recipient cells. Also, EV's content is dependent on the releasing cells, thus, EVs can be used as biomarkers for several diseases. Moreover, EVs have been proposed to be used as cell-free therapies that focus on their administration to slow or even reverse some hallmarks of physiological ageing. It is not surprising that EVs are also under study as next-generation therapies for age-related diseases.
Collapse
|
|
21
|
Mesenchymal Stem Cells in Radiation-Induced Pulmonary Fibrosis: Future Prospects. Cells 2022; 12:cells12010006. [PMID: 36611801 PMCID: PMC9818136 DOI: 10.3390/cells12010006] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/14/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
Radiation-induced pulmonary fibrosis (RIPF) is a general and fatal side effect of radiotherapy, while the pathogenesis has not been entirely understood yet. By now, there is still no effective clinical intervention available for treatment of RIPF. Recent studies revealed mesenchymal stromal cells (MSCs) as a promising therapy treatment due to their homing and differentiation ability, paracrine effects, immunomodulatory effects, and MSCs-derived exosomes. Nevertheless, problems and challenges in applying MSCs still need to be taken seriously. Herein, we reviewed the mechanisms and challenges in the applications of MSCs in treating RIPF.
Collapse
|
|
22
|
Najahi H, Alessio N, Squillaro T, Conti GO, Ferrante M, Di Bernardo G, Galderisi U, Messaoudi I, Minucci S, Banni M. Environmental microplastics (EMPs) exposure alter the differentiation potential of mesenchymal stromal cells. ENVIRONMENTAL RESEARCH 2022; 214:114088. [PMID: 35973457 DOI: 10.1016/j.envres.2022.114088] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 08/05/2022] [Accepted: 08/06/2022] [Indexed: 06/15/2023]
Abstract
Humans are exposed to environmental microplastic (MPs) that can be frequent in surrounding environment. The mesenchymal stromal cells are a heterogeneous population, which contain fibroblasts and stromal cells, progenitor cells and stem cells. They are part of the stromal component of most tissue and organs in our organisms. Any injury to their functions may impair tissue renewal and homeostasis. We evaluated the effects of different size MPs that could be present in water bottles on human bone marrow mesenchymal stromal cells (BMMSCs) and adipose mesenchymal stromal cells (AMSCs). MPs of polyethylene terephthalate (MPs-PET) (<1 μm and <2.6 μm) were tested in this study. PET treatments induced a reduction in proliferating cells (around 30%) associated either with the onset of senescence or increase in apoptosis. The AMSCs and BMMSCs exposed to PET showed an alteration of differentiation potential. AMSCs remained in an early stage of adipocyte differentiation as shown by high levels of mRNA for Peroxisome Proliferator Activated Receptor Gamma (PPARG) (7.51 vs 1.00) and reduction in Lipoprotein Lipase (LPL) mRNA levels (0.5 vs 1.0). A loss of differentiation capacity was also observed for the osteocyte phenotype in BMMSCs. In particular, we observed a reduction in Bone Gamma-Carboxy glutamate Protein (BGLAP) (0.4 for PET1 and 0.6 for PET2.6 vs 0.1 CTRL) and reduction in Osteopontin (SPP1) (0.3 for PET 1 and 0.64 for PET 2.6 vs 0.1 CTRL). This pioneering mesenchymal cell response study demonstrated that environmental microplastic could be bioavailable for cell uptake and may further lead to irreversible diseases.
Collapse
Affiliation(s)
- Hana Najahi
- Laboratory of Agrobiodiversity and Ecotoxicology LR21AGR02, Sousse University, Chott-Mariem, 4042, Sousse, Tunisia; Higher Institute of Biotechnology, Monastir University, Tunisia
| | - Nicola Alessio
- Department of Experimental Medicine, "Luigi Vanvitelli" Campania University, 81038, Napoli, Italy
| | - Tiziana Squillaro
- Department of Experimental Medicine, "Luigi Vanvitelli" Campania University, 81038, Napoli, Italy
| | - Gea Oliveri Conti
- Environmental and Food Hygiene Laboratory (LIAA), Department of Medical, Surgical Sciences and Advanced Technologies G. F. Ingrassia, Catania University, Via Santa Sofia 87, 95123, Catania, Italy
| | - Margherita Ferrante
- Environmental and Food Hygiene Laboratory (LIAA), Department of Medical, Surgical Sciences and Advanced Technologies G. F. Ingrassia, Catania University, Via Santa Sofia 87, 95123, Catania, Italy
| | - Giovanni Di Bernardo
- Department of Experimental Medicine, "Luigi Vanvitelli" Campania University, 81038, Napoli, Italy
| | - Umberto Galderisi
- Department of Experimental Medicine, "Luigi Vanvitelli" Campania University, 81038, Napoli, Italy
| | - Imed Messaoudi
- Higher Institute of Biotechnology, Monastir University, Tunisia
| | - Sergio Minucci
- Department of Experimental Medicine, "Luigi Vanvitelli" Campania University, 81038, Napoli, Italy
| | - Mohamed Banni
- Laboratory of Agrobiodiversity and Ecotoxicology LR21AGR02, Sousse University, Chott-Mariem, 4042, Sousse, Tunisia; Higher Institute of Biotechnology, Monastir University, Tunisia.
| |
Collapse
|
|
23
|
Nagy G, Szekely TE, Somogyi A, Herold M, Herold Z. New therapeutic approaches for type 1 diabetes: Disease-modifying therapies. World J Diabetes 2022; 13:835-850. [PMID: 36312000 PMCID: PMC9606789 DOI: 10.4239/wjd.v13.i10.835] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 08/08/2022] [Accepted: 09/15/2022] [Indexed: 02/05/2023] Open
Abstract
It has been 100 years since the first successful clinical use of insulin, yet it remains the only treatment option for type 1 diabetes mellitus (T1DM) patients. Advances in diabetes care, such as insulin analogue therapies and new devices, including continuous glucose monitoring with continuous subcutaneous insulin infusion have improved the quality of life of patients but have no impact on the pathogenesis of the disease. They do not eliminate long-term complications and require several lifestyle sacrifices. A more ideal future therapy for T1DM, instead of supplementing the insufficient hormone production (a consequence of β-cell destruction), would also aim to stop or slow down the destructive autoimmune process. The discovery of the autoimmune nature of type 1 diabetes mellitus has presented several targets by which disease progression may be altered. The goal of disease-modifying therapies is to target autoimmune mechanisms and prevent β-cell destruction. T1DM patients with better β-cell function have better glycemic control, reduced incidence of long-term complications and hypoglycemic episodes. Unfortunately, at the time symptomatic T1DM is diagnosed, most of the insulin secreting β cells are usually lost. Therefore, to maximize the salvageable β-cell mass by disease-modifying therapies, detecting autoimmune markers in an early, optimally presymptomatic phase of T1DM is of great importance. Disease-modifying therapies, such as immuno- and regenerative therapies are expected to take a relevant place in diabetology. The aim of this article was to provide a brief insight into the pathogenesis and course of T1DM and present the current state of disease-modifying therapeutic interventions that may impact future diabetes treatment.
Collapse
Affiliation(s)
- Geza Nagy
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Tekla Evelin Szekely
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Aniko Somogyi
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Magdolna Herold
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Zoltan Herold
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest H-1083, Hungary
| |
Collapse
|
|
24
|
Ma X, Wang Y, Shi Y, Li S, Liu J, Li X, Zhong W, Pan Q. Exosomal miR-132-3p from mesenchymal stromal cells improves synaptic dysfunction and cognitive decline in vascular dementia. Stem Cell Res Ther 2022; 13:315. [PMID: 35841005 PMCID: PMC9284820 DOI: 10.1186/s13287-022-02995-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 01/26/2022] [Indexed: 12/28/2022] Open
Abstract
Background/aims Vascular dementia (VD) results in cognition and memory deficit. Exosomes and their carried microRNAs (miRs) contribute to the neuroprotective effects of mesenchymal stromal cells, and miR-132-3p plays a key role in neuron plasticity. Here, we investigated the role and underlying mechanism of MSC EX and their miR-132-3p cargo in rescuing cognition and memory deficit in VD mice. Methods Bilateral carotid artery occlusion was used to generate a VD mouse model. MiR-132-3p and MSC EX levels in the hippocampus and cortex were measured. At 24-h post-VD induction, mice were administered with MSC EX infected with control lentivirus (EXCon), pre-miR-132-3p-expressing lentivirus (EXmiR-132-3p), or miR-132-3p antago lentivirus (EXantagomiR-132-3p) intravenously. Behavioral and cognitive tests were performed, and the mice were killed in 21 days after VD. The effects of MSC EX on neuron number, synaptic plasticity, dendritic spine density, and Aβ and p-Tau levels in the hippocampus and cortex were determined. The effects of MSC EX on oxygen–glucose deprivation (OGD)-injured neurons with respect to apoptosis, and neurite elongation and branching were determined. Finally, the expression levels of Ras, phosphorylation of Akt, GSK-3β, and Tau were also measured. Results Compared with normal mice, VD mice exhibited significantly decreased miR-132-3p and MSC EX levels in the cortex and hippocampus. Compared with EXCon treatment, the infusion of EXmiR-132-3p was more effective at improving cognitive function and increasing miR-132-3p level, neuron number, synaptic plasticity, and dendritic spine density, while decreasing Aβ and p-Tau levels in the cortex and hippocampus of VD mice. Conversely, EXantagomiR-132-3p treatment significantly decreased miR-132-3p expression in cortex and hippocampus, as well as attenuated EXmiR-132-3p treatment-induced functional improvement. In vitro, EXmiR-132-3p treatment inhibited RASA1 protein expression, but increased Ras and the phosphorylation of Akt and GSK-3β, and decreased p-Tau levels in primary neurons by delivering miR-132-3p, which resulted in reduced apoptosis, and increased neurite elongation and branching in OGD-injured neurons. Conclusions Our studies suggest that miR-132-3p cluster-enriched MSC EX promotes the recovery of cognitive function by improving neuronal and synaptic dysfunction through activation of the Ras/Akt/GSK-3β pathway induced by downregulation of RASA1. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02995-w.
Collapse
Affiliation(s)
- Xiaotang Ma
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Yan Wang
- Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, 524001, China
| | - Yumeng Shi
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Suqing Li
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Jinhua Liu
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Xiangyong Li
- Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, 524001, China
| | - Wangtao Zhong
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Qunwen Pan
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| |
Collapse
|
|
25
|
Intratracheal administration of mesenchymal stem cells modulates lung macrophage polarization and exerts anti-asthmatic effects. Sci Rep 2022; 12:11728. [PMID: 35821386 PMCID: PMC9276742 DOI: 10.1038/s41598-022-14846-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 06/13/2022] [Indexed: 12/24/2022] Open
Abstract
Mesenchymal stem cells (MSCs) possess immunomodulatory properties that have therapeutic potential for the treatment of inflammatory diseases. This study investigates the effects of direct MSC administration on asthmatic airways. Umbilical cord MSCs (ucMSCs) were intratracheally administered to six-week-old female BALB/c mice sensitized and challenged with ovalbumin; airway hyperresponsiveness (AHR), analyses of airway inflammatory cells, lung histology, flow cytometry, and quantitative real-time PCR were performed. Furthermore, ex vivo and in vitro experiments were performed to assess the effects of ucMSC on M2 activation. Intratracheally administered ucMSCs decreased degree of airway resistance and the number of inflammatory cells such as T helper 2 (Th2) cells, type 2 innate lymphoid cells (ILC2), and macrophages in the murine asthma model. Particularly, MHCII and CD86 expression diminished in dendritic cells and alveolar macrophages (AMs) following ucMSC treatment. SiglecF+CD11c+CD11b- AMs show a negative correlation with type II inflammatory cells including Th2 cells, ILC2, and eosinophils in asthmatic mice and were restored following intratracheal ucMSCs treatment. In addition, ucMSCs decreased the macrophage polarization to M2, particularly M2a. The expression levels of markers associated with M2 polarization and Th2 inflammation were also decreased. ucMSC reduced Il-12 and Tnfa expression as well as that of M2 markers such as Cd206 and Retnla ex vivo. Furthermore, the in vitro study using IL-4 treated macrophages confirmed that both direct and indirect MSC treatment significantly reduced the expression of Il-5 and Il-13. In conclusion, ucMSCs appear to suppress type II inflammation by regulating lung macrophages via soluble mediators.
Collapse
|
|
26
|
Manocha E, Consonni A, Baggi F, Ciusani E, Cocce V, Paino F, Tremolada C, Caruso A, Alessandri G. CD146+ Pericytes Subset Isolated from Human Micro-Fragmented Fat Tissue Display a Strong Interaction with Endothelial Cells: A Potential Cell Target for Therapeutic Angiogenesis. Int J Mol Sci 2022; 23:ijms23105806. [PMID: 35628617 PMCID: PMC9144360 DOI: 10.3390/ijms23105806] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 02/04/2023] Open
Abstract
Pericytes (PCs) are mesenchymal stromal cells (MSCs) that function as support cells and play a role in tissue regeneration and, in particular, vascular homeostasis. PCs promote endothelial cells (ECs) survival which is critical for vessel stabilization, maturation, and remodeling. In this study, PCs were isolated from human micro-fragmented adipose tissue (MFAT) obtained from fat lipoaspirate and were characterized as NG2+/PDGFRβ+/CD105+ cells. Here, we tested the fat-derived PCs for the dispensability of the CD146 marker with the aim of better understanding the role of these PC subpopulations on angiogenesis. Cells from both CD146-positive (CD146+) and negative (CD146−) populations were observed to interact with human umbilical vein ECs (HUVECs). In addition, fat-derived PCs were able to induce angiogenesis of ECs in spheroids assay; and conditioned medium (CM) from both PCs and fat tissue itself led to the proliferation of ECs, thereby marking their role in angiogenesis stimulation. However, we found that CD146+ cells were more responsive to PDGF-BB-stimulated migration, adhesion, and angiogenic interaction with ECs, possibly owing to their higher expression of NCAM/CD56 than the corresponding CD146− subpopulation. We conclude that in fat tissue, CD146-expressing cells may represent a more mature pericyte subpopulation that may have higher efficacy in controlling and stimulating vascular regeneration and stabilization than their CD146-negative counterpart.
Collapse
Affiliation(s)
- Ekta Manocha
- Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy; (A.C.); (G.A.)
- Correspondence:
| | - Alessandra Consonni
- Neurology IV—Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (A.C.); (F.B.)
| | - Fulvio Baggi
- Neurology IV—Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (A.C.); (F.B.)
| | - Emilio Ciusani
- Laboratory of Neurological Biochemistry and Neuropharmacology, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy;
| | - Valentina Cocce
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; (V.C.); (F.P.)
| | - Francesca Paino
- CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; (V.C.); (F.P.)
| | - Carlo Tremolada
- Department of Stem Cells and Regenerative Medicine, Image Institute, 20122 Milan, Italy;
| | - Arnaldo Caruso
- Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy; (A.C.); (G.A.)
| | - Giulio Alessandri
- Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy; (A.C.); (G.A.)
- Department of Stem Cells and Regenerative Medicine, Image Institute, 20122 Milan, Italy;
| |
Collapse
|
|
27
|
Holthaus M, Santhakumar N, Wahlers T, Paunel-Görgülü A. The Secretome of Preconditioned Mesenchymal Stem Cells Drives Polarization and Reprogramming of M2a Macrophages toward an IL-10-Producing Phenotype. Int J Mol Sci 2022; 23:ijms23084104. [PMID: 35456922 PMCID: PMC9024470 DOI: 10.3390/ijms23084104] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/29/2022] [Accepted: 04/04/2022] [Indexed: 12/13/2022] Open
Abstract
The preconditioning of mesenchymal stem cells (MSCs) has been recognized as an attractive tool to improve their regenerative and immunomodulatory capacities based on their paracrine effects. In this study, we examined the potential of an MSC-conditioned medium (MSC-CM) to alter the phenotype of murine macrophages and to drive reprogramming toward an anti-inflammatory, M2-like state in vitro. We further explored the impact of MSC cytokine preconditioning on the immunosuppressive properties of the MSC secretome. The MSC-CM suppressed the expression of proinflammatory genes in murine M1 macrophages, but only the CM from preconditioned MSCs (preMSC-CM) downregulated their expression during M1 polarization. Remarkably, only the preMSC-CM significantly increased the expression of M2a-, M2b- and M2c-specific genes and proteins during M2a polarization. Further, macrophages were found to secrete high levels of anti-inflammatory IL-10. Similarly, M2a macrophages cultured in the presence of the preMSC-CM displayed an enhanced expression of M2b/M2c-specific markers, suggesting that the secretome of preMSC promotes the repolarization of M2a-like macrophages to M2b/M2c subtypes. The preMSC-CM was found to be enriched in molecules involved in M2 polarization. Additionally, a unique downregulation of extracellular matrix components was observed. Altogether, the preMSC-CM may provide an attractive strategy to dampen inflammation by suppressing the expression of proinflammatory mediators and promoting the polarization and phenotype switch of M2a cells to IL-10-secreting M2b/M2c-like macrophages.
Collapse
Affiliation(s)
- Michelle Holthaus
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, 50937 Cologne, Germany
| | - Nivethiha Santhakumar
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, 50937 Cologne, Germany
| | - Thorsten Wahlers
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, 50937 Cologne, Germany
| | - Adnana Paunel-Görgülü
- Department of Cardiothoracic Surgery, Heart Center, University of Cologne, 50937 Cologne, Germany
| |
Collapse
|
|
28
|
Floriano JF, Emanueli C, Vega S, Barbosa AMP, Oliveira RGD, Floriano EAF, Graeff CFDO, Abbade JF, Herculano RD, Sobrevia L, Rudge MVC. Pro-angiogenic approach for skeletal muscle regeneration. Biochim Biophys Acta Gen Subj 2022; 1866:130059. [PMID: 34793875 DOI: 10.1016/j.bbagen.2021.130059] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 11/01/2021] [Indexed: 12/19/2022]
Abstract
The angiogenesis process is a phenomenon in which numerous molecules participate in the stimulation of the new vessels' formation from pre-existing vessels. Angiogenesis is a crucial step in tissue regeneration and recovery of organ and tissue function. Muscle diseases affect millions of people worldwide overcome the ability of skeletal muscle to self-repair. Pro-angiogenic therapies are key in skeletal muscle regeneration where both myogenesis and angiogenesis occur. These therapies have been based on mesenchymal stem cells (MSCs), exosomes, microRNAs (miRs) and delivery of biological factors. The use of different calls of biomaterials is another approach, including ceramics, composites, and polymers. Natural polymers are use due its bioactivity and biocompatibility in addition to its use as scaffolds and in drug delivery systems. One of these polymers is the natural rubber latex (NRL) which is biocompatible, bioactive, versatile, low-costing, and capable of promoting tissue regeneration and angiogenesis. In this review, the advances in the field of pro-angiogenic therapies are discussed.
Collapse
Affiliation(s)
- Juliana Ferreira Floriano
- São Paulo State University (UNESP), Botucatu Medical School, Botucatu, São Paulo 18.618-687, Brazil; National Heart and Lung Institute, Imperial College London, London, UK.
| | - Costanza Emanueli
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Sofia Vega
- São Paulo State University (UNESP), Botucatu Medical School, Botucatu, São Paulo 18.618-687, Brazil; Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | | | | | | | | | - Joelcio Francisco Abbade
- São Paulo State University (UNESP), Botucatu Medical School, Botucatu, São Paulo 18.618-687, Brazil
| | | | - Luis Sobrevia
- São Paulo State University (UNESP), Botucatu Medical School, Botucatu, São Paulo 18.618-687, Brazil; Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville E-41012, Spain; University of Queensland, Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston, QLD, 4029, Queensland, Australia; Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, the Netherlands.
| | | |
Collapse
|
|
29
|
Vassallo V, Tsianaka A, Alessio N, Grübel J, Cammarota M, Tovar GEM, Southan A, Schiraldi C. Evaluation of novel biomaterials for cartilage regeneration based on gelatin methacryloyl interpenetrated with extractive chondroitin sulfate or unsulfated biotechnological chondroitin. J Biomed Mater Res A 2022; 110:1210-1223. [PMID: 35088923 PMCID: PMC9306773 DOI: 10.1002/jbm.a.37364] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 01/10/2023]
Abstract
Gelatin is widely proposed as scaffold for cartilage tissue regeneration due to its high similarities to the extracellular matrix. However, poor mechanical properties and high sensitivity to enzymatic degradation encouraged the scientific community to develop strategies to obtain better performing hydrogels. Gelatin networks, specifically gelatin‐methacryloyl (GM), have been coupled to hyaluronan or chondroitin sulfate (CS). In this study, we evaluated the biophysical properties of an innovative photocross‐linked hydrogel based on GM with the addition of CS or a new unsulfated biotechnological chondroitin (BC). Biophysical, mechanical, and biochemical characterization have been assessed to compare GM hydrogels to the chondroitin containing networks. Moreover, mesenchymal stem cells (MSCs) were seeded on these biomaterials in order to evaluate the differentiation toward the chondrocyte phenotype in 21 days. Rheological characterization showed that both CS and BC increased the stiffness (G' was about 2‐fold), providing a stronger rigid matrix, with respect to GM alone. The biological tests confirmed the onset of MSCs differentiation process starting from 14 days of in vitro culture. In particular, the combination GM + BC resulted to be more effective than GM + CS in the up‐regulation of key genes such as collagen type 2A1 (COLII), SOX‐9, and aggrecan). In addition, the scanning microscope analyses revealed the cellular adhesion on materials and production of extracellular vesicles. Immunofluorescence staining confirmed an increase of COLII in presence of both chondroitins. Finally, the outcomes suggest that BC entangled within cross‐linked GM matrix may represent a promising new biomaterial with potential applications in cartilage regeneration.
Collapse
Affiliation(s)
- Valentina Vassallo
- Department of Experimental Medicine, Section of Biotechnology, Medical Histology and Molecular Biology, University of Campania "Luigi Vanvitelli", Naples
| | - Anastasia Tsianaka
- Institute of Interfacial Process Engineering and Plasma Technology IGVP, University of Stuttgart, Stuttgart, Germany
| | - Nicola Alessio
- Department of Experimental Medicine, Section of Biotechnology, Medical Histology and Molecular Biology, University of Campania "Luigi Vanvitelli", Naples
| | - Jana Grübel
- Institute of Interfacial Process Engineering and Plasma Technology IGVP, University of Stuttgart, Stuttgart, Germany
| | - Marcella Cammarota
- Department of Experimental Medicine, Section of Biotechnology, Medical Histology and Molecular Biology, University of Campania "Luigi Vanvitelli", Naples
| | - Günter E M Tovar
- Institute of Interfacial Process Engineering and Plasma Technology IGVP, University of Stuttgart, Stuttgart, Germany.,Fraunhofer Institute of Interfacial Engineering and Biotechnology IGB, Stuttgart, Germany
| | - Alexander Southan
- Institute of Interfacial Process Engineering and Plasma Technology IGVP, University of Stuttgart, Stuttgart, Germany
| | - Chiara Schiraldi
- Department of Experimental Medicine, Section of Biotechnology, Medical Histology and Molecular Biology, University of Campania "Luigi Vanvitelli", Naples
| |
Collapse
|
|
30
|
Cui L, Saeed Y, Li H, Yang J. Regenerative medicine and traumatic brain injury: from stem cell to cell-free therapeutic strategies. Regen Med 2021; 17:37-53. [PMID: 34905963 DOI: 10.2217/rme-2021-0069] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Traumatic brain injury (TBI) is a serious health concern, yet there is a lack of standardized treatment to combat its long-lasting effects. The objective of the present study was to provide an overview of the limitation of conventional stem-cell therapy in the treatment of TBI and to discuss the application of novel acellular therapies and their advanced strategies to enhance the efficacy of stem cells derived therapies in the light of published study data. Moreover, we also discussed the factor to optimize the therapeutic efficiency of stem cell-derived acellular therapy by overcoming the challenges for its clinical translation. Hence, we concluded that acellular therapy possesses the potential to bring a breakthrough in the field of regenerative medicine to treat TBI.
Collapse
Affiliation(s)
- Lianxu Cui
- Department of Neurosurgery, The First People's Hospital of Foshan, 81 North Lingnan Road, Foshan, Guangdong, 528300, PR China
| | - Yasmeen Saeed
- Guangdong VitaLife Biotechnology Co., LTD, 61 Xiannan Road, Nanhai District, Foshan, Guangdong, 528200, PR China
| | - Haomin Li
- Department of Neurosurgery, The First People's Hospital of Foshan, 81 North Lingnan Road, Foshan, Guangdong, 528300, PR China
| | - Jingli Yang
- School of medicine, Foshan University, 18 Jiangwan Road, Foshan, Guangdong, 528000, PR China
| |
Collapse
|
|
31
|
Valatkaitė E, Baušytė R, Vitkevičienė A, Ramašauskaitė D, Navakauskienė R. Decidualization Potency and Epigenetic Changes in Human Endometrial Origin Stem Cells During Propagation. Front Cell Dev Biol 2021; 9:765265. [PMID: 34869358 PMCID: PMC8640123 DOI: 10.3389/fcell.2021.765265] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/18/2021] [Indexed: 01/10/2023] Open
Abstract
Human endometrium derived mesenchymal stem cells (hEndSCs) offer a great promise for regenerative medicine and reproductive system disorders treatment methods based on cell therapy due to their broad differentiation potential and highly efficient proliferation. In our study, we investigated the characteristics of hEndSCs that were isolated from two sources: endometrium and menstrual blood, which both contain endometrial origin stem cells. Changes in gene and protein expression levels during long-term cultivation and decidualization potential were examined in endometrial stem cells (EndSCs) and menstrual blood stem cells (MenSCs). The decidualization process was induced on early and late passages of hEndSCs using dibutyryl cyclic-AMP (db-cAMP) and medroxyprogesterone acetate (MPA) agents. We demonstrated that after long-term cultivation of hEndSCs the expression of typical mesenchymal stromal cell surface markers such as CD44, CD73, CD90, CD105 and perivascular marker CD146 remains at a similar level throughout long-term cultivation. Additionally, hematopoietic and endothelial markers CD34, CD45 were also tested, they were negative in all cases. Analyzed stem cells gene markers, such as OCT4, SOX2, NANOG, KLF4, showed similar expression in all passages of hEndSCs. RT-qPCR results demonstrated that the expression of cell cycle control associated genes - CDK2, CCNA2, CCNE2, p21, p53 and Rb, among all groups was very similar. Expression of genes associated with senescence (ATM, JUND, TOP2A, MYC) was maintained at a similar level throughout passaging. In addition, Western blot analysis was used to assess changes in proteins’ levels associated to epigenetics (EZH2, SUZ12, H3K27me3) and cell cycle control (cyclinE1, p53) during long-term cultivation. The levels of proteins associated with epigenetic changes were fluctuated slightly depending on the patient. Also, we demonstrated that in all induced hEndSCs the expression of decidualization markers Prolactin (PRL), IGFBP1 and WNT4 was upregulated. In conclusion, we demonstrated successful decidualization of stem cells derived from two reproductive system resources: endometrium and menstrual blood by using db-cAMP and MPA regardless of the length of the stem cell passaging. According these findings, we suppose that endometrium derived stem cells and menstrual blood derived stem cells could have a potency not only for endometrium tissue regeneration, but could also become a successful therapy for reproductive system disorders, including infertility or recurrent pregnancy loss.
Collapse
Affiliation(s)
- Elvina Valatkaitė
- Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Raminta Baušytė
- Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania.,Centre of Obstetrics and Gynaecology of the Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Aida Vitkevičienė
- Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Diana Ramašauskaitė
- Centre of Obstetrics and Gynaecology of the Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Rūta Navakauskienė
- Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| |
Collapse
|
|
32
|
Wang P, Wang S, Ji F, Zhang R. Muse Cells Have Higher Stress Tolerance than Adipose Stem Cells due to the Overexpression of the CCNA2 Gene. Stem Cells Dev 2021; 30:1056-1069. [PMID: 34486391 DOI: 10.1089/scd.2021.0088] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
This study aimed to investigate the stress tolerance mechanism of multilineage-differentiating stress enduring (Muse) cells and elucidate the means to improve the stress tolerance of mesenchymal stem cells. Cell viability, apoptosis, and senescence-related protein expression were detected under H2O2 stress by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium reduction assay, flow cytometry in combination with Annexin V-FITC/PI staining, and western blotting analysis, respectively. A significant increase in the CCNA2 gene level within Muse cells relative to adipose stem cells (ASCs) was observed. In the H2O2 stress environment in vitro, the survival rate of Muse cells remarkably increased compared with the survival rate of the ASCs. In addition, a reduced level of apoptosis and senescence-related protein expression of Muse cells relative to ASCs was documented. The miR-29b-3p-induced negative regulation of CCNA2 gene expression was confirmed by in vitro luciferase assay. A significant upregulation of CCNA2 gene expression in ASCs, transfected with antagomir-29b-3p, improved the survival rate of ASCs under H2O2 stress but dramatically reduced the apoptosis and expression of the senescence-related gene; agomir-29b-3p could partially reverse these effects. In conclusion, high expression of the CCNA2 gene is associated with an increased stress tolerance of Muse cells. Regulating the expression of CCNA2 by miR-29b-3p can alter the stress tolerance of ASCs.
Collapse
Affiliation(s)
- Peng Wang
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China.,Department of Intensive Care Unit, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Shengyi Wang
- The Dermal and Venereal Department, Xuzhou Central Hospital, Xuzhou, China.,The Dermal and Venereal Department, The Third Affiliated Hospital of Suzhou University, Changzhou, China
| | - Fuhai Ji
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ruzhi Zhang
- The Dermal and Venereal Department, The Third Affiliated Hospital of Suzhou University, Changzhou, China
| |
Collapse
|
|
33
|
Pluripotent stem cell-derived mesenchymal stromal cells improve cardiac function and vascularity after myocardial infarction. Cytotherapy 2021; 23:1074-1084. [PMID: 34588150 DOI: 10.1016/j.jcyt.2021.07.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 07/27/2021] [Accepted: 07/28/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells (MSCs) have been shown to improve cardiac function after injury and are the subject of ongoing clinical trials. In this study, the authors tested the cardiac regenerative potential of an induced pluripotent stem cell-derived MSC (iPSC-MSC) population (Cymerus MSCs) in a rat model of myocardial ischemia-reperfusion (I/R). Furthermore, the authors compared this efficacy with bone marrow-derived MSCs (BM-MSCs), which are the predominant cell type in clinical trials. METHODS Four days after myocardial I/R injury, rats were randomly assigned to (i) a Cymerus MSC group (n = 15), (ii) a BM-MSC group (n = 15) or (iii) a vehicle control group (n = 14). For cell-treated animals, a total of 5 × 106 cells were injected at three sites within the infarcted left ventricular (LV) wall. RESULTS One month after cell transplantation, Cymerus MSCs improved LV function (assessed by echocardiography) compared with vehicle and BM-MSCs. Interestingly, Cymerus MSCs enhanced angiogenesis without sustained engraftment or significant impact on infarct scar size. Suggesting safety, Cymerus MSCs had no effect on inducible tachycardia or the ventricular scar heterogeneity that provides a substrate for cardiac re-entrant circuits. CONCLUSIONS The authors here demonstrate that intra-myocardial administration of iPSC-MSCs (Cymerus MSCs) provide better therapeutic effects compared with conventional BM-MSCs in a rodent model of myocardial I/R. Because of its manufacturing scalability, iPSC-MSC therapy offers an exciting opportunity for an "off-the-shelf" stem cell therapy for cardiac repair.
Collapse
|
|
34
|
Mesenchymal Stem Cells in the Treatment of COVID-19, a Promising Future. Cells 2021; 10:cells10102588. [PMID: 34685567 PMCID: PMC8533906 DOI: 10.3390/cells10102588] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/11/2021] [Accepted: 09/17/2021] [Indexed: 12/20/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have a potent self-renewal capacity and can differentiate into multiple cell types. They also affect the ambient tissue by the paracrine secretion of numerous factors in vivo, including the induction of other stem cells’ differentiation. In vitro, the culture media supernatant is named secretome and contains soluble molecules and extracellular vesicles that retain potent biological function in tissue regeneration. MSCs are considered safe for human treatment; their use does not involve ethical issues, as embryonic stem cells do not require genetic manipulation as induced pluripotent stem cells, and after intravenous injection, they are mainly found in the lugs. Therefore, these cells are currently being tested in various preclinical and clinical trials for several diseases, including COVID-19. Several affected COVID-19 patients develop induced acute respiratory distress syndrome (ARDS) associated with an uncontrolled inflammatory response. This condition causes extensive damage to the lungs and may leave serious post-COVID-19 sequelae. As the disease may cause systemic alterations, such as thromboembolism and compromised renal and cardiac function, the intravenous injection of MSCs may be a therapeutic alternative against multiple pathological manifestations. In this work, we reviewed the literature about MSCs biology, focusing on their function in pulmonary regeneration and their use in COVID-19 treatment.
Collapse
|
|
35
|
Guo S, Bai Y, Li Y, Chen T. A Large Central Bronchopleural Fistula Closed by Bronchoscopic Administration of Recombinant Bovine Basic Fibroblast Growth Factor: A Case Report. Respiration 2021; 100:1000-1004. [PMID: 34515226 DOI: 10.1159/000514717] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 01/14/2021] [Indexed: 11/19/2022] Open
Abstract
A large central bronchopleural fistula (BPF) surrounded by mediastinal tissue was successfully closed by local administration of recombinant bovine basic fibroblast growth factor (rbFGF) using the bronchoscope. No complications were observed during and after this bronchoscopic treatment. This is the first report of the bronchoscopic treatment of a large central BPF by the local spray of rbFGF. The bronchoscopic treatment with rbFGF is a potentially cost-effective method for central BPF surrounded by mediastinal tissue.
Collapse
Affiliation(s)
- Shuliang Guo
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yang Bai
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yishi Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tao Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
36
|
Yan YY, Zhou WM, Wang YQ, Guo QR, Zhao FX, Zhu ZY, Xing YX, Zhang HY, Aljofan M, Jarrahi AM, Makabel B, Zhang JY. The Potential Role of Extracellular Vesicles in COVID-19 Treatment: Opportunity and Challenge. Front Mol Biosci 2021; 8:699929. [PMID: 34368228 PMCID: PMC8345113 DOI: 10.3389/fmolb.2021.699929] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 07/08/2021] [Indexed: 12/13/2022] Open
Abstract
SARS-CoV-2 infection has become an urgent public health concern worldwide, severely affecting our society and economy due to the long incubation time and high prevalence. People spare no effort on the rapid development of vaccine and treatment all over the world. Amongst the numerous ways of tackling this pandemic, some approaches using extracellular vesicles (EVs) are emerging. In this review, we summarize current prevalence and pathogenesis of COVID-19, involving the combination of SARS-CoV-2 and virus receptor ACE2, endothelial dysfunction and micro thrombosis, together with cytokine storm. We also discuss the ongoing EVs-based strategies for the treatment of COVID-19, including mesenchymal stem cell (MSC)-EVs, drug-EVs, vaccine-EVs, platelet-EVs, and others. This manuscript provides the foundation for the development of targeted drugs and vaccines for SARS-CoV-2 infections.
Collapse
Affiliation(s)
- Yan-yan Yan
- School of Medicine, Shanxi Datong University, Datong, China
| | - Wen-min Zhou
- Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yu-qing Wang
- Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Qiao-ru Guo
- Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- Xinjiang Institute of Materia Medica, Urumqi, China
| | - Fu-xi Zhao
- School of Medicine, Shanxi Datong University, Datong, China
| | - Zhuang-yan Zhu
- School of Medicine, Shanxi Datong University, Datong, China
| | - Yan-xia Xing
- School of Medicine, Shanxi Datong University, Datong, China
| | - Hai-yan Zhang
- School of Medicine, Shanxi Datong University, Datong, China
| | - Mohamad Aljofan
- Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan
| | | | | | - Jian-ye Zhang
- Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
|
37
|
Machhi J, Shahjin F, Das S, Patel M, Abdelmoaty MM, Cohen JD, Singh PA, Baldi A, Bajwa N, Kumar R, Vora LK, Patel TA, Oleynikov MD, Soni D, Yeapuri P, Mukadam I, Chakraborty R, Saksena CG, Herskovitz J, Hasan M, Oupicky D, Das S, Donnelly RF, Hettie KS, Chang L, Gendelman HE, Kevadiya BD. A Role for Extracellular Vesicles in SARS-CoV-2 Therapeutics and Prevention. J Neuroimmune Pharmacol 2021; 16:270-288. [PMID: 33544324 PMCID: PMC7862527 DOI: 10.1007/s11481-020-09981-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 12/28/2020] [Indexed: 12/13/2022]
Abstract
Extracellular vesicles (EVs) are the common designation for ectosomes, microparticles and microvesicles serving dominant roles in intercellular communication. Both viable and dying cells release EVs to the extracellular environment for transfer of cell, immune and infectious materials. Defined morphologically as lipid bi-layered structures EVs show molecular, biochemical, distribution, and entry mechanisms similar to viruses within cells and tissues. In recent years their functional capacities have been harnessed to deliver biomolecules and drugs and immunological agents to specific cells and organs of interest or disease. Interest in EVs as putative vaccines or drug delivery vehicles are substantial. The vesicles have properties of receptors nanoassembly on their surface. EVs can interact with specific immunocytes that include antigen presenting cells (dendritic cells and other mononuclear phagocytes) to elicit immune responses or affect tissue and cellular homeostasis or disease. Due to potential advantages like biocompatibility, biodegradation and efficient immune activation, EVs have gained attraction for the development of treatment or a vaccine system against the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infection. In this review efforts to use EVs to contain SARS CoV-2 and affect the current viral pandemic are discussed. An emphasis is made on mesenchymal stem cell derived EVs' as a vaccine candidate delivery system.
Collapse
Affiliation(s)
- Jatin Machhi
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Farah Shahjin
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Srijanee Das
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Milankumar Patel
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Mai Mohamed Abdelmoaty
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Giza, Egypt
| | - Jacob D Cohen
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Preet Amol Singh
- Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, PB, India
| | - Ashish Baldi
- Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, PB, India
| | - Neha Bajwa
- Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, PB, India
| | - Raj Kumar
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Lalit K Vora
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Tapan A Patel
- Department of Biological Sciences, P. D. Patel Institute of Applied Sciences (PDPIAS), Charotar University of Science and Technology (CHARUSAT), Changa, Anand, Gujarat, 388421, India
| | - Maxim D Oleynikov
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Dhruvkumar Soni
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Pravin Yeapuri
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Insiya Mukadam
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Rajashree Chakraborty
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Caroline G Saksena
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Jonathan Herskovitz
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mahmudul Hasan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - David Oupicky
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Suvarthi Das
- Department of Medicine, Stanford Medical School, Stanford University, 94304, Palo Alto, CA, USA
| | - Ryan F Donnelly
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Kenneth S Hettie
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Department of Otolaryngology - Head & Neck Surgery, Stanford University, 94304, Palo Alto, CA, USA
| | - Linda Chang
- Departments of Diagnostic Radiology & Nuclear Medicine, and Neurology, School of Medicine, University of Maryland, 21201, Baltimore, MD, USA
| | - Howard E Gendelman
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.
- Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda, PB, India.
| | - Bhavesh D Kevadiya
- Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| |
Collapse
|
|
38
|
Sandonà M, Di Pietro L, Esposito F, Ventura A, Silini AR, Parolini O, Saccone V. Mesenchymal Stromal Cells and Their Secretome: New Therapeutic Perspectives for Skeletal Muscle Regeneration. Front Bioeng Biotechnol 2021; 9:652970. [PMID: 34095095 PMCID: PMC8172230 DOI: 10.3389/fbioe.2021.652970] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/01/2021] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are multipotent cells found in different tissues: bone marrow, peripheral blood, adipose tissues, skeletal muscle, perinatal tissues, and dental pulp. MSCs are able to self-renew and to differentiate into multiple lineages, and they have been extensively used for cell therapy mostly owing to their anti-fibrotic and immunoregulatory properties that have been suggested to be at the basis for their regenerative capability. MSCs exert their effects by releasing a variety of biologically active molecules such as growth factors, chemokines, and cytokines, either as soluble proteins or enclosed in extracellular vesicles (EVs). Analyses of MSC-derived secretome and in particular studies on EVs are attracting great attention from a medical point of view due to their ability to mimic all the therapeutic effects produced by the MSCs (i.e., endogenous tissue repair and regulation of the immune system). MSC-EVs could be advantageous compared with the parental cells because of their specific cargo containing mRNAs, miRNAs, and proteins that can be biologically transferred to recipient cells. MSC-EV storage, transfer, and production are easier; and their administration is also safer than MSC therapy. The skeletal muscle is a very adaptive tissue, but its regenerative potential is altered during acute and chronic conditions. Recent works demonstrate that both MSCs and their secretome are able to help myofiber regeneration enhancing myogenesis and, interestingly, can be manipulated as a novel strategy for therapeutic interventions in muscular diseases like muscular dystrophies or atrophy. In particular, MSC-EVs represent promising candidates for cell free-based muscle regeneration. In this review, we aim to give a complete picture of the therapeutic properties and advantages of MSCs and their products (MSC-derived EVs and secreted factors) relevant for skeletal muscle regeneration in main muscular diseases.
Collapse
Affiliation(s)
- Martina Sandonà
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Rome, Italy
| | - Lorena Di Pietro
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Federica Esposito
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Rome, Italy
| | - Alessia Ventura
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Rome, Italy
| | - Antonietta Rosa Silini
- Centro di Ricerca "E. Menni", Fondazione Poliambulanza - Istituto Ospedaliero, Brescia, Italy
| | - Ornella Parolini
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy.,Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, Italy
| | - Valentina Saccone
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Rome, Italy.,Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
| |
Collapse
|
|
39
|
Progress of Interference of Traditional Chinese Medicine on Cirrhosis Treated with Bone Marrow Mesenchymal Stem Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5569274. [PMID: 34055009 PMCID: PMC8131131 DOI: 10.1155/2021/5569274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/18/2021] [Accepted: 05/04/2021] [Indexed: 11/18/2022]
Abstract
Transplantation of bone marrow mesenchymal stem cells has attracted more and more attention as a regenerative therapy for the treatment of liver diseases. A large number of studies have shown that this kind of cells can inhibit the activation of hepatic stellate cells and regulate tissue homeostasis and immune system via a variety of ways. Meanwhile, bone marrow mesenchymal stem cells can inhibit apoptosis of hepatocyte, improve liver function, and reduce inflammation through multiple pathways. These cells have a broad prospect in the treatment of liver cirrhosis. At present, there are many studies on the specific mechanism of bone marrow mesenchymal stem cells transplantation in the treatment of liver cirrhosis. This paper reviews the pathogenesis of liver cirrhosis and the mechanism of bone marrow mesenchymal stem cells transplantation in the treatment of liver cirrhosis, discusses the effectiveness of traditional Chinese medicine method in enhancing the efficacy of bone marrow mesenchymal stem cells transplantation, and looks forward to its application prospect in the future.
Collapse
|
|
40
|
Denu RA, Hematti P. Optimization of oxidative stress for mesenchymal stromal/stem cell engraftment, function and longevity. Free Radic Biol Med 2021; 167:193-200. [PMID: 33677063 DOI: 10.1016/j.freeradbiomed.2021.02.042] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/24/2021] [Accepted: 02/26/2021] [Indexed: 12/18/2022]
Abstract
Mesenchymal stromal/stem cells (MSCs) are multipotent cells that possess great potential as a cellular therapeutic based on their ability to differentiate to different lineages and to modulate immune responses. However, their potential is limited by their low tissue abundance, and thus the need for robust ex vivo expansion prior to their application. This creates its own issues, namely replicative senescence, which could lead to reduced MSC functionality and negatively impact their engraftment. Ex vivo expansion and MSC aging are associated with greater oxidative stress. Therefore, there is great need to identify strategies to reduce oxidative stress in MSCs. This review summarizes the achievements made to date in addressing oxidative stress in MSCs and speculates about interesting avenues of future investigation to solve this critical problem.
Collapse
Affiliation(s)
- Ryan A Denu
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
| | - Peiman Hematti
- Departments of Medicine, Pediatrics, Surgery and Biomedical Engineering, Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| |
Collapse
|
|
41
|
Alessio N, Stellavato A, Aprile D, Cimini D, Vassallo V, Di Bernardo G, Galderisi U, Schiraldi C. Timely Supplementation of Hydrogels Containing Sulfated or Unsulfated Chondroitin and Hyaluronic Acid Affects Mesenchymal Stromal Cells Commitment Toward Chondrogenic Differentiation. Front Cell Dev Biol 2021; 9:641529. [PMID: 33912558 PMCID: PMC8072340 DOI: 10.3389/fcell.2021.641529] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 03/22/2021] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are currently used for cartilage cell therapy because of their well proven capacity to differentiate in chondrocytes. The advantage of MSC-based therapy is the possibility of producing a high number of chondrocytes for implants. The transplant procedure, however, has some limitations, since MSCs may produce non-functional chondrocytes. This limit has been challenged by cultivating MSC in media with hydrogels containing hyaluronic acid (HA), extractive chondroitin sulfate (CS), or bio-fermentative unsulphated chondroitin (BC) alone or in combination. Nevertheless, a clear study of the effect of glycosaminoglycans (GAGs) on chondrocyte differentiation is still lacking, especially for the newly obtained unsulfated chondroitin of biotechnological origin. Are these GAGs playing a role in the commitment of stem cells to chondrocyte progenitors and in the differentiation of progenitors to mature chondrocytes? Alternatively, do they have a role only in one of these biological processes? We evaluated the role of HA, CS, and - above all - BC in cell commitment and chondrocyte differentiation of MSCs by supplementing these GAGs in different phases of in vitro cultivation. Our data provided evidence that a combination of HA and CS or of HA and BC supplemented during the terminal in vitro differentiation and not during cell commitment of MSCs improved chondrocytes differentiation without the presence of fibrosis (reduced expression of Type I collagen). This result suggests that a careful evaluation of extracellular cues for chondrocyte differentiation is fundamental to obtaining a proper maturation process.
Collapse
Affiliation(s)
- Nicola Alessio
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
| | - Antonietta Stellavato
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
| | - Domenico Aprile
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
| | - Donatella Cimini
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
| | - Valentina Vassallo
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
| | - Giovanni Di Bernardo
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, United States
| | - Umberto Galderisi
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, United States
- Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey
| | - Chiara Schiraldi
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
| |
Collapse
|
|
42
|
Lanzillotti C, De Mattei M, Mazziotta C, Taraballi F, Rotondo JC, Tognon M, Martini F. Long Non-coding RNAs and MicroRNAs Interplay in Osteogenic Differentiation of Mesenchymal Stem Cells. Front Cell Dev Biol 2021; 9:646032. [PMID: 33898434 PMCID: PMC8063120 DOI: 10.3389/fcell.2021.646032] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 03/11/2021] [Indexed: 12/23/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) have gained great attention as epigenetic regulators of gene expression in many tissues. Increasing evidence indicates that lncRNAs, together with microRNAs (miRNAs), play a pivotal role in osteogenesis. While miRNA action mechanism relies mainly on miRNA-mRNA interaction, resulting in suppressed expression, lncRNAs affect mRNA functionality through different activities, including interaction with miRNAs. Recent advances in RNA sequencing technology have improved knowledge into the molecular pathways regulated by the interaction of lncRNAs and miRNAs. This review reports on the recent knowledge of lncRNAs and miRNAs roles as key regulators of osteogenic differentiation. Specifically, we described herein the recent discoveries on lncRNA-miRNA crosstalk during the osteogenic differentiation of mesenchymal stem cells (MSCs) derived from bone marrow (BM), as well as from different other anatomical regions. The deep understanding of the connection between miRNAs and lncRNAs during the osteogenic differentiation will strongly improve knowledge into the molecular mechanisms of bone growth and development, ultimately leading to discover innovative diagnostic and therapeutic tools for osteogenic disorders and bone diseases.
Collapse
Affiliation(s)
- Carmen Lanzillotti
- Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy
| | - Monica De Mattei
- Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy
| | - Chiara Mazziotta
- Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy
| | - Francesca Taraballi
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, United States
- Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX, United States
| | - John Charles Rotondo
- Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy
| | - Mauro Tognon
- Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy
| | - Fernanda Martini
- Section of Experimental Medicine, Department of Medical Sciences, School of Medicine, University of Ferrara, Ferrara, Italy
- Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy
| |
Collapse
|
|
43
|
Aprile D, Alessio N, Demirsoy IH, Squillaro T, Peluso G, Di Bernardo G, Galderisi U. MUSE Stem Cells Can Be Isolated from Stromal Compartment of Mouse Bone Marrow, Adipose Tissue, and Ear Connective Tissue: A Comparative Study of Their In Vitro Properties. Cells 2021; 10:761. [PMID: 33808472 PMCID: PMC8065981 DOI: 10.3390/cells10040761] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/25/2021] [Accepted: 03/29/2021] [Indexed: 01/10/2023] Open
Abstract
The cells present in the stromal compartment of many tissues are a heterogeneous population containing stem cells, progenitor cells, fibroblasts, and other stromal cells. A SSEA3(+) cell subpopulation isolated from human stromal compartments showed stem cell properties. These cells, known as multilineage-differentiating stress-enduring (MUSE) cells, are capable of resisting stress and possess an excellent ability to repair DNA damage. We isolated MUSE cells from different mouse stromal compartments, such as those present in bone marrow, subcutaneous white adipose tissue, and ear connective tissue. These cells showed overlapping in vitro biological properties. The mouse MUSE cells were positive for stemness markers such as SOX2, OCT3/4, and NANOG. They also expressed TERT, the catalytic telomerase subunit. The mouse MUSE cells showed spontaneous commitment to differentiation in meso/ecto/endodermal derivatives. The demonstration that multilineage stem cells can be isolated from an animal model, such as the mouse, could offer a valid alternative to the use of other stem cells for disease studies and envisage of cellular therapies.
Collapse
Affiliation(s)
- Domenico Aprile
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (N.A.); (I.H.D.); (T.S.); (G.D.B.)
| | - Nicola Alessio
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (N.A.); (I.H.D.); (T.S.); (G.D.B.)
| | - Ibrahim H. Demirsoy
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (N.A.); (I.H.D.); (T.S.); (G.D.B.)
| | - Tiziana Squillaro
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (N.A.); (I.H.D.); (T.S.); (G.D.B.)
| | | | - Giovanni Di Bernardo
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (N.A.); (I.H.D.); (T.S.); (G.D.B.)
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA 19122, USA
| | - Umberto Galderisi
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (N.A.); (I.H.D.); (T.S.); (G.D.B.)
- Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA 19122, USA
- Genome and Stem Cell Center (GENKOK), Erciyes University, 38280 Kayseri, Turkey
| |
Collapse
|
|
44
|
Niu S, Zhang Y. Applications and therapeutic mechanisms of action of mesenchymal stem cells in radiation-induced lung injury. Stem Cell Res Ther 2021; 12:212. [PMID: 33766127 PMCID: PMC7993004 DOI: 10.1186/s13287-021-02279-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 03/10/2021] [Indexed: 12/28/2022] Open
Abstract
Radiation-induced lung injury (RILI) is one of the most common complications associated with radiotherapy, characterized by early-stage radiation pneumonia and subsequent radiation pulmonary fibrosis. However, effective therapeutic strategies for RILI are currently lacking. Recently, an increasing number of studies reported that mesenchymal stem cells (MSCs) can enhance the regeneration of damaged tissue, modulate the inflammatory response, reduce the levels of fibrotic cytokines and reactive oxygen species, and inhibit epithelial-mesenchymal transformation. Interestingly, MSCs can also exert immunosuppressive effects, which highlights a new potential therapeutic activity of MSCs for managing RILI. Here, we reviewed the potential applications and therapeutic mechanisms of action of MSCs in RILI, which will represent a good compendium of information for researchers in this field.
Collapse
Affiliation(s)
- Shiying Niu
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China.,Department of Experimental Pathology, Institute of Basic Medicine, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, 250062, Shandong, China
| | - Yueying Zhang
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China. .,Department of Experimental Pathology, Institute of Basic Medicine, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, 250062, Shandong, China.
| |
Collapse
|
|
45
|
Alessio N, Aprile D, Cappabianca S, Peluso G, Di Bernardo G, Galderisi U. Different Stages of Quiescence, Senescence, and Cell Stress Identified by Molecular Algorithm Based on the Expression of Ki67, RPS6, and Beta-Galactosidase Activity. Int J Mol Sci 2021; 22:3102. [PMID: 33803589 PMCID: PMC8002939 DOI: 10.3390/ijms22063102] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/16/2021] [Accepted: 03/12/2021] [Indexed: 12/11/2022] Open
Abstract
During their life span, cells have two possible states: a non-cycling, quiescent state (G0) and a cycling, activated state. Cells may enter a reversible G0 state of quiescence or, alternatively, they may undergo an irreversible G0 state. The latter may be a physiological differentiation or, following a stress event, a senescent status. Discrimination among the several G0 states represents a significant investigation, since quiescence, differentiation, and senescence are progressive phenomena with intermediate transitional stages. We used the expression of Ki67, RPS6, and beta-galactosidase to identify healthy cells that progressively enter and leave quiescence through G0-entry, G0 and G0-alert states. We then evaluated how cells may enter senescence following a genotoxic stressful event. We identified an initial stress stage with the expression of beta-galactosidase and Ki67 proliferation marker. Cells may recover from stress events or become senescent passing through early and late senescence states. Discrimination between quiescence and senescence was based on the expression of RPS6, a marker of active protein synthesis that is present in senescent cells but absent in quiescent cells. Even taking into account that fixed G0 states do not exist, our molecular algorithm may represent a method for identifying turning points of G0 transitional states that continuously change.
Collapse
Affiliation(s)
- Nicola Alessio
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (N.A.); (D.A.); (G.D.B.)
| | - Domenico Aprile
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (N.A.); (D.A.); (G.D.B.)
| | - Salvatore Cappabianca
- Department of Precision Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy;
| | | | - Giovanni Di Bernardo
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (N.A.); (D.A.); (G.D.B.)
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
| | - Umberto Galderisi
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (N.A.); (D.A.); (G.D.B.)
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
- Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri 38280, Turkey
| |
Collapse
|
|
46
|
Acar MB, Aprile D, Ayaz-Guner S, Guner H, Tez C, Di Bernardo G, Peluso G, Ozcan S, Galderisi U. Why Do Muse Stem Cells Present an Enduring Stress Capacity? Hints from a Comparative Proteome Analysis. Int J Mol Sci 2021; 22:2064. [PMID: 33669748 PMCID: PMC7922977 DOI: 10.3390/ijms22042064] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/12/2021] [Accepted: 02/16/2021] [Indexed: 12/21/2022] Open
Abstract
Muse cells are adult stem cells that are present in the stroma of several organs and possess an enduring capacity to cope with endogenous and exogenous genotoxic stress. In cell therapy, the peculiar biological properties of Muse cells render them a possible natural alternative to mesenchymal stromal cells (MSCs) or to in vitro-generated pluripotent stem cells (iPSCs). Indeed, some studies have proved that Muse cells can survive in adverse microenvironments, such as those present in damaged/injured tissues. We performed an evaluation of Muse cells' proteome under basic conditions and followed oxidative stress treatment in order to identify ontologies, pathways, and networks that can be related to their enduring stress capacity. We executed the same analysis on iPSCs and MSCs, as a comparison. The Muse cells are enriched in several ontologies and pathways, such as endosomal vacuolar trafficking related to stress response, ubiquitin and proteasome degradation, and reactive oxygen scavenging. In Muse cells, the protein-protein interacting network has two key nodes with a high connectivity degree and betweenness: NFKB and CRKL. The protein NFKB is an almost-ubiquitous transcription factor related to many biological processes and can also have a role in protecting cells from apoptosis during exposure to a variety of stressors. CRKL is an adaptor protein and constitutes an integral part of the stress-activated protein kinase (SAPK) pathway. The identified pathways and networks are all involved in the quality control of cell components and may explain the stress resistance of Muse cells.
Collapse
Affiliation(s)
- Mustafa B. Acar
- Graduate School of Natural and Applied Sciences, Erciyes University, Kayseri 38039, Turkey;
- Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri 38039, Turkey;
| | - Domenico Aprile
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (G.D.B.)
| | - Serife Ayaz-Guner
- Department of Molecular Biology and Genetics, Faculty of Life and Natural Science, Abdullah Gul University, Kayseri 38090, Turkey; (S.A.-G.); (H.G.)
| | - Huseyin Guner
- Department of Molecular Biology and Genetics, Faculty of Life and Natural Science, Abdullah Gul University, Kayseri 38090, Turkey; (S.A.-G.); (H.G.)
| | - Coskun Tez
- Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri 38039, Turkey;
- Department of Biology, Faculty of Sciences, Erciyes University, Kayseri 38039, Turkey
| | - Giovanni Di Bernardo
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (G.D.B.)
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
| | | | - Servet Ozcan
- Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri 38039, Turkey;
- Department of Biology, Faculty of Sciences, Erciyes University, Kayseri 38039, Turkey
| | - Umberto Galderisi
- Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri 38039, Turkey;
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy; (D.A.); (G.D.B.)
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
| |
Collapse
|
|
47
|
Rubanenko M, Manturova N, Ustiugov A, Porshina O, Petunina V, Zorin V, Zorina A, Palinkash A. Epidermolysis bullosa. Possible methods of treatment. KLINICHESKAYA DERMATOLOGIYA I VENEROLOGIYA 2021; 20:22. [DOI: 10.17116/klinderma20212004122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
|
|
48
|
Wang Y, Shan SK, Guo B, Li F, Zheng MH, Lei LM, Xu QS, Ullah MHE, Xu F, Lin X, Yuan LQ. The Multi-Therapeutic Role of MSCs in Diabetic Nephropathy. Front Endocrinol (Lausanne) 2021; 12:671566. [PMID: 34163437 PMCID: PMC8216044 DOI: 10.3389/fendo.2021.671566] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 05/20/2021] [Indexed: 12/16/2022] Open
Abstract
Diabetic nephropathy (DN) is one of the most common diabetes mellitus (DM) microvascular complications, which always ends with end-stage renal disease (ESRD). Up to now, as the treatment of DN in clinic is still complicated, ESRD has become the main cause of death in diabetic patients. Mesenchymal stem cells (MSCs), with multi-differentiation potential and paracrine function, have attracted considerable attention in cell therapy recently. Increasing studies concerning the mechanisms and therapeutic effect of MSCs in DN emerged. This review summarizes several mechanisms of MSCs, especially MSCs derived exosomes in DN therapy, including hyperglycemia regulation, anti-inflammatory, anti-fibrosis, pro-angiogenesis, and renal function protection. We also emphasize the limitation of MSCs application in the clinic and the enhanced therapeutic role of pre-treated MSCs in the DN therapy. This review provides balanced and impartial views for MSC therapy as a promising strategy in diabetic kidney disease amelioration.
Collapse
Affiliation(s)
- Yi Wang
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Su-Kang Shan
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Bei Guo
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Fuxingzi Li
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Ming-Hui Zheng
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Li-Min Lei
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiu-Shuang Xu
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Muhammad Hasnain Ehsan Ullah
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Feng Xu
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiao Lin
- Department of Radiology, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Ling-Qing Yuan
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Ling-Qing Yuan,
| |
Collapse
|
|
49
|
Acar MB, Ayaz-Güner Ş, Di Bernardo G, Güner H, Murat A, Peluso G, Özcan S, Galderisi U. Obesity induced by high-fat diet is associated with critical changes in biological and molecular functions of mesenchymal stromal cells present in visceral adipose tissue. Aging (Albany NY) 2020; 12:24894-24913. [PMID: 33361524 PMCID: PMC7803587 DOI: 10.18632/aging.202423] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 11/27/2020] [Indexed: 12/27/2022]
Abstract
The mesenchymal stromal cells (MSCs) residing within the stromal component of visceral adipose tissue appear to be greatly affected by obesity, with impairment of their functions and presence of senescence. To gain further insight into these phenomena, we analyzed the changes in total proteome content and secretome of mouse MSCs after a high-fat diet (HFD) treatment compared to a normal diet (ND). In healthy conditions, MSCs are endowed with functions mainly devoted to vesicle trafficking. These cells have an immunoregulatory role, affecting leukocyte activation and migration, acute inflammation phase response, chemokine signaling, and platelet activities. They also present a robust response to stress. We identified four signaling pathways (TGF-β, VEGFR2, HMGB1, and Leptin) that appear to govern the cells' functions. In the obese mice, MSCs showed a change in their functions. The immunoregulation shifted toward pro-inflammatory tasks with the activation of interleukin-1 pathway and of Granzyme A signaling. Moreover, the methionine degradation pathway and the processing of capped intronless pre-mRNAs may be related to the inflammation process. The signaling pathways we identified in ND MSCs were replaced by MET, WNT, and FGFR2 signal transduction, which may play a role in promoting inflammation, cancer, and aging.
Collapse
Affiliation(s)
- Mustafa Burak Acar
- Genome and Stem Cell Center (GENKÖK) Erciyes University, Kayseri, Turkey
| | - Şerife Ayaz-Güner
- Department of Molecular Biology and Genetics, Faculty of Life and Natural Science, Abdullah Gül University, Kayseri, Turkey
| | - Giovanni Di Bernardo
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
| | - Hüseyin Güner
- Department of Molecular Biology and Genetics, Faculty of Life and Natural Science, Abdullah Gül University, Kayseri, Turkey
| | - Ayşegül Murat
- Genome and Stem Cell Center (GENKÖK) Erciyes University, Kayseri, Turkey
| | | | - Servet Özcan
- Genome and Stem Cell Center (GENKÖK) Erciyes University, Kayseri, Turkey
- Department of Biology, Faculty of Science, Erciyes University, Kayseri, Turkey
| | - Umberto Galderisi
- Genome and Stem Cell Center (GENKÖK) Erciyes University, Kayseri, Turkey
- Department of Experimental Medicine, Luigi Vanvitelli Campania University, Naples, Italy
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA
| |
Collapse
|
|
50
|
Liu J, Qiu X, Lv Y, Zheng C, Dong Y, Dou G, Zhu B, Liu A, Wang W, Zhou J, Liu S, Liu S, Gao B, Jin Y. Apoptotic bodies derived from mesenchymal stem cells promote cutaneous wound healing via regulating the functions of macrophages. Stem Cell Res Ther 2020; 11:507. [PMID: 33246491 PMCID: PMC7694913 DOI: 10.1186/s13287-020-02014-w] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 11/03/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND As the major interface between the body and the external environment, the skin is liable to various injuries. Skin injuries often lead to severe disability, and the exploration of promising therapeutic strategies is of great importance. Exogenous mesenchymal stem cell (MSC)-based therapy is a potential strategy due to the apparent therapeutic effects, while the underlying mechanism is still elusive. Interestingly, we observed the extensive apoptosis of exogenous bone marrow mesenchymal stem cells (BMMSCs) in a short time after transplantation in mouse skin wound healing models. Considering the roles of extracellular vesicles (EVs) in intercellular communication, we hypothesized that the numerous apoptotic bodies (ABs) released during apoptosis may partially contribute to the therapeutic effects. METHODS ABs derived from MSCs were extracted, characterized, and applied in mouse skin wound healing models, and the therapeutic effects were evaluated. Then, the target cells of ABs were explored, and the effects of ABs on macrophages were investigated in vitro. RESULTS We found ABs derived from MSCs promoted cutaneous wound healing via triggering the polarization of macrophages towards M2 phenotype. In addition, the functional converted macrophages further enhanced the migration and proliferation abilities of fibroblasts, which together facilitated the wound healing process. CONCLUSIONS Collectively, our study demonstrated that transplanted MSCs promoted cutaneous wound healing partially through releasing apoptotic bodies which could convert the macrophages towards an anti-inflammatory phenotype that plays a crucial role in the tissue repair process.
Collapse
Affiliation(s)
- Jin Liu
- State Key Laboratory of Military Stomatology& National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.,State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Xinyu Qiu
- State Key Laboratory of Military Stomatology& National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yajie Lv
- State Key Laboratory of Military Stomatology& National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.,Department of Dermatology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China
| | - Chenxi Zheng
- State Key Laboratory of Military Stomatology& National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yan Dong
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Geng Dou
- State Key Laboratory of Military Stomatology& National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Bin Zhu
- State Key Laboratory of Military Stomatology& National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.,Department of Stomatology, General Hospital of Tibet Military Region, Lhasa, 850007, Tibet, China
| | - Anqi Liu
- State Key Laboratory of Military Stomatology& National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Wei Wang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Department of Operative Dentistry and Endodontics, Fourth Military Medical University, Xi'an, China
| | - Jun Zhou
- State Key Laboratory of Military Stomatology& National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Siying Liu
- State Key Laboratory of Military Stomatology& National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Shiyu Liu
- State Key Laboratory of Military Stomatology& National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Bo Gao
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Yan Jin
- State Key Laboratory of Military Stomatology& National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| |
Collapse
|