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Afrose D, Alfonso-Sánchez S, McClements L. Targeting oxidative stress in preeclampsia. Hypertens Pregnancy 2025; 44:2445556. [PMID: 39726411 DOI: 10.1080/10641955.2024.2445556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 12/16/2024] [Indexed: 12/28/2024]
Abstract
Preeclampsia is a complex condition characterized by elevated blood pressure and organ damage involving kidneys or liver, resulting in significant morbidity and mortality for both the mother and the fetus. Increasing evidence suggests that oxidative stress, often caused by mitochondrial dysfunction within fetal trophoblast cells may play a major role in the development and progression of preeclampsia. Oxidative stress occurs as a result of an imbalance between the production of reactive oxygen species (ROS) and the capacity of antioxidant defenses, which can lead to placental cellular damage and endothelial cell dysfunction. Targeting oxidative stress appears to be a promising therapeutic approach that has the potential to improve both short- and long-term maternal and fetal outcomes, thus reducing the global burden of preeclampsia. The purpose of this review is to provide a comprehensive account of the mechanisms of oxidative stress in preeclampsia. Furthermore, it also examines potential interventions for reducing oxidative stress in preeclampsia, including natural antioxidant supplements, lifestyle modifications, mitochondrial targeting antioxidants, and pharmacological agents.A better understanding of the mechanism of action of proposed therapeutic strategies targeting oxidative stress is essential for the identification of companion biomarkers and personalized medicine approaches for the development of effective treatments of preeclampsia.
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Affiliation(s)
- Dinara Afrose
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
| | - Sofía Alfonso-Sánchez
- School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, Sydney, NSW, Australia
| | - Lana McClements
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
- Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
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2
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Ababneh NA, Aldiqs R, Nashwan S, Ismail MA, Barham R, Al Hadidi S, Alrefae A, Alhallaq FK, Abu-Humaidan AH, Saleh T, Awidi A. Distinct anticancer properties of exosomes from induced mesenchymal stem cells vs. bone marrow-derived stem cells in MCF7 and A549 models. Biomed Rep 2025; 23:116. [PMID: 40420975 PMCID: PMC12105100 DOI: 10.3892/br.2025.1994] [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: 10/23/2024] [Accepted: 04/15/2025] [Indexed: 05/28/2025] Open
Abstract
Mesenchymal stem cells (MSCs) have significant potential in regenerative medicine due to their multipotency, however, they face clinical challenges such as limited expansion and heterogeneity. Induced pluripotent stem cell-derived MSCs (iMSCs) are promising alternatives. The present study compared the effects of exosomes from bone marrow stromal MSCs (BMSCs) and iMSCs on A549 and MCF7 cancer cells to explore the unique properties of iMSCs. Proliferation assays revealed that both exosome types inhibited MCF7 and A549 cell proliferation at 24 h (P≤0.0001 for both) compared with the control, with BMSC-exosomes (Exos) exerting a more significant effect on MCF7 cells (P≤0.01). After 48 h, the significant effects of the BMSC-Exos were no longer observed on either cell line, whereas the iMSC-Exos continued to suppress A549 cell proliferation (P≤0.001 compared with the control; P≤0.01 compared with BMSC-Exos), indicating a longer-lasting effect. An investigation of senescence-associated β-galactosidase (SA-βGal) activity revealed no significant effect on senescence induction in MCF7 cells treated with either type of exosomes. By contrast, compared with the control treatment, the treatment of A549 cells with exosomes resulted in a significant increase in the number of senescent cells (P≤0.0001). While the apoptosis assay performed by flow cytometry revealed no significant effect on apoptosis, this increase in senescence aligned with the decreased proliferation observed in A549 cells, indicating that the antitumor effect of the exosomes on A549 cells was mediated partially through the induction of senescence. Wound healing assays revealed that BMSC-Exos significantly increased the migration of MCF7 cells at 20 h (P≤0.01). However, this effect was reversed at 47 h (P≤0.05), indicating a time-dependent effect of BMSC-Exos. In A549 cells, no significant difference in migration was observed after treatment with either exosome preparation. These findings highlight the distinct effects of iMSC- and BMSC-derived exosomes on cancer cells, emphasizing the need for further investigations into their therapeutic potential and underlying mechanisms.
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Affiliation(s)
- Nidaa A. Ababneh
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Razan Aldiqs
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Sura Nashwan
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | | | - Raghda Barham
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Sabal Al Hadidi
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Aya Alrefae
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | | | - Anas Ha Abu-Humaidan
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Tareq Saleh
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa 13133, Jordan
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Arabian Gulf University, Manama 26671, Bahrain
| | - Abdalla Awidi
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
- Hemostasis and Thrombosis Laboratory, School of Medicine, The University of Jordan, Amman 11942, Jordan
- Department of Hematology and Oncology, Jordan University Hospital, Amman 11942, Jordan
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3
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Lu W, Allickson J. Mesenchymal stromal cell therapy: Progress to date and future outlook. Mol Ther 2025; 33:2679-2688. [PMID: 39916329 DOI: 10.1016/j.ymthe.2025.02.003] [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: 11/07/2024] [Revised: 01/16/2025] [Accepted: 02/03/2025] [Indexed: 02/28/2025] Open
Abstract
In clinical trials, mesenchymal stromal/stem cells (MSCs) have consistently demonstrated safety. However, demonstration of efficacy has been inconsistent and many MSC trials have failed to meet their efficacy endpoint. This disappointing reality is reflected by the limited number MSC therapies approved by regulatory agencies, despite the large number of MSC trials registered on clinicaltrials.gov. Notably, there has been a recent approval of an MSC therapy for pediatric graft-vs.-host disease in the United States, marking the first MSC therapy approved by the U.S. Food and Drug Administration. This review provides a background of the history and potential therapeutic value of MSCs, an overview of MSC products with regulatory approval, and a summary of registered MSC trials. It concludes with a discussion on current and ongoing challenges and questions surrounding MSC therapy that remains to be resolved before becoming available for routine clinical use outside of clinical trials.
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Affiliation(s)
- Wen Lu
- Department of Laboratory Medicine and Pathology, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN, USA.
| | - Julie Allickson
- Department of Laboratory Medicine and Pathology, Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN, USA
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Seth G, Singh S, Sharma G, Suvedi D, Kumar D, Nagraik R, Sharma A. Harnessing the power of stem cell-derived exosomes: a rejuvenating therapeutic for skin and regenerative medicine. 3 Biotech 2025; 15:184. [PMID: 40417660 PMCID: PMC12102458 DOI: 10.1007/s13205-025-04345-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 05/04/2025] [Indexed: 05/27/2025] Open
Abstract
Exosomes are small extracellular vesicles produced by most cell types and contain proteins, lipids, and nucleic acids (non-coding RNAs, mRNA, and DNA) that can be released by donor cells to influence the function of recipient cells. Skin photoaging is the premature aging of skin structures caused by prolonged exposure to ultraviolet (UV), as demonstrated by depigmentation, roughness, rhytides, elastosis, and precancerous alterations. Exosomes are associated with aging processes such as oxidative damage, inflammation, and senescence. Exosomes' anti-aging properties have been linked to various in vitro and preclinical investigations. There are still several unanswered questions about the use of MSC exosomes for skin rejuvenation, despite encouraging results. Uncertainty surrounds the precise processes by which exosomes stimulate the creation of collagen, skin tissue via a variety of mechanisms, including reduced matrix metalloproteinase (MMP) expression, increased collagen and elastin production, and modulation of intracellular signaling pathways and intercellular communication. These findings suggest the therapeutic potential of exosomes in skin aging. This review provides information on the molecular mechanisms and consequences of exosome anti-aging.
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Affiliation(s)
- Gracy Seth
- Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal Pradesh 173229 India
| | - Siddharth Singh
- Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal Pradesh 173229 India
| | - Geetansh Sharma
- Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal Pradesh 173229 India
| | - Divyesh Suvedi
- Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal Pradesh 173229 India
| | - Dinesh Kumar
- Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal Pradesh 173229 India
| | - Rupak Nagraik
- Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal Pradesh 173229 India
- Department of Biotechnology, Graphic Era (Deemed to Be University), Dehradun, 248002 India
| | - Avinash Sharma
- Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal Pradesh 173229 India
- Department of Biotechnology, Graphic Era (Deemed to Be University), Dehradun, 248002 India
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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.
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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.
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Lv K, Gao J, Yang L, Yuan X. The role of mesenchymal stem cell‑derived exosomes in asthma (Review). Mol Med Rep 2025; 31:166. [PMID: 40242981 PMCID: PMC12012432 DOI: 10.3892/mmr.2025.13531] [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: 11/04/2024] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
Asthma is a chronic respiratory disorder characterized by persistent inflammation, airway hyper‑responsiveness and remodeling, leading to notable morbidity and decreased quality of life for patients. Mesenchymal stem cells (MSCs) have potential in regenerative medicine due to their potent immunomodulatory properties and anti‑inflammatory effects. The therapeutic benefits of MSCs are largely mediated by secreted exosomes that facilitate intercellular communication by transferring bioactive molecules, including proteins, lipids and microRNAs. The present review explores the therapeutic potential of MSC‑derived exosomes in asthma, highlighting their ability to modulate key pathological mechanisms underlying the disease.
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Affiliation(s)
- Kaiying Lv
- Department of Graduate Studies, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Jiawei Gao
- Department of Graduate Studies, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Liuxin Yang
- Department of Graduate Studies, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Xingxing Yuan
- Department of Graduate Studies, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, Heilongjiang 150006, P.R. China
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Goyal A, Afzal M, Goyal K, Ganesan S, Kumari M, Sunitha S, Dash A, Saini S, Rana M, Gupta G, Ali H, Wong LS, Kumarasamy V, Subramaniyan V. MSC-derived extracellular vesicles: Precision miRNA delivery for overcoming cancer therapy resistance. Regen Ther 2025; 29:303-318. [PMID: 40237010 PMCID: PMC11999318 DOI: 10.1016/j.reth.2025.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/04/2025] [Accepted: 03/18/2025] [Indexed: 04/17/2025] Open
Abstract
Cancer remains a prominent worldwide health concern, presenting existing therapies with frequent difficulties, including major toxicity, limited effectiveness, and treatment resistance emergence. These issues highlight the necessity for novel and enhanced remedies. Exosomes, tiny extracellular vesicles that facilitate intercellular communication, have attracted interest for their potential medicinal applications. Carrying a variety of molecules, including microRNAs, small interfering RNAs, long non-coding RNAs, proteins, lipids, and DNA, these vesicles are positioned as promising cancer treatment options. Current studies have increasingly investigated the capacity of microRNAs as a strategic approach for combating malignancy. Mesenchymal stem cells (MSC) are recognized for their aptitude to augment blood vessel formation, safeguard against cellular death, and modulate immune responses. Consequently, researchers examine exosomes derived from MSCs as a safer, non-cellular choice over therapies employing MSCs, which risk undesirable differentiation. The focus is shifting towards employing miRNA-encapsulated exosomes sourced from MSCs to target and heal cancerous cells selectively. However, the exact functions of miRNAs within MSC-derived exosomes in the context of cancer are still not fully understood. Additional exploration is necessary to clarify the role of these miRNAs in malignancy progression and to pinpoint viable therapeutic targets. This review offers a comprehensive examination of exosomes derived from mesenchymal stem cells, focusing on the encapsulation of miRNAs, methods for enhancing cellular uptake and stability, and their potential applications in cancer treatment. It also addresses the difficulties linked to this methodology and considers future avenues, including insights from current clinical oncology research.
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Affiliation(s)
- Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, UP, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah, 21442, Saudi Arabia
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, 248002, Dehradun, India
| | - Subbulakshmi Ganesan
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Mukesh Kumari
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - S. Sunitha
- Department of CHEMISTRY, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Aniruddh Dash
- Department of Orthopaedics IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, Odisha, 751030, India
| | - Suman Saini
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Ling Shing Wong
- Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, Malaysia
| | - Vinoth Kumarasamy
- Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Vetriselvan Subramaniyan
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, 47500, Subang Jaya, Selangor, Malaysia
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Ruan T, Han J, Xue C, Wang F, Lin J. Mesenchymal stem cells protect the integrity of the alveolar epithelial barrier through extracellular vesicles by inhibiting MAPK-mediated necroptosis. Stem Cell Res Ther 2025; 16:250. [PMID: 40390004 PMCID: PMC12090679 DOI: 10.1186/s13287-025-04388-1] [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: 09/11/2024] [Accepted: 05/09/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND Alveolar‒capillary barrier disruption is a hallmark of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The contribution of necroptosis to the compromised alveolar-barrier in ALI remains unclear. Mesenchymal stem cells (MSCs) may contribute to tissue repair in ALI and ARDS. Here we evaluated the efficacy and explored the molecular mechanisms of menstrual blood-derived endometrial stem cells (MenSCs) and MenSC-derived extracellular vesicles (MenSC-EVs) in ALI-induced alveolar epithelial barrier dysfunction. METHODS Human lung epithelial cells were stimulated with endotoxin and treated with MenSCs or MenSC-EVs, and their barrier properties were evaluated. Lipopolysaccharide (LPS)-injured mice were treated with MenSCs or MSC-EVs, and the degree of lung injury and the alveolar epithelial barrier of the lung tissue were assessed. RESULTS We found that MenSCs reduced lung injury and restored alveolar-barrier integrity in lung tissue. In vitro, MenSCs reduced paracellular permeability and restored barrier integrity in human lung epithelial cells. MenSC-EVs replicated all these MenSC-mediated changes. Mechanistic research revealed that MenSCs inhibited MAPK signaling and necroptosis. JNK inhibition SP600125, and ERK inhibition U0126 or inhibition of necroptosis with Nec-1 or GSK872 diminished the beneficial anti-epithelial barrier dysfunction effects of MenSCs or MenSC-EVs. CONCLUSIONS Our results suggest that human menstrual blood-derived endometrial stem cells mitigate lung injury and improve alveolar barrier properties by inhibiting MAPK-mediated necroptosis through extracellular vesicles, supporting the application of MenSCs or MenSC-derived extracellular vesicles to treat ALI or ARDS.
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Affiliation(s)
- Tao Ruan
- Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
| | - Jiaming Han
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China
| | - Chengxu Xue
- Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Fengyuan Wang
- Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Juntang Lin
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang, 453003, China.
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Zeng J, Wang J, Zhang Y, Wang Z, Zhu Y, Hou Y, Li X, Peng H, Lobie PE, Ma S. Mesenchymal stem cells attenuate diabetic vascular complication by reducing irregular extracellular matrix production in human blood vessel organoids. LAB ON A CHIP 2025. [PMID: 40341804 DOI: 10.1039/d5lc00107b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2025]
Abstract
Mesenchymal stem cells (MSCs) hold potential for treating diabetic vascular complications, but current models fail to adequately replicate the complexities of diabetic vascular disease, limiting our ability to accurately assess their therapeutic effects. To this end, we developed a co-culture system using a combination of human embryonic stem cell-derived blood vessel organoids (BVOs) and MSCs. This system could accurately replicate key aspects of diabetic pathology, including basement membrane thickening and excessive extracellular matrix (ECM) deposition. The results showed that MSCs were effective in attenuating basement membrane thickening and reducing ECM deposition in BVOs under diabetic conditions. Subsequent transcriptomics demonstrated that the MSC-treated group exhibited a notable normalization of ECM-related gene expression, particularly in collagen IV levels. Furthermore, the inhibition of the NF-κB signaling pathway was identified as a crucial mechanism underlying the therapeutic efficacy of MSCs. This study demonstrates the potential of MSCs to counteract diabetic vascular complications and emphasizes the co-culture system as a more physiologically relevant model to investigate the preventive and therapeutic potential of MSCs in diabetic pathology.
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Affiliation(s)
- Junhong Zeng
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
| | - Jiaqi Wang
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
| | - Yu Zhang
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
| | - Zitian Wang
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
- Key Lab of Industrial Biocatalysis Ministry of Education, Tsinghua University, Beijing 100084, China
| | - Yu Zhu
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
| | - Yibo Hou
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
| | - Xiangsai Li
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
| | - Haiying Peng
- General Hospital of the Southern Theater Command of the Chinese People's Liberation Army, Guangzhou 510010, China
| | - Peter E Lobie
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
- Key Lab of Industrial Biocatalysis Ministry of Education, Tsinghua University, Beijing 100084, China
| | - Shaohua Ma
- Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen 518055, China.
- Key Lab of Industrial Biocatalysis Ministry of Education, Tsinghua University, Beijing 100084, China
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Dauphin T, de Beaurepaire L, Salama A, Pruvost Q, Claire C, Haurogné K, Sourice S, Dupont A, Bach JM, Hervé J, Olmos E, Bosch S, Lieubeau B, Mosser M. Scalability of spheroid-derived small extracellular vesicles production in stirred systems. Front Bioeng Biotechnol 2025; 13:1516482. [PMID: 40365014 PMCID: PMC12069995 DOI: 10.3389/fbioe.2025.1516482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 04/10/2025] [Indexed: 05/15/2025] Open
Abstract
Introduction Small extracellular vesicle (sEV)-based therapies have gained widespread interest, but challenges persist to ensure standardization and high-scale production. Implementing upstream processes in a chemically defined media in stirred-tank bioreactors (STBr) is mandatory to closely control the cell environment, and to scale-up production, but it remains a significant challenge for anchorage-dependent cells. Methods We used a human β cell line, grown as monolayer or in suspension as spheroid in stirred systems. We assessed the consequences of culturing these cells in 3D with, or without fetal bovine serum in a chemically defined medium, for cell growth, viability and metabolism. We next explored how different scale-up strategies might influence cell and spheroid formation in spinner flask, with the aim to transfer the process in instrumented Ambr®250 STBr. Lastly, we analyzed and characterized sEV production in monolayer, spinner flask and STBr. Results and discussion Generation of spheroids in a chemically defined medium allowed the culture of highly viable cells in suspension in stirred systems. Spheroid size depended on the system's volumetric power input (P/V), and maintaining this parameter constant during scale-up proved to be the optimal strategy for standardizing the process. However, transferring the spinner flask (SpF) process to the Ambr®250 STBr at constant P/V modified spheroid size, due to important geometric differences and impeller design. Compared to a monolayer reference process, sEV yield decreased two-fold in SpF, but increased two-fold in STBr. Additionally, a lower expression of the CD63 tetraspanin was observed in sEV produced in both stirred systems, suggesting a reduced release of exosomes compared to ectosomes. This study addresses the main issues encountered in spheroid culture scale-up in stirred systems, rather conducive for the production of ectosomes.
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Affiliation(s)
| | | | | | | | - Clémentine Claire
- Oniris VetAgroBio, INRAE, IECM, Nantes, France
- Oniris VetAgroBio, B-FHIT, Nantes, France
| | | | | | - Aurélien Dupont
- CNRS, INSERM, BIOSIT_UAR 3480, Univ Rennes, Inserm 018, Rennes, France
| | - Jean-Marie Bach
- Oniris VetAgroBio, INRAE, IECM, Nantes, France
- Oniris VetAgroBio, B-FHIT, Nantes, France
| | - Julie Hervé
- Oniris VetAgroBio, INRAE, IECM, Nantes, France
| | - Eric Olmos
- University of Lorraine, CNRS, LRGP, Nancy, France
| | | | | | - Mathilde Mosser
- Oniris VetAgroBio, INRAE, IECM, Nantes, France
- Oniris VetAgroBio, B-FHIT, Nantes, France
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Wang H, Bai Z, Qiu Y, Kou J, Zhu Y, Tan Q, Chen C, Mo R. Empagliflozin-Pretreated MSC-Derived Exosomes Enhance Angiogenesis and Wound Healing via PTEN/AKT/VEGF Pathway. Int J Nanomedicine 2025; 20:5119-5136. [PMID: 40297404 PMCID: PMC12035755 DOI: 10.2147/ijn.s512074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 04/08/2025] [Indexed: 04/30/2025] Open
Abstract
Background Diabetic wounds are a common and challenging complication of diabetes, characterized by delayed healing and increased risk of infection. Current treatment methods are limited and often ineffective in promoting wound repair. Mesenchymal stem cell (MSC)-derived exosomes have shown promise in regenerative medicine, but enhancing their therapeutic potential remains a key area of research. Methods In this study, MSCs were pretreated with empagliflozin (EMPA), and exosomes were isolated using ultracentrifugation. The morphology, size, and protein markers of EMPA-Exos were characterized. Their effects on human umbilical vein endothelial cells (HUVECs) were assessed using EdU assays, CCK-8 assays, scratch assays, Transwell assays, and Matrigel tube formation assays. The PTEN/AKT/VEGF signaling pathway was analyzed through Western blotting. In vivo, diabetic mouse wound models were used to evaluate the healing efficacy of EMPA-Exos. Results EMPA pretreatment enhanced the functional properties of MSC-derived exosomes, significantly improving HUVECs' proliferation, migration, invasion, and angiogenesis compared to non-pretreated exosomes (P < 0.05). Transcriptomic analysis and pathway activation studies revealed that EMPA-Exos promoted angiogenesis through the PTEN/AKT/VEGF signaling pathway. In vivo experiments demonstrated accelerated wound healing and increased vascularization in diabetic mice treated with EMPA-Exos (P < 0.05). Conclusion EMPA-pretreated MSC-derived exosomes effectively enhance angiogenesis and accelerate diabetic wound healing by activating the PTEN/AKT/VEGF signaling pathway. This strategy offers a promising approach for improving diabetic wound repair and provides a potential new therapeutic avenue in regenerative medicine.
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Affiliation(s)
- Hao Wang
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
- Department of Cardiothoracic Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Zihao Bai
- Nanjing Children’s Hospital, Clinical Teaching Hospital of Medical School, Nanjing, Jiangsu, People’s Republic of China
| | - Yan Qiu
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Jiaxi Kou
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Yanqing Zhu
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Qian Tan
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Chen Chen
- Department of Nutrition, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Ran Mo
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
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Wang M, Chen D, Pan R, Sun Y, He X, Qiu Y, Hu Y, Wu X, Xi X, Hu R, Jiao Z. Neural stem cell-derived small extracellular vesicles: a new therapy approach in neurological diseases. Front Immunol 2025; 16:1548206. [PMID: 40308614 PMCID: PMC12040699 DOI: 10.3389/fimmu.2025.1548206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/28/2025] [Indexed: 05/02/2025] Open
Abstract
Neural stem cells (NSCs) possess pluripotent characteristics, proliferative capacity, and the ability to self-renew. In the context of neurological diseases, transplantation of NSCs has been shown to facilitate neurological repair through paracrine mechanisms. NSC-derived small extracellular vesicles (NSC-sEVs), a prominent component of the NSC secretome, play a crucial role in modulating various physiological and pathological processes, such as regulating the NSC microenvironment, promoting endogenous NSC differentiation, and facilitating the maturation of neurons and glial cells. Moreover, NSC-sEVs exhibit reduced immunogenicity, decreased tumorigenic potential, and enhanced ability to traverse the blood-brain barrier. Consequently, NSC-sEVs present novel therapeutic approaches as non-cellular treatments for neurological disorders and are poised to serve as a viable alternative to stem cell therapies. Furthermore, NSC-sEVs can be manipulated to enhance production efficiency, improve biological activity, and optimize targeting specificity, thereby significantly advancing the utilization of NSC-sEVs in clinical settings for neurological conditions. This review provides a comprehensive overview of the biological functions of NSC-sEVs, their therapeutic implications and underlying molecular mechanisms in diverse neurological disorders, as well as the potential for engineering NSC-sEVs as drug delivery platforms. Additionally, the limitations and challenges faced by NSC-sEVs in practical applications were discussed in depth, and targeted solutions were proposed.
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Affiliation(s)
- Mengyao Wang
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- College of Medical Technology, Gannan Medical University, Ganzhou, China
| | - Dongdong Chen
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- College of Medical Technology, Gannan Medical University, Ganzhou, China
| | - Renjie Pan
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- College of Medical Technology, Gannan Medical University, Ganzhou, China
| | - Yue Sun
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- College of Medical Technology, Gannan Medical University, Ganzhou, China
| | - Xinyu He
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- College of Medical Technology, Gannan Medical University, Ganzhou, China
| | - Youming Qiu
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
| | - Yuexin Hu
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- College of Medical Technology, Gannan Medical University, Ganzhou, China
| | - Xiangsheng Wu
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- College of Medical Technology, Gannan Medical University, Ganzhou, China
| | - Xuxiang Xi
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- College of Medical Technology, Gannan Medical University, Ganzhou, China
| | - Rong Hu
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- College of Medical Technology, Gannan Medical University, Ganzhou, China
| | - Zhigang Jiao
- Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- College of Medical Technology, Gannan Medical University, Ganzhou, China
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, China
- Precision Medicine Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi, China
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Chen Y, Lin F, Zhang T, Xiao Z, Chen Y, Hua D, Wang Y, Wei J, Jin T, Lv X. Engineering Extracellular Vesicles Derived from 3D Cultivation of BMSCs Enriched with HGF Ameliorate Sepsis-Induced Lung Epithelial Barrier Damage. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2500637. [PMID: 40041965 PMCID: PMC12021063 DOI: 10.1002/advs.202500637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 02/06/2025] [Indexed: 04/26/2025]
Abstract
Sepsis is a critical condition with high mortality, often leading to acute lung injury (ALI) due to uncontrolled inflammatory responses and alveolar epithelial damage. Extracellular vesicles (EVs), particularly mesenchymal stem cell-derived EVs, have shown therapeutic potential in sepsis-related organ dysfunction by transferring RNAs and proteins. However, their clinical use is limited by low efficacy and yield. To address this, 3D-cultured MSCs (3D-MSCs) are generated using MicroTissues 3D Petri Dish. These 3D-MSCs demonstrate improved protection and proliferation of MLE-12 cells in vitro. Mechanistic studies are conducted to explore the enhanced protective effects of 3D-MSCs derived EVs (3D-EVs) in a septic-ALI model. Proteomic and molecular analyses of 3D-EVs revealed that they are enriched in hepatocyte growth factor (HGF). HGF helps maintain the barrier function of damaged alveolar epithelium through the PI3K-AKT signaling pathway. Overall, 3D-EVs effectively ameliorate sepsis-induced ALI and enhance prognosis by enriching and delivering HGF, suggesting that their application represents a promising treatment strategy for septic ALI.
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Affiliation(s)
- Yong Chen
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
- Department of AnesthesiologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou325000China
| | - Feihong Lin
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Tong Zhang
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Zhuoran Xiao
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Yuanli Chen
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Dongsheng Hua
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Yu Wang
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Juan Wei
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Tian Jin
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
| | - Xin Lv
- Department of AnesthesiologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433China
- Shanghai Institute of Acupuncture and AnesthesiaShanghai200433China
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Ghanem R, Youf R, Haute T, Buin X, Riool M, Pourchez J, Montier T. The (re)emergence of aerosol delivery: Treatment of pulmonary diseases and its clinical challenges. J Control Release 2025; 379:421-439. [PMID: 39800241 DOI: 10.1016/j.jconrel.2025.01.017] [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: 10/04/2024] [Revised: 01/03/2025] [Accepted: 01/07/2025] [Indexed: 01/15/2025]
Abstract
Aerosol delivery represents a rapid and non-invasive way to directly reach the lungs while escaping the hepatic first-pass effect. The development of pulmonary drugs for respiratory diseases such as cystic fibrosis, lung infections, pulmonary fibrosis or lung cancer requires an enhanced understanding of the relationships between the natural physiology of the respiratory system and the pathophysiology of these conditions. This knowledge is crucial to better predict and thereby control drug deposition. Moreover, aerosol administration faces several challenges, including the pulmonary tract, immune system, mucociliary clearance, the presence of fluid on the airway surfaces, and, in some cases, bacterial colonisation. Each of them directly influences on the bioavailability of the active molecule. In addition to these challenges, particle size and the device used to administer the treatment are critical factors that can significantly impact the biodistribution of the drugs. Nanoparticles are very promising in the development of new formulations for aerosol drug delivery, as they can be fine-tuned to reach the entire pulmonary tract and overcome the difficulties encountered along the way. However, to properly assess drug delivery, preclinical studies need to be more thorough to efficiently enhance drug delivery.
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Affiliation(s)
- Rosy Ghanem
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France; CHU de Brest, Service de Génétique Médicale et de Biologie de la Reproduction, F-29200 Brest, France
| | - Raphaëlle Youf
- Department of Trauma Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
| | - Tanguy Haute
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France
| | - Xavier Buin
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France
| | - Martijn Riool
- Department of Trauma Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
| | - Jérémie Pourchez
- Mines Saint-Etienne, Univ Lyon, Univ Jean Monnet, INSERM, U 1059 Sainbiose, Centre CIS, F - 42023 Saint-Etienne, France
| | - Tristan Montier
- Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France; CHU de Brest, Service de Génétique Médicale et de Biologie de la Reproduction, F-29200 Brest, France.
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15
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Camacho-Cardenosa M, Pulido-Escribano V, Estrella-Guisado G, Dorado G, Herrera-Martínez AD, Gálvez-Moreno MÁ, Casado-Díaz A. Bioprinted Hydrogels as Vehicles for the Application of Extracellular Vesicles in Regenerative Medicine. Gels 2025; 11:191. [PMID: 40136896 PMCID: PMC11941778 DOI: 10.3390/gels11030191] [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: 02/17/2025] [Revised: 03/06/2025] [Accepted: 03/07/2025] [Indexed: 03/27/2025] Open
Abstract
Three-dimensional bioprinting is a new advance in tissue engineering and regenerative medicine. Bioprinting allows manufacturing three-dimensional (3D) structures that mimic tissues or organs. The bioinks used are mainly made of natural or synthetic polymers that must be biocompatible, printable, and biodegradable. These bioinks may incorporate progenitor cells, favoring graft implantation and regeneration of injured tissues. However, the natures of biomaterials, bioprinting processes, a lack of vascularization, and immune responses are factors that limit the viability and functionality of implanted cells and the regeneration of damaged tissues. These limitations can be addressed by incorporating extracellular vesicles (EV) into bioinks. Indeed, EV from progenitor cells may have regenerative capacities, being similar to those of their source cells. Therefore, their combinations with biomaterials can be used in cell-free therapies. Likewise, they can complement the manufacture of bioinks by increasing the viability, differentiation, and regenerative ability of incorporated cells. Thus, the main objective of this review is to show how the use of 3D bioprinting technology can be used for the application of EV in regenerative medicine by incorporating these nanovesicles into hydrogels used as bioinks. To this end, the latest advances derived from in vitro and in vivo studies have been described. Together, these studies show the high therapeutic potential of this strategy in regenerative medicine.
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Affiliation(s)
- Marta Camacho-Cardenosa
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (M.C.-C.); (V.P.-E.); (G.E.-G.); (A.D.H.-M.)
| | - Victoria Pulido-Escribano
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (M.C.-C.); (V.P.-E.); (G.E.-G.); (A.D.H.-M.)
| | - Guadalupe Estrella-Guisado
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (M.C.-C.); (V.P.-E.); (G.E.-G.); (A.D.H.-M.)
| | - Gabriel Dorado
- Departamento Bioquímica y Biología Molecular, Campus Rabanales C6-1-E17, Campus de Excelencia Internacional Agroalimentario (ceiA3), Universidad de Córdoba, 14071 Córdoba, Spain;
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), 14004 Córdoba, Spain
| | - Aura D. Herrera-Martínez
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (M.C.-C.); (V.P.-E.); (G.E.-G.); (A.D.H.-M.)
| | - María Ángeles Gálvez-Moreno
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (M.C.-C.); (V.P.-E.); (G.E.-G.); (A.D.H.-M.)
| | - Antonio Casado-Díaz
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (M.C.-C.); (V.P.-E.); (G.E.-G.); (A.D.H.-M.)
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), 14004 Córdoba, Spain
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Chen Y, Yang F, Wang Y, Shi Y, Liu L, Luo W, Zhou J, Yan Y. Mesenchymal stem cell-derived small extracellular vesicles reduced hepatic lipid accumulation in MASLD by suppressing mitochondrial fission. Stem Cell Res Ther 2025; 16:116. [PMID: 40045380 PMCID: PMC11884000 DOI: 10.1186/s13287-025-04228-2] [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: 11/22/2024] [Accepted: 02/11/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease characterized by lipid accumulation in liver cells. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have great potential in repairing and regenerating liver diseases. However, it is still unclear whether MSC-sEV can inhibit hepatocyte lipid accumulation by regulating mitochondrial fission. METHODS We investigated the effects of MSC-sEV on mitochondrial fission and its potential mechanism in lipotoxic hepatocytes and high-fat diet (HFD)-induced MASLD mice. RESULTS We found that MSC-sEV can effectively inhibit the expression of the Dynamin-related protein 1 (DRP1), thereby reducing mitochondrial fission, mitochondrial damage, and lipid deposition in lipotoxic hepatocytes and livers of HFD-induced MASLD in mice. Further mechanistic studies revealed that RING finger protein 31 (RNF31) played a crucial role in mediating the inhibitory effect of MSC-sEV on DRP1 and mitochondrial fission. RNF31 can suppress DRP1 expression and mitochondrial fission, thereby improving mitochondrial dysfunction and reducing hepatocyte lipid deposition. These findings suggest that MSC-sEV may downregulate hepatocyte DRP1-mediated mitochondrial fission by transporting RNF31, ultimately inhibiting hepatocyte lipid accumulation. CONCLUSIONS The insights from this study provide a new perspective on the mechanism of MSC-sEV in reducing lipid accumulation and offer a potential therapeutic target by targeting DRP1 to inhibit hepatocyte steatosis and the progression of MASLD.
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Affiliation(s)
- Yifei Chen
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Fuji Yang
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Yanjin Wang
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Yujie Shi
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Likang Liu
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Wei Luo
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China
- Changzhou Key Laboratory of Exosome Foundation and Transformation Application, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University, Changzhou, 213017, China
| | - Jing Zhou
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China
- Changzhou Key Laboratory of Exosome Foundation and Transformation Application, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University, Changzhou, 213017, China
| | - Yongmin Yan
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China.
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China.
- Changzhou Key Laboratory of Exosome Foundation and Transformation Application, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University, Changzhou, 213017, China.
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Kawasumi R, Kawamura T, Yamashita K, Tominaga Y, Harada A, Ito E, Takeda M, Kita S, Shimomura I, Miyagawa S. Systemic administration of induced pluripotent stem cell-derived mesenchymal stem cells improves cardiac function through extracellular vesicle-mediated tissue repair in a rat model of ischemic cardiomyopathy. Regen Ther 2025; 28:253-261. [PMID: 39834593 PMCID: PMC11745812 DOI: 10.1016/j.reth.2024.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 12/03/2024] [Accepted: 12/11/2024] [Indexed: 01/22/2025] Open
Abstract
Introduction Systemic administration of induced pluripotent stem cell-derived mesenchymal stem cells (iPS-MSCs) has a therapeutic effect on myocardial ischemia. However, the therapeutic mechanism underlying systemic iPS-MSC-based therapy for ischemic cardiomyopathy (ICM) remains unclear. We investigated the therapeutic effects of iPS-MSCs through extracellular vesicle (EV)-mediated tissue repair in a rat model of ICM. Methods A rat ICM model was created by left anterior descending coronary artery ligation. iPS-MSCs were administered intravenously every week for four weeks in the iPS-MSC group, whereas saline was administered to the control group. Alix, a protein involved in the biogenesis of EVs, was knocked down, and Alix-knockdown iPS-MSCs were administered to the siAlix group. We analyzed sequential cardiac function using echocardiography, histological analysis, cell tracking analysis with fluorescent dyes, and comprehensive RNA sequencing of the border zone of the myocardium after treatment. Results Left ventricular ejection fraction (LVEF) was significantly improved in the iPS-MSC group compared with that in the control group. In the siAlix group, LVEF was significantly lower than that in the iPS-MSC group. Histological analysis showed a significant decrease in fibrosis area and significant increase in microvascular density in the iPS-MSC group. A cell-tracking assay revealed iPS-MSC accumulation in the border zone of the myocardium during the acute phase. Comprehensive microRNA sequencing analysis revealed that EVs from iPS-MSCs contained miRNAs associated with anti-fibrosis and angiogenesis. Gene ontology analysis of differentially expressed genes in myocardial tissue also showed upregulation of pathways related to antifibrosis and neovascularization and downregulation of pathways linked to inflammation and T-cell differentiation. Conclusions Systemic administration of iPS-MSCs improved cardiac function through EV-mediated angiogenetic and antifibrotic effects in an ICM, suggesting the clinical possibility of treating chronic heart failure.
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Affiliation(s)
- Ryo Kawasumi
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takuji Kawamura
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kizuku Yamashita
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yuji Tominaga
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Akima Harada
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Emiko Ito
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Maki Takeda
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Shunbun Kita
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
- Department of Adipose Management, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Iichiro Shimomura
- Department of Adipose Management, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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18
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Garcia‐Aponte OF, Kahlenberg S, Kouroupis D, Egger D, Kasper C. Effects of Hydrogels on Mesenchymal Stem/Stromal Cells Paracrine Activity and Extracellular Vesicles Production. J Extracell Vesicles 2025; 14:e70057. [PMID: 40091440 PMCID: PMC11911545 DOI: 10.1002/jev2.70057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 12/10/2024] [Accepted: 02/11/2025] [Indexed: 03/19/2025] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are a valuable source of paracrine factors, as they have a remarkable secretory capacity, and there is a sizeable knowledge base to develop industrial and clinical production protocols. Promising cell-free approaches for tissue regeneration and immunomodulation are driving research towards secretome applications, among which extracellular vesicles (EVs) are steadily gaining attention. However, the manufacturing and application of EVs is limited by insufficient yields, knowledge gaps, and low standardization. Facing these limitations, hydrogels represent a versatile three-dimensional (3D) culture platform that can incorporate extracellular matrix (ECM) components to mimic the natural stem cell environment in vitro; via these niche-mimicking properties, hydrogels can regulate MSCs' morphology, adhesion, proliferation, differentiation and secretion capacities. However, the impact of the hydrogel's architectural, biochemical and biomechanical properties on the production of EVs remains poorly understood, as the field is still in its infancy and the interdependency of culture parameters compromises the comparability of the studies. Therefore, this review summarizes and discusses the reported effects of hydrogel encapsulation and culture on the secretion of MSC-EVs. Considering the effects of cell-material interactions on the overall paracrine activity of MSCs, we identify persistent challenges from low standardization and process control, and outline future paths of research, such as the synergic use of hydrogels and bioreactors to enhance MSC-EV generation.
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Affiliation(s)
- Oscar Fabian Garcia‐Aponte
- Department of Biotechnology and Food Science, Institute of Cell and Tissue Culture TechnologiesUniversity of Natural Resources and Life SciencesViennaAustria
| | - Simon Kahlenberg
- Department of Biotechnology and Food Science, Institute of Cell and Tissue Culture TechnologiesUniversity of Natural Resources and Life SciencesViennaAustria
| | - Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, Miller School of MedicineUniversity of MiamiMiamiFloridaUSA
- Diabetes Research Institute & Cell Transplant Center, Miller School of MedicineUniversity of MiamiMiamiFloridaUSA
| | - Dominik Egger
- Institute of Cell Biology and BiophysicsLeibniz University HannoverHannoverGermany
| | - Cornelia Kasper
- Department of Biotechnology and Food Science, Institute of Cell and Tissue Culture TechnologiesUniversity of Natural Resources and Life SciencesViennaAustria
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19
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Barathan M, Ham KJ, Wong HY, Law JX. The Role of Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles in Modulating Dermal Fibroblast Activity: A Pathway to Enhanced Tissue Regeneration. BIOLOGY 2025; 14:150. [PMID: 40001918 PMCID: PMC11852171 DOI: 10.3390/biology14020150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/27/2025]
Abstract
Extracellular vesicles (EVs) secreted by umbilical cord-derived mesenchymal stem cells (UC-MSCs) hold significant promise as therapeutic agents in regenerative medicine. This study investigates the effects of UC-MSC-derived EVs on dermal fibroblast function, and their potential in wound healing applications. EVs were characterized by nanoparticle tracking analysis and transmission electron microscopy, revealing a mean size of 118.6 nm, consistent with exosomal properties. Dermal fibroblasts were treated with varying concentrations of EVs (25-100 µg/mL), and their impacts on cellular metabolism, mitochondrial activity, reactive oxygen species (ROS) production, wound closure, inflammatory cytokine secretion, growth factor production, and extracellular matrix (ECM) gene expression were evaluated. At lower concentrations (25-50 µg/mL), EVs significantly enhanced fibroblast metabolic and mitochondrial activity. However, higher concentrations (≥75 µg/mL) increased ROS levels, suggesting potential hormetic effects. EVs also modulated inflammation by reducing pro-inflammatory cytokines (IL-6, TNF-α) while promoting pro-regenerative cytokines (IL-33, TGF-β). Treatment with 50 µg/mL of EVs optimally stimulated wound closure and growth factor secretion (VEGF, BDNF, KGF, IGF), and upregulated ECM-related gene expression (type I and III collagen, fibronectin). These findings demonstrate that UC-MSC-derived EVs exert multifaceted effects on dermal fibroblast function, including enhanced cellular energetics, stimulation of cell migration, regulation of inflammation, promotion of growth factor production, and increased ECM synthesis. This study highlights the potential of EVs as a novel therapeutic strategy for wound healing and tissue regeneration, emphasizing the importance of optimizing EV concentration for maximal therapeutic efficacy.
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Affiliation(s)
- Muttiah Barathan
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia;
| | - Kow Jack Ham
- Humanrace Sdn. Bhd., 8-5, Setia Avenue, Jalan Setia Prima (S) U13/S, Setia Alam, Seksyen 13, Shah Alam 40170, Selangor, Malaysia; (K.J.H.); (H.Y.W.)
- Nexus Scientific Sdn. Bhd., 8-5, Setia Avenue, Jalan Setia Prima (S) U13/S, Setia Alam, Seksyen 13, Shah Alam 40170, Selangor, Malaysia
| | - Hui Yin Wong
- Humanrace Sdn. Bhd., 8-5, Setia Avenue, Jalan Setia Prima (S) U13/S, Setia Alam, Seksyen 13, Shah Alam 40170, Selangor, Malaysia; (K.J.H.); (H.Y.W.)
- Nexus Scientific Sdn. Bhd., 8-5, Setia Avenue, Jalan Setia Prima (S) U13/S, Setia Alam, Seksyen 13, Shah Alam 40170, Selangor, Malaysia
| | - Jia Xian Law
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia;
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20
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Vipin CL, Kumar GSV. Exosome laden sprayable thermo-sensitive polysaccharide-based hydrogel for enhanced burn wound healing. Int J Biol Macromol 2025; 290:138712. [PMID: 39710019 DOI: 10.1016/j.ijbiomac.2024.138712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 11/26/2024] [Accepted: 12/10/2024] [Indexed: 12/24/2024]
Abstract
Severe burns pose significant threats to patient well-being, characterized by pain, inflammation, bacterial infection, and extended recovery periods. While exosome-loaded hydrogels have demonstrated considerable promise in wound healing, current formulations often fall short of achieving optimal therapeutic efficacy for burn wounds due to challenges related to their adaptability to wound shape and limited anti-bacterial capabilities. In this study a novel exosome laden sprayable thermosensitive polysaccharide-based hydrogel (ADA-aPF127@LL18/Exo) comprising alginate dialdehyde (ADA) and aminated Pluronic F127 (aPF127) was fabricated via Schiff base reaction. ADA-aPF127@LL18/Exo exhibited sustained release of exosome and enhanced antibacterial efficacy. Furthermore, the biological assessments displayed excellent biocompatibility and enhanced in vitro cell proliferation and migration. In a deep partial thickness burn model, ADA-aPF127@LL18/Exo significantly augmented wound healing processes by accelerating epithelialization, promoting granulation tissue formation and collagen deposition, inducing hair follicle regeneration, effectively mitigating inflammatory responses, and facilitating enhanced neovascularization. In conclusion, ADA-aPF127@LL18/Exo represents a highly promising therapeutic dressing for the treatment of deep burns, exhibiting multifaceted properties conducive to efficient wound management.
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Affiliation(s)
- C L Vipin
- Nano Drug Delivery Systems (NDDS), Cancer Biology Division, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thycaud P.O, Poojappura, Thiruvananthapuram, Kerala 695014, India; Regional Centre for Biotechnology (BRIC-RCB), Faridabad, Haryana 121001, India
| | - G S Vinod Kumar
- Nano Drug Delivery Systems (NDDS), Cancer Biology Division, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thycaud P.O, Poojappura, Thiruvananthapuram, Kerala 695014, India.
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21
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Liao S, Guo F, Xiao Z, Xiao H, Pan QR, Guo Y, Chen J, Wang X, Wang S, Huang H, Yang L, Liu HF, Pan Q. Autophagy activation within inflammatory microenvironment improved the therapeutic effect of MSC-Derived extracellular Vesicle in SLE. J Adv Res 2025:S2090-1232(25)00063-3. [PMID: 39880074 DOI: 10.1016/j.jare.2025.01.044] [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: 10/26/2024] [Revised: 01/06/2025] [Accepted: 01/25/2025] [Indexed: 01/31/2025] Open
Abstract
INTRODUCTION Developing strategies to improve the therapeutic efficacy of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in autoimmune diseases have garnered increased attention. OBJECTIVES To evaluate whether rapamycin-induced autophagy within the systemic lupus erythematosus (SLE) inflammatory microenvironment (Rapa-SLE) augments the therapeutic effects of MSC-derived EVs in SLE. METHODS The therapeutic potential of the resulting EVs (Rapa-SLE-EV) was assessed in MRL/lpr mice. Rapa-SLE-EVs were compared with EVs derived from MSCs from MSCs cultured with EV-depleted fetal bovine serum (FBS-EV), EVs from MSCs cultured with rapamycin-treated FBS (Rapa-FBS-EV), and EVs exposed to SLE serum without rapamycin (SLE-EV). The autoimmune response, renal function, and pathological damage were assessed among the mouse groups. Additionally, mechanistic investigations into the role of the anti-inflammatory protein IDO1 within the EVs. RESULTS Interaction with the SLE inflammatory microenvironment triggered autophagy in MSCs, which was further enhanced by rapamycin treatment. Rapa-SLE-EV administration significantly ameliorated the autoimmune response and renal damage in MRL/lpr mice, outperforming other MSC-EV groups. This treatment mitigated key manifestations of SLE, including reduced autoantibody levels, as well as splenomegaly, and lymphadenopathy. Furthermore, Rapa-SLE-EV demonstrated superior suppression of plasma inflammatory cytokines, preserved renal function, mitigated pathological damage, and reduced glomerular immune complex deposition. Mechanistically, Rapa-SLE-EV exhibits exceptional inhibitory effects on SLE-B cell function, benefited by the high expression of the anti-inflammatory protein IDO1, which was confirmed to enter SLE-B cells through EVs. CONCLUSIONS We developed a novel strategy to improve the therapeutic efficacy of MSC-EVs in SLE and confirmed that the immunomodulatory function of the MSC-EVs is enhanced through autophagic activation and interaction with the SLE serum microenvironment, a process likely benefited by the high expression of IDO1.
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Affiliation(s)
- Shuzhen Liao
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Clinical Research and Experimental Center, Department of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China; Yue Bei People's Hospital Postdoctoral Innovation Practice Base, Southern Medical University, Guangzhou 510515, China
| | - Fengbiao Guo
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Clinical Research and Experimental Center, Department of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Zengzhi Xiao
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Clinical Research and Experimental Center, Department of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Haiyan Xiao
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Quan-Ren Pan
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Clinical Research and Experimental Center, Department of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Yugan Guo
- Department of Radiation Oncology, Yuebei People's Hospital Affiliated to Shantou University School of Medicine, Shaoguan 512000, China
| | - Jiaxuan Chen
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Clinical Research and Experimental Center, Department of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Xi Wang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Clinical Research and Experimental Center, Department of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Shuting Wang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Clinical Research and Experimental Center, Department of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Haimin Huang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Clinical Research and Experimental Center, Department of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Lawei Yang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Clinical Research and Experimental Center, Department of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Hua-Feng Liu
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Clinical Research and Experimental Center, Department of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China.
| | - Qingjun Pan
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Clinical Research and Experimental Center, Department of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China; Department of Clinical Laboratory, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University. Guangzhou 510120, China.
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22
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Kundu D, Shin SY, Chilian WM, Dong F. The Potential of Mesenchymal Stem Cell-Derived Exosomes in Cardiac Repair. Int J Mol Sci 2024; 25:13494. [PMID: 39769256 PMCID: PMC11727646 DOI: 10.3390/ijms252413494] [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: 11/27/2024] [Revised: 12/12/2024] [Accepted: 12/15/2024] [Indexed: 01/12/2025] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and effectively repairing the heart following myocardial injuries remains a significant challenge. Research has increasingly shown that exosomes derived from mesenchymal stem cells (MSC-Exo) can ameliorate myocardial injuries and improve outcomes after such injuries. The therapeutic benefits of MSC-Exo are largely due to their capacity to deliver specific cargo, including microRNAs and proteins. MSC-Exo can modulate various signaling pathways and provide several beneficial effects, including cytoprotection, inflammation modulation, and angiogenesis promotion to help repair the damaged myocardium. In this review, we summarize the cardioprotective effects of MSC-Exo in myocardial injury, the underlying molecular mechanism involved in the process, and various approaches studied to enhance their efficacy based on recent findings.
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Affiliation(s)
| | | | | | - Feng Dong
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA; (D.K.); (S.Y.S.); (W.M.C.)
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23
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AlOraibi S, Taurin S, Alshammary S. Advancements in Umbilical Cord Biobanking: A Comprehensive Review of Current Trends and Future Prospects. Stem Cells Cloning 2024; 17:41-58. [PMID: 39655226 PMCID: PMC11626973 DOI: 10.2147/sccaa.s481072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 11/01/2024] [Indexed: 12/12/2024] Open
Abstract
Biobanking has emerged as a transformative concept in advancing the medical field, particularly with the exponential growth of umbilical cord (UC) biobanking in recent decades. UC blood and tissue provide a rich source of primitive hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) for clinical transplantation, offering distinct advantages over alternative adult stem cell sources. However, to fully realize the therapeutic potential of UC-derived stem cells and establish a comprehensive global UC-biobanking network, it is imperative to optimize and standardize UC processing, cryopreservation methods, quality control protocols, and regulatory frameworks, alongside developing effective consent provisions. This review aims to comprehensively explore recent advancements in UC biobanking, focusing on the establishment of rigorous safety and quality control procedures, the standardization of biobanking operations, and the optimization and automation of UC processing and cryopreservation techniques. Additionally, the review examines the expanded clinical applications of UC stem cells, addresses the challenges associated with umbilical cord biobanking and UC-derived stem cell therapies, and discusses the promising role of artificial intelligence (AI) in enhancing various operational aspects of biobanking, streamlining data processing, and improving data analysis accuracy while ensuring compliance with safety and quality standards. By addressing these critical areas, this review seeks to provide insights into the future direction of UC biobanking and its potential to significantly impact regenerative medicine.
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Affiliation(s)
- Sahar AlOraibi
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
| | - Sebastien Taurin
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
| | - Sfoug Alshammary
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
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24
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Wiersema AF, Rennenberg A, Smith G, Varderidou-Minasian S, Pasterkamp RJ. Shared and distinct changes in the molecular cargo of extracellular vesicles in different neurodegenerative diseases. Cell Mol Life Sci 2024; 81:479. [PMID: 39627617 PMCID: PMC11615177 DOI: 10.1007/s00018-024-05522-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 10/18/2024] [Accepted: 11/18/2024] [Indexed: 12/06/2024]
Abstract
Neurodegenerative disorders such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) affect millions of people worldwide. Curative treatment for these neurodegenerative disorders is still lacking and therefore a further understanding of their cause and progression is urgently needed. Extracellular vesicles (EVs) are nanosized vesicles loaded with cargo, such as proteins and miRNAs, that are released by cells and play an important role in intercellular communication. Intercellular communication through EVs can contribute to the spread of pathological proteins, such as amyloid-beta and tau, or cause pathogenesis through other mechanisms. In addition, EVs may serve as potential biomarkers for diagnosis and for monitoring disease progression. In this review, we summarize and discuss recent advances in our understanding of the role of EVs in AD, ALS an PD with an emphasis on dysregulated cargo in each disease. We highlight shared dysregulated cargo between these diseases, discuss underlying pathways, and outline future implications for therapeutic strategies.
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Affiliation(s)
- Anna F Wiersema
- Department of Translational Neuroscience, University Medical Center Brain Center, Utrecht University, Utrecht, The Netherlands
| | - Alyssa Rennenberg
- Department of Translational Neuroscience, University Medical Center Brain Center, Utrecht University, Utrecht, The Netherlands
| | - Grace Smith
- Department of Translational Neuroscience, University Medical Center Brain Center, Utrecht University, Utrecht, The Netherlands
| | - Suzy Varderidou-Minasian
- Department of Translational Neuroscience, University Medical Center Brain Center, Utrecht University, Utrecht, The Netherlands
| | - R Jeroen Pasterkamp
- Department of Translational Neuroscience, University Medical Center Brain Center, Utrecht University, Utrecht, The Netherlands.
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25
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Li W, Yu L. Role and therapeutic perspectives of extracellular vesicles derived from liver and adipose tissue in metabolic dysfunction-associated steatotic liver disease. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2024; 52:355-369. [PMID: 38833340 DOI: 10.1080/21691401.2024.2360008] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 05/22/2024] [Indexed: 06/06/2024]
Abstract
The global epidemic of metabolic diseases has led to the emergence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), which pose a significant threat to human health. Despite recent advances in research on the pathogenesis and treatment of MASLD/MASH, there is still a lack of more effective and targeted therapies. Extracellular vesicles (EVs) discovered in a wide range of tissues and body fluids encapsulate different activated biomolecules and mediate intercellular communication. Recent studies have shown that EVs derived from the liver and adipose tissue (AT) play vital roles in MASLD/MASH pathogenesis and therapeutics, depending on their sources and intervention types. Besides, adipose-derived stem cell (ADSC)-derived EVs appear to be more effective in mitigating MASLD/MASH. This review presents an overview of the definition, extraction strategies, and characterisation of EVs, with a particular focus on the biogenesis and release of exosomes. It also reviews the effects and potential molecular mechanisms of liver- and AT-derived EVs on MASLD/MASH, and emphasises the contribution and clinical therapeutic potential of ADSC-derived EVs. Furthermore, the future perspective of EV therapy in a clinical setting is discussed.
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Affiliation(s)
- Wandi Li
- Senior Department of Burns and Plastic Surgery, the Fourth Medical Center of PLA General Hospital, Haidian District, Beijing, P.R. China
| | - Lili Yu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, P.R. China
- Endocrine Department, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Henan, P.R. China
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26
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Lee J, Geum D, Park DH, Kim JH. Molecular Targeting of Ischemic Stroke: The Promise of Naïve and Engineered Extracellular Vesicles. Pharmaceutics 2024; 16:1492. [PMID: 39771472 PMCID: PMC11678501 DOI: 10.3390/pharmaceutics16121492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 01/04/2025] Open
Abstract
Ischemic stroke (IS) remains a leading cause of mortality and long-term disability worldwide, with limited therapeutic options available. Despite the success of early interventions, such as tissue-type plasminogen activator administration and mechanical thrombectomy, many patients continue to experience persistent neurological deficits. The pathophysiology of IS is multifaceted, encompassing excitotoxicity, oxidative and nitrosative stress, inflammation, and blood-brain barrier disruption, all of which contribute to neural cell death, further complicating the treatment of IS. Recently, extracellular vesicles (EVs) secreted naturally by various cell types have emerged as promising therapeutic agents because of their ability to facilitate selective cell-to-cell communication, neuroprotection, and tissue regeneration. Furthermore, engineered EVs, designed to enhance targeted delivery and therapeutic cargo, hold the potential to improve their therapeutic benefits by mitigating neuronal damage and promoting neurogenesis and angiogenesis. This review summarizes the characteristics of EVs, the molecular mechanisms underlying IS pathophysiology, and the emerging role of EVs in IS treatment at the molecular level. This review also explores the recent advancements in EV engineering, including the incorporation of specific proteins, RNAs, or pharmacological agents into EVs to enhance their therapeutic efficacy.
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Affiliation(s)
- Jihun Lee
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea;
| | - Dongho Geum
- Department of Medical Science, College of Medicine, Korea University, Seoul 02841, Republic of Korea;
| | - Dong-Hyuk Park
- Department of Neurosurgery, Anam Hospital, College of Medicine, Korea University, Seoul 02841, Republic of Korea;
| | - Jong-Hoon Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea;
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27
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Yang G, Liu L, Xiao L, Ke S, Yang H, Lu Q. Accelerated scarless wound healing by dynamical regulation of angiogenesis and inflammation with immobilized asiaticoside and magnesium ions in silk nanofiber hydrogels. J Mater Chem B 2024; 12:11670-11684. [PMID: 39380345 DOI: 10.1039/d4tb01584c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2024]
Abstract
It remains a challenge to effectively regulate the complicated microenvironment during the wound healing process. The optimization of synergistic action of angiogenesis and inflammation is considered critical for quicker scarless wound regeneration. Here, the silk nanofiber (SNF) acts as a multifunctional carrier to load hydrophobic asiaticoside (AC) and hydrophilic Mg2+, and also serves as an element to assemble injectable hydrogels, forming a bioactive matrix with improved angiogenic and anti-inflammatory capacities (SNF-AC-Mg). Mg2+ and AC distributed homogeneously inside the silk nanofiber hydrogels without compromising the mechanical performance. Both Mg2+ and AC released slowly to continuously tune both angiogenic and inflammatory behaviors. The hydrogels exhibited good biocompatibility, inflammation inhibition, and pro-angiogenic properties in vitro, suggesting the synergistic bioactivity of AC and Mg2+. In vivo analysis revealed that the synergistic action of AC and Mg2+ resulted in better M2-type polarization of macrophages and angiogenesis during the inflammatory phase, while effectively achieving the inhibition of excessive accumulation of collagen and scar formation during the remodeling phases. The quicker scarless regeneration of the defects treated with SNF-AC-Mg implies the priority of SNFs in designing bioactive niches with complicated cues, which will favor the functional recovery of different tissues in the future.
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Affiliation(s)
- Gongwen Yang
- State Key Laboratory of Radiation Medicine and Radiation Protection, Institutes for Translational Medicine, Soochow University, Suzhou 215123, People's Republic of China.
| | - Lutong Liu
- Beijing Allgens Medical Science and Technology Co., Ltd., Beijing 100176, People's Republic of China
| | - Liying Xiao
- State Key Laboratory of Radiation Medicine and Radiation Protection, Institutes for Translational Medicine, Soochow University, Suzhou 215123, People's Republic of China.
- National Engineering Laboratory for Modern Silk & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215123, People's Republic of China
| | - Shiyu Ke
- National Engineering Laboratory for Modern Silk & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215123, People's Republic of China
| | - Huaxiang Yang
- National Engineering Laboratory for Modern Silk & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215123, People's Republic of China
| | - Qiang Lu
- State Key Laboratory of Radiation Medicine and Radiation Protection, Institutes for Translational Medicine, Soochow University, Suzhou 215123, People's Republic of China.
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28
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Yuan M, Tian X, Ma W, Zhang R, Zou X, Jin Y, Zheng N, Wu Z, Wang Y. miRNA-431-5p enriched in EVs derived from IFN-β stimulated MSCs potently inhibited ZIKV through CD95 downregulation. Stem Cell Res Ther 2024; 15:435. [PMID: 39563434 PMCID: PMC11575116 DOI: 10.1186/s13287-024-04040-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 11/03/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND Zika virus (ZIKV) primarily spreads through mosquito bites and can lead to microcephaly in infants and Guillain-Barre syndrome in adults. It is noteworthy that ZIKV can persist in the semen of infected males for extended periods and can be sexually transmitted. Infection with ZIKV has severe pathological manifestations on the testicular tissues of male mice, resulting in reduced sperm motility and fertility. However, there are no approved prophylactic vaccines or therapeutics available to treat Zika virus infection. METHODS Using a male type I and II interferon receptor-deficient (ifnar1(-/-) ifngr1(-/-)) C57BL/6 (AG6) mouse model infected with ZIKV as a representative model, we evaluated the degree of testicular damage and viral replication in various organs in mice treated with EVs derived from MSC-stimulated with IFN-β (IFNβ-EVs) and treated with controls. We measured testicle size, detected viral load in various organs, and analyzed gene expression to assess treatment efficacy. RESULTS Our findings demonstrated that intravenous administration of IFNβ-EVs effectively suppressed ZIKV replication in the testes. Investigation with in-depth RNA sequencing analysis found that IFN-β treatment changed the cargo miRNA of EVs. Notably, miR-431-5p was identified to be significantly enriched in IFNβ-EVs and exhibited potent antiviral activity in vitro. We showed that CD95 was a direct downstream target for miR-431-5p and played a role in facilitating ZIKV replication. miR-431-5p effectively downregulated the expression of CD95 protein, consequently promoted the phosphorylation and nuclear localization of NF-kB, which resulted in the activation of anti-viral status, leading to the suppression of viral replication. CONCLUSIONS Our study demonstrated that the EVs produced by IFNβ-treated MSCs could effectively convey antiviral activity.
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Affiliation(s)
- Meng Yuan
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, 210093, China
| | - Xiaoyan Tian
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, 210093, China
| | - Wenyuan Ma
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, 210093, China
| | - Rui Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, PR China
| | - Xue Zou
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Yu Jin
- Department of Clinical Medicine, Medical School of Nanjing University , Nanjing, 210093, China.
- Nanjing Children's Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
| | - Nan Zheng
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, 210093, China.
| | - Zhiwei Wu
- Center for Public Health Research, Medical School, Nanjing University, Nanjing, 210093, China.
- State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, People's Republic of China.
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, People's Republic of China.
| | - Yongxiang Wang
- Department of Orthopedics, Northern Jiangsu People's Hospital, Clinical Teaching Hospital of Medical School,Nanjing University, Yangzhou, China.
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Elashry MI, Speer J, De Marco I, Klymiuk MC, Wenisch S, Arnhold S. Extracellular Vesicles: A Novel Diagnostic Tool and Potential Therapeutic Approach for Equine Osteoarthritis. Curr Issues Mol Biol 2024; 46:13078-13104. [PMID: 39590374 PMCID: PMC11593097 DOI: 10.3390/cimb46110780] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 11/12/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
Osteoarthritis (OA) is a chronic progressive degenerative joint disease that affects a significant portion of the equine population and humans worldwide. Current treatment options for equine OA are limited and incompletely curative. Horses provide an excellent large-animal model for studying human OA. Recent advances in the field of regenerative medicine have led to the exploration of extracellular vesicles (EVs)-cargoes of microRNA, proteins, lipids, and nucleic acids-to evaluate their diagnostic value in terms of disease progression and severity, as well as a potential cell-free therapeutic approach for equine OA. EVs transmit molecular signals that influence various biological processes, including the inflammatory response, apoptosis, proliferation, and cell communication. In the present review, we summarize recent advances in the isolation and identification of EVs, the use of their biologically active components as biomarkers, and the distribution of the gap junction protein connexin 43. Moreover, we highlight the role of mesenchymal stem cell-derived EVs as a potential therapeutic tool for equine musculoskeletal disorders. This review aims to provide a comprehensive overview of the current understanding of the pathogenesis, diagnosis, and treatment strategies for OA. In particular, the roles of EVs as biomarkers in synovial fluid, chondrocytes, and plasma for the early detection of equine OA are discussed.
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Affiliation(s)
- Mohamed I. Elashry
- Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-University of Giessen, 35392 Giessen, Germany; (J.S.); (M.C.K.); (S.A.)
| | - Julia Speer
- Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-University of Giessen, 35392 Giessen, Germany; (J.S.); (M.C.K.); (S.A.)
| | - Isabelle De Marco
- Clinic of Small Animals, c/o Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-University of Giessen, 35392 Giessen, Germany; (I.D.M.); (S.W.)
| | - Michele C. Klymiuk
- Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-University of Giessen, 35392 Giessen, Germany; (J.S.); (M.C.K.); (S.A.)
| | - Sabine Wenisch
- Clinic of Small Animals, c/o Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-University of Giessen, 35392 Giessen, Germany; (I.D.M.); (S.W.)
| | - Stefan Arnhold
- Institute of Veterinary Anatomy, Histology and Embryology, Justus-Liebig-University of Giessen, 35392 Giessen, Germany; (J.S.); (M.C.K.); (S.A.)
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Peng D, Liu T, Lu H, Zhang L, Chen H, Huang Y, Hu B, Zhang Q. Intranasal delivery of engineered extracellular vesicles loaded with miR-206-3p antagomir ameliorates Alzheimer's disease phenotypes. Theranostics 2024; 14:7623-7644. [PMID: 39659569 PMCID: PMC11626949 DOI: 10.7150/thno.103596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 10/25/2024] [Indexed: 12/12/2024] Open
Abstract
Rationale: The level of miR-206-3p in the plasma and temporal cortex is increased in Alzheimer's disease (AD) patients. miR-206-3p antagomir injected into hippocampus ameliorates cognitive deficits by enhancing the level of BDNF. However, the trauma caused by brain injection and susceptibility to degradation limit its application. Methods: To overcome these challenges, we constructed engineered extracellular vesicles derived from mesenchymal stem cell (MSC-EVs) loaded with miR-206-3p antagomir (MSC-EVs-anta) by electroporation technology, and explored the therapeutic effects of MSC-EVs-anta delivered by intranasal administration on AD mice. Transcriptome sequencing and LC-MS/MS proteomic analysis were employed to disclose the mechanism underlying the attenuation of AD phenotypes by MSC-EVs-anta. Results: MSC-EVs-anta had favorable neuroprotection by promoting neurite outgrowth in vitro. Following intranasal administration, MSC-EVs-anta improved learning and memory deficits, promoted hippocampal neurogenesis and synaptic plasticity, and alleviated Aβ deposition. Compared with MSC-EVs or miR-206-3p antagomir alone, MSC-EVs-anta showed superior therapeutic effects. Mechanistically, MSC-EVs-anta significantly upregulated brain-derived neurotrophic factor (BDNF) in AD mice, and activated the BDNF/TrkB signaling pathway. The data from two-omics analyses demonstrated that the differentially expressed proteins and genes significantly regulated by MSC-EVs-anta were primarily enriched in the pathways involved in neurogenesis and synapse. Conclusions: Our findings highlight the intranasal administration of MSC-EVs-anta as a promising strategy for the treatment of AD.
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Affiliation(s)
- Dong Peng
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Tingting Liu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Huahui Lu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Lei Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Hongxia Chen
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China
| | - Yadong Huang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China
| | - Bo Hu
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Qihao Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China
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Zhao E, Liang R, Li P, Lu D, Chen S, Tan W, Qin Y, Zhang Y, Zhang Y, Zhang Q, Liu Q. Mesenchymal stromal cells alleviate APAP-induced liver injury via extracellular vesicle-mediated regulation of the miR-186-5p/CXCL1 axis. Stem Cell Res Ther 2024; 15:392. [PMID: 39490995 PMCID: PMC11533353 DOI: 10.1186/s13287-024-03995-8] [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: 08/18/2024] [Accepted: 10/13/2024] [Indexed: 11/05/2024] Open
Abstract
BACKGROUND Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury (DILI). N-acetylcysteine (NAC) is the first-line agent used in the clinic. However, it rarely benefits patients with advanced APAP toxicity. Mesenchymal stromal cells (MSCs) have demonstrated potential in treating DILI. However, the specific mechanism by which MSCs protect against APAP-induced liver injury remains unclear. METHODS APAP was injected intraperitoneally to induce a liver injury model. We then detected histopathology, biochemical indices, and inflammatory cytokine levels to assess the efficacy of MSCs and MSC extracellular vesicles (MSC-EVs). Flow cytometry was performed to reveal the immunoregulatory effects of MSCs and MSC-EVs on the neutrophils. RNA sequencing (RNA-Seq) of liver tissues was used to identify critical target genes for MSC treatment. RESULTS MSC and MSC-EV treatment effectively alleviated APAP-induced liver injury and inhibited neutrophil infiltration. RNA-Seq analysis and ELISA data indicated that C-X-C motif chemokine 1 (CXCL1), a chemoattractant for neutrophils, was a key molecule in the MSC-mediated amelioration of APAP-induced liver damage. In addition, neutralization of CXCL1 reduced APAP-induced liver damage, which was accompanied by decreased neutrophil infiltration. Importantly, we verified that MSC-EV-derived miR-186-5p directly binds to the 3'-UTR of Cxcl1 to inhibit its expression in hepatocytes. The agomir miR-186-5p showed excellent potential for the treatment of DILI. CONCLUSIONS Our findings suggest that MSCs and MSC-EVs are an effective approach to mitigate DILI. Targeting the miR-186-5p/CXCL1 axis is a promising approach to improve the efficacy of MSCs and MSC-EVs in the treatment of DILI.
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Affiliation(s)
- Erming Zhao
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Rukang Liang
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Panlong Li
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Di Lu
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Shuhan Chen
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Weikeng Tan
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yunfei Qin
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yana Zhang
- Department of Otolaryngology-Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
- Department of Allergy, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
| | - Yingcai Zhang
- Department of Hepatic Surgery and Liver Transplantation Centre, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
| | - Qi Zhang
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
| | - Qiuli Liu
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
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Tian L, Jin J, Lu Q, Zhang H, Tian S, Lai F, Liu C, Liang Y, Lu Y, Zhao Y, Yao S, Ren W. Bidirectional modulation of extracellular vesicle-autophagy axis in acute lung injury: Molecular mechanisms and therapeutic implications. Biomed Pharmacother 2024; 180:117566. [PMID: 39423751 DOI: 10.1016/j.biopha.2024.117566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/09/2024] [Indexed: 10/21/2024] Open
Abstract
Acute lung injury (ALI), a multifactorial pathological condition, manifests through heightened inflammatory responses, compromised lung epithelial-endothelial barrier function, and oxidative stress, potentially culminating in respiratory failure and mortality. This study explores the intricate interplay between two crucial cellular mechanisms-extracellular vesicles (EVs) and autophagy-in the context of ALI pathogenesis and potential therapeutic interventions.EVs, bioactive membrane-bound structures secreted by cells, serve as versatile carriers of molecular cargo, facilitating intercellular communication and significantly influencing disease progression. Concurrently, autophagy, an essential intracellular degradation process, maintains cellular homeostasis and has emerged as a promising therapeutic target in ALI and acute respiratory distress syndrome.Our research unveils a fascinating "EV-Autophagy dual-drive pathway," characterized by reciprocal regulation between these two processes. EVs modulate autophagy activation and inhibition, while autophagy influences EV production, creating a dynamic feedback loop. This study posits that precise manipulation of this pathway could revolutionize ALI treatment strategies.By elucidating the mechanisms underlying this cellular crosstalk, we open new avenues for targeted therapies. The potential for engineered EVs to fine-tune autophagy in ALI treatment is explored, alongside innovative concepts such as EV-based vaccines for ALI prevention and management. This research not only deepens our understanding of ALI pathophysiology but also paves the way for novel, more effective therapeutic approaches in critical care medicine.
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Affiliation(s)
- Linqiang Tian
- Henan Medical Key Laboratory for Research of Trauma and Orthopedics, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province 453003, China; Clinical Medical Center of Tissue Egineering and Regeneration, Xinxiang Medical University, Xinxiang, Henan Province 453003, China
| | - Jie Jin
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China
| | - Qianying Lu
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China
| | - Huajing Zhang
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China
| | - Sijia Tian
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China
| | - Feng Lai
- Henan Medical Key Laboratory for Research of Trauma and Orthopedics, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province 453003, China
| | - Chuanchuan Liu
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China
| | - Yangfan Liang
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China
| | - Yujia Lu
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China
| | - Yanmei Zhao
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China.
| | - Sanqiao Yao
- Institutes of Health Central Plain, Xinxiang Medical University, Xinxiang, Henan Province 453003, China; School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province 453003, China.
| | - Wenjie Ren
- Henan Medical Key Laboratory for Research of Trauma and Orthopedics, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province 453003, China; Clinical Medical Center of Tissue Egineering and Regeneration, Xinxiang Medical University, Xinxiang, Henan Province 453003, China; Institutes of Health Central Plain, Xinxiang Medical University, Xinxiang, Henan Province 453003, China.
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Gawish MF, Abd El-Baset SA, Shalabi SS, Ibrahem NE. Efficacy of ozone versus mesenchymal stem cell-derived microvesicles in ameliorating testicular changes after hypothyroidism in adult albino rats: a histological and immunohistochemical study. Ultrastruct Pathol 2024; 48:496-525. [PMID: 39552092 DOI: 10.1080/01913123.2024.2423863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/21/2024] [Accepted: 10/28/2024] [Indexed: 11/19/2024]
Abstract
This study was performed to: detect the histological, immunohistochemical, and biochemical alterations that may occur in the testes of adult rats in induced hypothyroidism. And to investigate which one, ozone or MSCs-MVs have better therapeutic effect on testicular changes after hypothyroidism. Eighty-four male adult rats were separated into: control group, hypothyroidism group: rats will be given carbimazole for 30 days, ozone group: rats treated as hypothyroidism group then will be injected with ozone intraperitoneal for 7 days. MSC-MVs group: rats treated as hypothyroidism group then will be injected with a single intravenous dose MSC-MVs. Specimens of testes were handled for light, electron microscope, and immunohistochemical of vimentin and S100. Biochemical analysis for; MDA and TNFα; serum testosterone, TSH, T3, and T4 was done, also, sperm count and morphology assay. Morphometric and statistical analysis were performed. Hypothyroidism group showed disorganized seminiferous tubules. A noticeable gap was between the basement membrane and the germinal epithelium. Wide interstitium had congested vessels and acidophilic homogenous material. Vacuolated germinal epithelium and few germ cells had dark nuclei with noticeable separation of between the basement membrane and the germinal epithelium. Ozone and MSCs-MVs induced improvement in all the previous parameters and restoration of spermatogenesis. In Conclusion MSCs-MVs has better ameliorative effect than ozone on hypothyroidism-exposed testes.
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Affiliation(s)
- Magdy F Gawish
- Medical Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | | | | | - Nahla E Ibrahem
- Medical Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Zhao R, Han F, Yu Q, Zhu Z, Tu Z, Xia T, Li B. A multifunctional scaffold that promotes the scaffold-tissue interface integration and rescues the ROS microenvironment for repair of annulus fibrosus defects. Bioact Mater 2024; 41:257-270. [PMID: 39149595 PMCID: PMC11325007 DOI: 10.1016/j.bioactmat.2024.03.007] [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: 10/17/2023] [Revised: 03/04/2024] [Accepted: 03/07/2024] [Indexed: 08/17/2024] Open
Abstract
Due to the limited self-repair ability of the annulus fibrosus (AF), current tissue engineering strategies tend to use structurally biomimetic scaffolds for AF defect repair. However, the poor integration between implanted scaffolds and tissue severely affects their therapeutic effects. To solve this issue, we prepared a multifunctional scaffold containing loaded lysyl oxidase (LOX) plasmid DNA exosomes and manganese dioxide nanoparticles (MnO2 NPs). LOX facilitates extracellular matrix (ECM) cross-linking, while MnO2 NPs inhibit excessive reactive oxygen species (ROS)-induced ECM degradation at the injury site, enhancing the crosslinking effect of LOX. Our results revealed that this multifunctional scaffold significantly facilitated the integration between the scaffold and AF tissue. Cells were able to migrate into the scaffold, indicating that the scaffold was not encapsulated as a foreign body by fibrous tissue. The functional scaffold was closely integrated with the tissue, effectively enhancing the mechanical properties, and preventing vascular invasion, which emphasized the importance of scaffold-tissue integration in AF repair.
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Affiliation(s)
- Runze Zhao
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, MOE Key Laboratory of Geriatric Diseases and Immunology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215000, China
- Center of Translational Medicine and Clinical Laboratory, The Fourth Affiliated Hospital to Soochow University, Suzhou, 215028, China
| | - Feng Han
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, MOE Key Laboratory of Geriatric Diseases and Immunology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215000, China
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China
| | - Qifan Yu
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, MOE Key Laboratory of Geriatric Diseases and Immunology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215000, China
| | - Zhuang Zhu
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, MOE Key Laboratory of Geriatric Diseases and Immunology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215000, China
| | - Zhengdong Tu
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, MOE Key Laboratory of Geriatric Diseases and Immunology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215000, China
- Second Department of Orthopaedics, Suzhou Kowloon Hospital, Shanghai Jiaotong University Medical School, Suzhou, 215127, China
| | - Tingting Xia
- Institute of Clinical Medicine Research, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, 215153, China
| | - Bin Li
- Medical 3D Printing Center, Orthopedic Institute, Department of Orthopedic Surgery, The First Affiliated Hospital, MOE Key Laboratory of Geriatric Diseases and Immunology, School of Biology and Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215000, China
- Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215000, China
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Huang M, Liu Y, Zhang L, Wang S, Wang X, He Z. Advancements in Research on Mesenchymal Stem-Cell-Derived Exosomal miRNAs: A Pivotal Insight into Aging and Age-Related Diseases. Biomolecules 2024; 14:1354. [PMID: 39595531 PMCID: PMC11592330 DOI: 10.3390/biom14111354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 11/28/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are capable of differentiating into various cell types and play a crucial role in repairing aging tissues and diseased organs. Aging manifests as a gradual loss of cellular, tissue, and organ function, leading to the progression of pathologies. Exosomes (Exos) are extracellular vesicles secreted by cells, which maintain cellular homeostasis, clear cellular debris, and facilitate communication between cells and organs. This review provides a comprehensive summary of the mechanisms for the synthesis and sorting of MSC-Exo miRNAs and summarizes the current research status of MSCs-Exos in mitigating aging and age-related diseases. It delves into the underlying molecular mechanisms, which encompass antioxidative stress, anti-inflammatory response, and the promotion of angiogenesis. Additionally, this review also discusses potential challenges in and future strategies for advancing MSC-Exo miRNA-based therapies in the treatment of aging and age-related diseases.
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Affiliation(s)
- Minglei Huang
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; (M.H.); (Y.L.); (S.W.)
| | - Ye Liu
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; (M.H.); (Y.L.); (S.W.)
| | - Longze Zhang
- Scientific Research Center, The First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi 563000, China;
| | - Shuangmin Wang
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; (M.H.); (Y.L.); (S.W.)
| | - Xianyao Wang
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China; (M.H.); (Y.L.); (S.W.)
| | - Zhixu He
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
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36
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Daga KR, Larey AM, Morfin MG, Chen K, Bitarafan S, Carpenter JM, Hynds HM, Hines KM, Wood LB, Marklein RA. Microglia morphological response to mesenchymal stromal cell extracellular vesicles demonstrates EV therapeutic potential for modulating neuroinflammation. J Biol Eng 2024; 18:58. [PMID: 39420399 PMCID: PMC11488223 DOI: 10.1186/s13036-024-00449-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 09/16/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) are a promising therapeutic for neuroinflammation. MSC-EVs can interact with microglia, the resident immune cells of the brain, to exert their immunomodulatory effects. In response to inflammatory cues, such as cytokines, microglia undergo phenotypic changes indicative of their function e.g. morphology and secretion. However, these changes in response to MSC-EVs are not well understood. Additionally, no disease-relevant screening tools to assess MSC-EV bioactivity exist, which has further impeded clinical translation. Here, we developed a quantitative, high throughput morphological profiling approach to assess the response of microglia to neuroinflammation- relevant signals and whether this morphological response can be used to indicate the bioactivity of MSC-EVs. RESULTS Using an immortalized human microglia cell-line, we observed increased size (perimeter, major axis length) and complexity (form factor) upon stimulation with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Upon treatment with MSC-EVs, the overall morphological score (determined using principal component analysis) shifted towards the unstimulated morphology, indicating that MSC-EVs are bioactive and modulate microglia. The morphological effects of MSC-EVs in TNF-α /IFN-γ stimulated cells were concomitant with reduced secretion of 14 chemokines/cytokines (e.g. CXCL6, CXCL9) and increased secretion of 12 chemokines/cytokines (e.g. CXCL8, CXCL10). Proteomic analysis of cell lysates revealed significant increases in 192 proteins (e.g. HIBADH, MEAK7, LAMC1) and decreases in 257 proteins (e.g. PTEN, TOM1, MFF) with MSC-EV treatment. Of note, many of these proteins are involved in regulation of cell morphology and migration. Gene Set Variation Analysis revealed upregulation of pathways associated with immune response, such as regulation of cytokine production, immune cell infiltration (e.g. T cells, NK cells) and morphological changes (e.g. Semaphorin, RHO/Rac signaling). Additionally, changes in microglia mitochondrial morphology were measured suggesting that MSC-EV modulate mitochondrial metabolism. CONCLUSION This study comprehensively demonstrates the effects of MSC-EVs on human microglial morphology, cytokine secretion, cellular proteome, and mitochondrial content. Our high-throughput, rapid, low-cost morphometric approach enables screening of MSC-EV batches and manufacturing conditions to enhance EV function and mitigate EV functional heterogeneity in a disease relevant manner. This approach is highly generalizable and can be further adapted and refined based on selection of the disease-relevant signal, target cell, and therapeutic product.
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Affiliation(s)
- Kanupriya R Daga
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Andrew M Larey
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Maria G Morfin
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
| | - Kailin Chen
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
- Franklin College of Arts and Sciences, University of Georgia, Athens, GA, USA
| | - Sara Bitarafan
- George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | | | - Hannah M Hynds
- Department of Chemistry, University of Georgia, Athens, GA, USA
| | - Kelly M Hines
- Department of Chemistry, University of Georgia, Athens, GA, USA
| | - Levi B Wood
- George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Ross A Marklein
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA.
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA.
- Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD, 20903, USA.
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Dong J, Gong Z, Bi H, Yang J, Wang B, Du K, Zhang C, Chen L. BMSC-derived exosomal miR-219-5p alleviates ferroptosis in neuronal cells caused by spinal cord injury via the UBE2Z/NRF2 pathway. Neuroscience 2024; 556:73-85. [PMID: 39084457 DOI: 10.1016/j.neuroscience.2024.06.011] [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: 01/10/2024] [Revised: 06/05/2024] [Accepted: 06/15/2024] [Indexed: 08/02/2024]
Abstract
OBJECTIVE The aim of this study was to investigate the molecular mechanism of exosomal miR-219-5p derived from bone marrow mesenchymal stem cells (BMSCs) in the treatment of spinal cord injury (SCI). METHODS Basso Beattie Bresnahan (BBB) score and tissue staining were used to assess SCI and neuronal survival in rats. The contents of Fe2+, malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were detected by a kit. The expression levels of ubiquitin-conjugating enzyme E2 Z (UBE2Z), nuclear factor erythroid 2-related Factor 2 (NRF2) and ferroptosis-related proteins were detected by Western blotting. In addition, the ability of BMSC-derived exosomes to inhibit ferroptosis in neuronal cells in rats with SCI was validated by in vivo injection of ferroptosis inhibitors/inducers. RESULTS In this study, we found that miR-219-5p-rich BMSC-derived exosomes inhibited ferroptosis in SCI rats and that the alleviating effect of BMSC-Exos on SCI was achieved by inhibiting the ferroptosis signaling pathway and that NRF2 played a key role in this process. Our study confirmed that BMSC exosome-specific delivery of miR-219-5p can target UBE2Z to regulate its stability and that overexpression of UBE2Z reverses miR-219-5p regulation of NRF2. In addition, in vivo experiments showed that BMSC exosomes alleviated ferroptosis in neuronal SCI progression, and inhibiting the expression of miR-219-5p in BMSCs reduced the alleviating effect of exosomes on ferroptosis in neuronal cells and SCI. CONCLUSION miR-219-5p in BMSC-derived exosomes can repair the injured spinal cord. In addition, miR-219-5p alleviates ferroptosis in neuronal cells induced by SCI through the UBE2Z/NRF2 pathway.
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Affiliation(s)
- Junjie Dong
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Zhiqiang Gong
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Hangchuan Bi
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Jin Yang
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Bing Wang
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Kaili Du
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Chunqiang Zhang
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China
| | - Lingqiang Chen
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan, China.
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38
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Abraham BD, Gysel E, Kallos MS, Hu J. Biofunctionalization of Cellulose Microcarriers Using a Carbohydrate Binding Module Linked with Fibroblast Growth Factor for the Expansion of Human Umbilical Mesenchymal Stromal Cells in Stirred Suspension Bioreactors. ACS APPLIED BIO MATERIALS 2024; 7:5956-5964. [PMID: 39190068 DOI: 10.1021/acsabm.4c00513] [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: 08/28/2024]
Abstract
Mesenchymal stromal cells (MSCs) have the potential to be used as autologous or allogenic cell therapy in several diseases due to their beneficial secretome and capacity for immunomodulation and differentiation. However, clinical trials using MSCs require a large number of cells. As an alternative to traditional culture flasks, suspension bioreactors provide a scalable platform to produce clinically relevant quantities of cells. When cultured in bioreactors, anchorage-dependent cells like MSCs require the addition of microcarriers, which provide a surface for cell attachment while in suspension. The best performing microcarriers are typically coated in animal derived proteins, which increases cellular attachment and proliferation but present issues from a regulatory perspective. To overcome this issue, a recombinant fusion protein was generated linking basic fibroblast growth factor (bFGF) to a cellulose-specific carbohydrate binding module (CBM) and used to functionalize the surface of cellulose microcarriers for the expansion of human umbilical MSCs in suspension bioreactors. The fusion protein was shown to support the growth of MSCs when used as a soluble growth factor in the absence of cellulose, readily bound to cellulose microcarriers in a dose-dependent manner, and ultimately improved the expansion of MSCs when grown in bioreactors using cellulose microcarriers. The use of CBM fusion proteins offers a simple method for the surface immobilization of growth factors to animal component-free substrates such as cellulose, which can be used alongside bioreactors to increase growth factor lifespan, decrease culture medium cost, and increase cell production in the manufacturing of therapeutic cells.
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Affiliation(s)
- Brett D Abraham
- Department of Biomedical Engineering, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada
| | - Emilie Gysel
- Department of Biomedical Engineering, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada
| | - Michael S Kallos
- Department of Biomedical Engineering, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada
| | - Jinguang Hu
- Department of Chemical and Petroleum Engineering, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada
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Shan Y, Zhang M, Tao E, Wang J, Wei N, Lu Y, Liu Q, Hao K, Zhou F, Wang G. Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges. Signal Transduct Target Ther 2024; 9:242. [PMID: 39271680 PMCID: PMC11399464 DOI: 10.1038/s41392-024-01936-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 07/04/2024] [Accepted: 07/23/2024] [Indexed: 09/15/2024] Open
Abstract
Over the past two decades, mesenchymal stem/stromal cell (MSC) therapy has made substantial strides, transitioning from experimental clinical applications to commercial products. MSC therapies hold considerable promise for treating refractory and critical conditions such as acute graft-versus-host disease, amyotrophic lateral sclerosis, and acute respiratory distress syndrome. Despite recent successes in clinical and commercial applications, MSC therapy still faces challenges when used as a commercial product. Current detection methods have limitations, leaving the dynamic biodistribution, persistence in injured tissues, and ultimate fate of MSCs in patients unclear. Clarifying the relationship between the pharmacokinetic characteristics of MSCs and their therapeutic effects is crucial for patient stratification and the formulation of precise therapeutic regimens. Moreover, the development of advanced imaging and tracking technologies is essential to address these clinical challenges. This review provides a comprehensive analysis of the kinetic properties, key regulatory molecules, different fates, and detection methods relevant to MSCs and discusses concerns in evaluating MSC druggability from the perspective of integrating pharmacokinetics and efficacy. A better understanding of these challenges could improve MSC clinical efficacy and speed up the introduction of MSC therapy products to the market.
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Affiliation(s)
- Yunlong Shan
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Mengying Zhang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Enxiang Tao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Jing Wang
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Ning Wei
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Yi Lu
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Qing Liu
- Jiangsu Renocell Biotech Co. Ltd., Nanjing, China
| | - Kun Hao
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Fang Zhou
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
| | - Guangji Wang
- Key Laboratory of Drug Metabolism and Pharmacokinetics, Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
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40
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Barekzai J, Refflinghaus L, Okpara M, Tasto L, Tertel T, Giebel B, Czermak P, Salzig D. Process development for the production of mesenchymal stromal cell-derived extracellular vesicles in conventional 2D systems. Cytotherapy 2024; 26:999-1012. [PMID: 38819363 DOI: 10.1016/j.jcyt.2024.04.071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/23/2024] [Accepted: 04/24/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND In recent years, the importance of extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) has increased significantly. For their widespread use, a standardized EV manufacturing is needed which often includes conventional, static 2D systems. For these system critical process parameters need to be determined. METHODS We studied the impact of process parameters on MSC proliferation, MSC-derived particle production including EVs, EV- and MSC-specific marker expression, and particle functionality in a HaCaT cell migration assay. RESULTS We found that cell culture growth surface and media affected MSCs and their secretory behavior. Interestingly, the materials that promoted MSC proliferation did not necessarily result in the most functional MSC-derived particles. In addition, we found that MSCs seeded at 4 × 103 cells cm-2 produced particles with improved functional properties compared to higher seeding densities. MSCs in a highly proliferative state did not produce the most particles, although these particles were significantly more effective in promoting HaCaT cell migration. The same correlation was found when investigating the cultivation temperature. A physiological temperature of 37°C was not optimal for particle yield, although it resulted in the most functional particles. We observed a proliferation-associated particle production and found potential correlations between particle production and glucose consumption, enabling the estimation of final particle yields. CONCLUSIONS Our findings suggest that parameters, which must be defined prior to each individual cultivation and do not require complex and expensive equipment, can significantly increase MSC-derived particle production including EVs. Integrating these parameters into a standardized EV process development paves the way for robust and efficient EV manufacturing for early clinical phases.
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Affiliation(s)
- Jan Barekzai
- Institute of Bioprocess Engineering and Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
| | - Laura Refflinghaus
- Institute of Bioprocess Engineering and Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
| | - Maduwuike Okpara
- Institute of Bioprocess Engineering and Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
| | - Lars Tasto
- Institute of Bioprocess Engineering and Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany
| | - Tobias Tertel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Peter Czermak
- Institute of Bioprocess Engineering and Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany; Faculty of Biology and Chemistry, Justus-Liebig-University of Giessen, Giessen Germany
| | - Denise Salzig
- Institute of Bioprocess Engineering and Pharmaceutical Technology, University of Applied Sciences Mittelhessen, Giessen, Germany; Faculty of Biology and Chemistry, Justus-Liebig-University of Giessen, Giessen Germany.
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41
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Costa-Ferro ZSM, Rocha GV, da Silva KN, Paredes BD, Loiola EC, Silva JD, Santos JLDS, Dias RB, Figueira CP, de Oliveira CI, de Moura LD, Ribeiro LNDM, de Paula E, Zanette DL, Rocha CAG, Rocco PRM, Souza BSDF. GMP-compliant extracellular vesicles derived from umbilical cord mesenchymal stromal cells: manufacturing and pre-clinical evaluation in ARDS treatment. Cytotherapy 2024; 26:1013-1025. [PMID: 38762805 DOI: 10.1016/j.jcyt.2024.04.074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/23/2024] [Accepted: 04/27/2024] [Indexed: 05/20/2024]
Abstract
BACKGROUND AIMS Extracellular vesicles (EVs) represent a new axis of intercellular communication that can be harnessed for therapeutic purposes, as cell-free therapies. The clinical application of mesenchymal stromal cell (MSC)-derived EVs, however, is still in its infancy and faces many challenges. The heterogeneity inherent to MSCs, differences among donors, tissue sources, and variations in manufacturing conditions may influence the release of EVs and their cargo, thus potentially affecting the quality and consistency of the final product. We investigated the influence of cell culture and conditioned medium harvesting conditions on the physicochemical and proteomic profile of human umbilical cord MSC-derived EVs (hUCMSC-EVs) produced under current good manufacturing practice (cGMP) standards. We also evaluated the efficiency of the protocol in terms of yield, purity, productivity, and expression of surface markers, and assessed the biodistribution, toxicity and potential efficacy of hUCMSC-EVs in pre-clinical studies using the LPS-induced acute lung injury model. METHODS hUCMSCs were isolated from a cord tissue, cultured, cryopreserved, and characterized at a cGMP facility. The conditioned medium was harvested at 24, 48, and 72 h after the addition of EV collection medium. Three conventional methods (nanoparticle tracking analysis, transmission electron microscopy, and nanoflow cytometry) and mass spectrometry were used to characterize hUCMSC-EVs. Safety (toxicity of single and repeated doses) and biodistribution were evaluated in naive mice after intravenous administration of the product. Efficacy was evaluated in an LPS-induced acute lung injury model. RESULTS hUCMSC-EVs were successfully isolated using a cGMP-compliant protocol. Comparison of hUCMSC-EVs purified from multiple harvests revealed progressive EV productivity and slight changes in the proteomic profile, presenting higher homogeneity at later timepoints of conditioned medium harvesting. Pooled hUCMSC-EVs showed a non-toxic profile after single and repeated intravenous administration to naive mice. Biodistribution studies demonstrated a major concentration in liver, spleen and lungs. HUCMSC-EVs reduced lung damage and inflammation in a model of LPS-induced acute lung injury. CONCLUSIONS hUCMSC-EVs were successfully obtained following a cGMP-compliant protocol, with consistent characteristics and pre-clinical safety profile, supporting their future clinical development as cell-free therapies.
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Affiliation(s)
- Zaquer Suzana Munhoz Costa-Ferro
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil; D'Or Institute for Research and Education (IDOR), Salvador, Brazil
| | - Gisele Vieira Rocha
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil; D'Or Institute for Research and Education (IDOR), Salvador, Brazil
| | - Katia Nunes da Silva
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil
| | - Bruno Diaz Paredes
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil; D'Or Institute for Research and Education (IDOR), Salvador, Brazil
| | - Erick Correia Loiola
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil; D'Or Institute for Research and Education (IDOR), Salvador, Brazil
| | - Johnatas Dutra Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSaúde, Research Support Foundation of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - John Lenon de Souza Santos
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil; Gonçalo Moniz Institute, FIOCRUZ, Salvador, Brazil
| | - Rosane Borges Dias
- Gonçalo Moniz Institute, FIOCRUZ, Salvador, Brazil; Federal University of Bahia, UFBA, Salvador, Brazil
| | | | | | | | - Lígia Nunes de Morais Ribeiro
- Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil; Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, Brazil
| | - Eneida de Paula
- Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil
| | | | - Clarissa Araújo Gurgel Rocha
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil; D'Or Institute for Research and Education (IDOR), Salvador, Brazil; Gonçalo Moniz Institute, FIOCRUZ, Salvador, Brazil; Federal University of Bahia, UFBA, Salvador, Brazil
| | - Patricia Rieken Macedo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil; Rio de Janeiro Innovation Network in Nanosystems for Health-NanoSaúde, Research Support Foundation of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Bruno Solano de Freitas Souza
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil; D'Or Institute for Research and Education (IDOR), Salvador, Brazil; Gonçalo Moniz Institute, FIOCRUZ, Salvador, Brazil.
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Farag A, Koung Ngeun S, Kaneda M, Aboubakr M, Tanaka R. Optimizing Cardiomyocyte Differentiation: Comparative Analysis of Bone Marrow and Adipose-Derived Mesenchymal Stem Cells in Rats Using 5-Azacytidine and Low-Dose FGF and IGF Treatment. Biomedicines 2024; 12:1923. [PMID: 39200387 PMCID: PMC11352160 DOI: 10.3390/biomedicines12081923] [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: 07/19/2024] [Revised: 08/09/2024] [Accepted: 08/19/2024] [Indexed: 09/02/2024] Open
Abstract
Mesenchymal stem cells (MSCs) exhibit multipotency, self-renewal, and immune-modulatory properties, making them promising in regenerative medicine, particularly in cardiovascular treatments. However, optimizing the MSC source and induction method of cardiac differentiation is challenging. This study compares the cardiomyogenic potential of bone marrow (BM)-MSCs and adipose-derived (AD)-MSCs using 5-Azacytidine (5-Aza) alone or combined with low doses of Fibroblast Growth Factor (FGF) and Insulin-like Growth Factor (IGF). BM-MSCs and AD-MSCs were differentiated using two protocols: 10 μmol 5-Aza alone and 10 μmol 5-Aza with 1 ng/mL FGF and 10 ng/mL IGF. Morphological, transcriptional, and translational analyses, along with cell viability assessments, were performed. Both the MSC types exhibited similar morphological changes; however, AD-MSCs achieved 70-80% confluence faster than BM-MSCs. Surface marker profiling confirmed CD29 and CD90 positivity and CD45 negativity. The differentiation protocols led to cell flattening and myotube formation, with earlier differentiation in AD-MSCs. The combined protocol reduced cell mortality in BM-MSCs and enhanced the expression of cardiac markers (MEF2c, Troponin I, GSK-3β), particularly in BM-MSCs. Immunofluorescence confirmed cardiac-specific protein expression in all the treated groups. Both MSC types exhibited the expression of cardiac-specific markers indicative of cardiomyogenic differentiation, with the combined treatment showing superior efficiency for BM-MSCs.
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Affiliation(s)
- Ahmed Farag
- Veterinary Teaching Hospital, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Sai Koung Ngeun
- Laboratory of Veterinary Diagnostic Imaging, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan;
| | - Masahiro Kaneda
- Laboratory of Veterinary Anatomy, Division of Animal Life Science, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan;
| | - Mohamed Aboubakr
- Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, Toukh 13736, Egypt;
| | - Ryou Tanaka
- Veterinary Teaching Hospital, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
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Wisdom EC, Lamont A, Martinez H, Rockovich M, Lee W, Gilchrist KH, Ho VB, Klarmann GJ. An Exosome-Laden Hydrogel Wound Dressing That Can Be Point-of-Need Manufactured in Austere and Operational Environments. Bioengineering (Basel) 2024; 11:804. [PMID: 39199762 PMCID: PMC11351238 DOI: 10.3390/bioengineering11080804] [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: 07/22/2024] [Revised: 08/05/2024] [Accepted: 08/07/2024] [Indexed: 09/01/2024] Open
Abstract
Skin wounds often form scar tissue during healing. Early intervention with tissue-engineered materials and cell therapies may promote scar-free healing. Exosomes and extracellular vesicles (EV) secreted by mesenchymal stromal cells (MSC) are believed to have high regenerative capacity. EV bioactivity is preserved after lyophilization and storage to enable use in remote and typically resource-constrained environments. We developed a bioprinted bandage containing reconstituted EVs that can be fabricated at the point-of-need. An alginate/carboxymethyl cellulose (CMC) biomaterial ink was prepared, and printability and mechanical properties were assessed with rheology and compression testing. Three-dimensional printed constructs were evaluated for Young's modulus relative to infill density and crosslinking to yield material with stiffness suitable for use as a wound dressing. We purified EVs from human MSC-conditioned media and characterized them with nanoparticle tracking analysis and mass spectroscopy, which gave a peak size of 118 nm and identification of known EV proteins. Fluorescently labeled EVs were mixed to form bio-ink and bioprinted to characterize EV release. EV bandages were bioprinted on both a commercial laboratory bioprinter and a custom ruggedized 3D printer with bioprinting capabilities, and lyophilized EVs, biomaterial ink, and thermoplastic filament were deployed to an austere Arctic environment and bioprinted. This work demonstrates that EVs can be bioprinted with an alginate/CMC hydrogel and released over time when in contact with a skin-like substitute. The technology is suitable for operational medical applications, notably in resource-limited locations, including large-scale natural disasters, humanitarian crises, and combat zones.
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Affiliation(s)
- E. Cate Wisdom
- USU Center for Biotechnology (4DBio3), Department of Radiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA (K.H.G.); (V.B.H.); (G.J.K.)
- The Geneva Foundation, 917 Pacific Ave, Tacoma, WA 98402, USA
| | - Andrew Lamont
- USU Center for Biotechnology (4DBio3), Department of Radiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA (K.H.G.); (V.B.H.); (G.J.K.)
- The Geneva Foundation, 917 Pacific Ave, Tacoma, WA 98402, USA
| | - Hannah Martinez
- The United States Air Force Academy, 2304 Cadet Drive, USAF Academy, CO 80840, USA
- School of Medicine, Uniformed Service University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA
| | - Michael Rockovich
- The United States Naval Academy, 121 Blake Rd., Annapolis, MD 21402, USA
| | - Woojin Lee
- The United States Military Academy, 606 Thayer Rd., West Point, NY 10996, USA
| | - Kristin H. Gilchrist
- USU Center for Biotechnology (4DBio3), Department of Radiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA (K.H.G.); (V.B.H.); (G.J.K.)
- The Geneva Foundation, 917 Pacific Ave, Tacoma, WA 98402, USA
| | - Vincent B. Ho
- USU Center for Biotechnology (4DBio3), Department of Radiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA (K.H.G.); (V.B.H.); (G.J.K.)
| | - George J. Klarmann
- USU Center for Biotechnology (4DBio3), Department of Radiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA (K.H.G.); (V.B.H.); (G.J.K.)
- The Geneva Foundation, 917 Pacific Ave, Tacoma, WA 98402, USA
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Yang W, Yang Y, Wang Y, Gao Z, Zhang J, Gao W, Chen Y, Lu Y, Wang H, Zhou L, Wang Y, Li J, Tao H. Metformin prevents the onset and progression of intervertebral disc degeneration: New insights and potential mechanisms (Review). Int J Mol Med 2024; 54:71. [PMID: 38963023 PMCID: PMC11232665 DOI: 10.3892/ijmm.2024.5395] [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: 01/16/2024] [Accepted: 05/02/2024] [Indexed: 07/05/2024] Open
Abstract
Metformin has been the go‑to medical treatment for addressing type 2 diabetes mellitus (T2DM) as a frontline oral antidiabetic. Obesity, cancer and bone deterioration are linked to T2DM, which is considered a metabolic illness. Numerous diseases associated with T2DM, such as tumours, cardiovascular disease and bone deterioration, may be treated with metformin. Intervertebral disc degeneration (IVDD) is distinguished by degeneration of the spinal disc, accompanied by the gradual depletion of proteoglycans and water in the nucleus pulposus (NP) of the IVD, resulting in lower back pain. The therapeutic effect of metformin on IVDD has also attracted much attention. By stimulating AMP‑activated kinase, metformin could enhance autophagy and suppress cell senescence, apoptosis and inflammation, thus effectively delaying IVDD. The present review aimed to systematically explain the development of IVDD and mechanism of metformin in the treatment and prevention of IVDD to provide a reference for the clinical application of metformin as adjuvant therapy in the treatment of IVDD.
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Affiliation(s)
- Wenzhi Yang
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- Department of Spine Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- Department of Clinical Medicine, School of The First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yipin Yang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Yong Wang
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- Department of Spine Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- Department of Clinical Medicine, School of The First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Zongshi Gao
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- Department of Spine Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- Department of Clinical Medicine, School of The First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Jingtang Zhang
- Department of Clinical Medicine, School of The First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Weimin Gao
- Department of Clinical Medicine, School of The First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yanjun Chen
- Department of Clinical Medicine, School of The First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - You Lu
- Department of Clinical Medicine, School of The First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Haoyu Wang
- Department of Clinical Medicine, School of The First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Lingyan Zhou
- Department of Clinical Medicine, School of The First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Yifan Wang
- Department of Clinical Medicine, School of The First Clinical Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Jie Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Hui Tao
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
- Department of Spine Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
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45
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Din MAU, Wan A, Chu Y, Zhou J, Yan Y, Xu Z. Therapeutic role of extracellular vesicles from human umbilical cord mesenchymal stem cells and their wide therapeutic implications in inflammatory bowel disease and other inflammatory disorder. Front Med (Lausanne) 2024; 11:1406547. [PMID: 39139783 PMCID: PMC11319305 DOI: 10.3389/fmed.2024.1406547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 07/18/2024] [Indexed: 08/15/2024] Open
Abstract
The chronic immune-mediated inflammatory condition known as inflammatory bowel disease (IBD) significantly affects the gastrointestinal system. While the precise etiology of IBD remains elusive, extensive research suggests that a range of pathophysiological pathways and immunopathological mechanisms may significantly contribute as potential factors. Mesenchymal stem cells (MSCs) have shown significant potential in the development of novel therapeutic approaches for various medical conditions. However, some MSCs have been found to exhibit tumorigenic characteristics, which limit their potential for medical treatments. The extracellular vesicles (EVs), paracrine factors play a crucial role in the therapeutic benefits conferred by MSCs. The EVs consist of proteins, microRNAs, and lipids, and are instrumental in facilitating intercellular communication. Due to the ease of maintenance, and decreased immunogenicity, tumorigenicity the EVs have become a new and exciting option for whole cell treatment. This review comprehensively assesses recent preclinical research on human umbilical cord mesenchymal stem cell (hUC-MSC)-derived EVs as a potential IBD therapy. It comprehensively addresses key aspects of various conditions, including diabetes, cancer, dermal injuries, neurological disorders, cardiovascular issues, liver and kidney diseases, and bone-related afflictions.
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Affiliation(s)
- Muhammad Azhar Ud Din
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine Jiangsu University, Zhenjiang, China
| | | | - Ying Chu
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
| | - Jing Zhou
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
| | - Yongmin Yan
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
| | - Zhiliang Xu
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
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Lanci A, Iacono E, Merlo B. Therapeutic Application of Extracellular Vesicles Derived from Mesenchymal Stem Cells in Domestic Animals. Animals (Basel) 2024; 14:2147. [PMID: 39123673 PMCID: PMC11310970 DOI: 10.3390/ani14152147] [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: 06/09/2024] [Revised: 07/12/2024] [Accepted: 07/20/2024] [Indexed: 08/12/2024] Open
Abstract
Recently, the therapeutic potential of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) has been extensively studied in both human and veterinary medicine. EVs are nano-sized particles containing biological components commonly found in other biological materials. For that reason, EV isolation and characterization are critical to draw precise conclusions during their investigation. Research on EVs within veterinary medicine is still considered in its early phases, yet numerous papers were published in recent years. The conventional adult tissues for deriving MSCs include adipose tissue and bone marrow. Nonetheless, alternative sources such as synovial fluid, endometrium, gingiva, and milk have also been intermittently used. Fetal adnexa are amniotic membrane/fluid, umbilical cord and Wharton's jelly. Cells derived from fetal adnexa exhibit an intermediate state between embryonic and adult cells, demonstrating higher proliferative and differentiative potential and longer telomeres compared to cells from adult tissues. Summarized here are the principal and recent preclinical and clinical studies performed in domestic animals such as horse, cattle, dog and cat. To minimize the use of antibiotics and address the serious issue of antibiotic resistance as a public health concern, they will undoubtedly also be utilized in the future to treat infections in domestic animals. A number of concerns, including large-scale production with standardization of EV separation and characterization techniques, must be resolved for clinical application.
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Affiliation(s)
- Aliai Lanci
- Department of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sora 50, Ozzano dell’Emilia, 40064 Bologna, Italy; (E.I.); (B.M.)
| | - Eleonora Iacono
- Department of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sora 50, Ozzano dell’Emilia, 40064 Bologna, Italy; (E.I.); (B.M.)
- Health Science and Technologies Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, 40100 Bologna, Italy
| | - Barbara Merlo
- Department of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sora 50, Ozzano dell’Emilia, 40064 Bologna, Italy; (E.I.); (B.M.)
- Health Science and Technologies Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, 40100 Bologna, Italy
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Jha SK, Imran M, Anwaar S, Hansbro PM, Paudel KR, Mohammed Y. Mesenchymal stem cell membrane-coated nanoconstructs: why have they not yet found a home in clinical practice? Nanomedicine (Lond) 2024; 19:1507-1510. [PMID: 38953891 PMCID: PMC11321396 DOI: 10.1080/17435889.2024.2369495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 06/14/2024] [Indexed: 07/04/2024] Open
Affiliation(s)
- Saurav Kumar Jha
- Department of Biological Sciences & Bioengineering (BSBE), Indian Institute of Technology, Kanpur208016, Uttar Pradesh, India
| | - Mohammad Imran
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane4102, Australia
| | - Shoaib Anwaar
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane4102, Australia
| | - Philip M Hansbro
- Centre for Inflammation, Faculty of Science, School of Life Science, Centenary Institute & University of Technology Sydney, Sydney2007, Australia
| | - Keshav Raj Paudel
- Centre for Inflammation, Faculty of Science, School of Life Science, Centenary Institute & University of Technology Sydney, Sydney2007, Australia
| | - Yousuf Mohammed
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane4102, Australia
- School of Pharmacy, The University of Queensland, Brisbane4102, Australia
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48
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Li X, Zhang C, Yue W, Jiang Y. Modulatory effects of cancer stem cell-derived extracellular vesicles on the tumor immune microenvironment. Front Immunol 2024; 15:1362120. [PMID: 38962016 PMCID: PMC11219812 DOI: 10.3389/fimmu.2024.1362120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 06/03/2024] [Indexed: 07/05/2024] Open
Abstract
Cancer stem cells (CSCs), accounting for only a minor cell proportion (< 1%) within tumors, have profound implications in tumor initiation, metastasis, recurrence, and treatment resistance due to their inherent ability of self-renewal, multi-lineage differentiation, and tumor-initiating potential. In recent years, accumulating studies indicate that CSCs and tumor immune microenvironment act reciprocally in driving tumor progression and diminishing the efficacy of cancer therapies. Extracellular vesicles (EVs), pivotal mediators of intercellular communications, build indispensable biological connections between CSCs and immune cells. By transferring bioactive molecules, including proteins, nucleic acids, and lipids, EVs can exert mutual influence on both CSCs and immune cells. This interaction plays a significant role in reshaping the tumor immune microenvironment, creating conditions favorable for the sustenance and propagation of CSCs. Deciphering the intricate interplay between CSCs and immune cells would provide valuable insights into the mechanisms of CSCs being more susceptible to immune escape. This review will highlight the EV-mediated communications between CSCs and each immune cell lineage in the tumor microenvironment and explore potential therapeutic opportunities.
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Affiliation(s)
- Xinyu Li
- Department of Animal Science, College of Animal Science, Hebei North University, Zhangjiakou, Hebei, China
- Department of Gynecology and Obstetrics, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Cuilian Zhang
- Reproductive Medicine Center, Henan Provincial People’s Hospital, Zhengzhou University, Zhengzhou, China
| | - Wei Yue
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction, Peking University, Ministry of Education, Beijing, China
| | - Yuening Jiang
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction, Peking University, Ministry of Education, Beijing, China
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Hao X, Wang S, Wang L, Li J, Li Y, Liu J. Exosomes as drug delivery systems in glioma immunotherapy. J Nanobiotechnology 2024; 22:340. [PMID: 38890722 PMCID: PMC11184820 DOI: 10.1186/s12951-024-02611-4] [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: 03/04/2024] [Accepted: 06/02/2024] [Indexed: 06/20/2024] Open
Abstract
Recently, the significant benefits of cancer immunotherapy for most cancers have been demonstrated in clinical and preclinical studies. However, the efficacy of these immunotherapies for gliomas is limited, owing to restricted drug delivery and insufficient immune activation. As drug carriers, exosomes offer the advantages of low toxicity, good biocompatibility, and intrinsic cell targeting, which could enhance glioma immunotherapy efficacy. However, a review of exosome-based drug delivery systems for glioma immunotherapy has not been presented. This review introduces the current problems in glioma immunotherapy and the role of exosomes in addressing these issues. Meanwhile, preparation and application strategies of exosome-based drug delivery systems for glioma immunotherapy are discussed, especially for enhancing immunogenicity and reversing the immunosuppressive tumor microenvironment. Finally, we briefly describe the challenges of exosome-based drug delivery systems in clinical translation. We anticipate that this review will guide the use of exosomes as drug carriers for glioma immunotherapy.
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Affiliation(s)
- Xinqing Hao
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, No. 193 Lianhe Road, Dalian, Liaoning, 116011, China
- Dalian Innovation Institute of Stem Cell and Precision Medicine, No. 57 Xinda Road, Dalian, Liaoning, 116085, China
| | - Shiming Wang
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, No. 193 Lianhe Road, Dalian, Liaoning, 116011, China
| | - Liang Wang
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, No. 193 Lianhe Road, Dalian, Liaoning, 116011, China
- Dalian Innovation Institute of Stem Cell and Precision Medicine, No. 57 Xinda Road, Dalian, Liaoning, 116085, China
| | - Jiaqi Li
- Reproductive Medicine Center, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian, 116011, China
| | - Ying Li
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, No. 193 Lianhe Road, Dalian, Liaoning, 116011, China.
- Dalian Innovation Institute of Stem Cell and Precision Medicine, No. 57 Xinda Road, Dalian, Liaoning, 116085, China.
| | - Jing Liu
- Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, No. 193 Lianhe Road, Dalian, Liaoning, 116011, China.
- Dalian Innovation Institute of Stem Cell and Precision Medicine, No. 57 Xinda Road, Dalian, Liaoning, 116085, China.
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Guerricchio L, Barile L, Bollini S. Evolving Strategies for Extracellular Vesicles as Future Cardiac Therapeutics: From Macro- to Nano-Applications. Int J Mol Sci 2024; 25:6187. [PMID: 38892376 PMCID: PMC11173118 DOI: 10.3390/ijms25116187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/28/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024] Open
Abstract
Cardiovascular disease represents the foremost cause of mortality and morbidity worldwide, with a steadily increasing incidence due to the growth of the ageing population. Cardiac dysfunction leading to heart failure may arise from acute myocardial infarction (MI) as well as inflammatory- and cancer-related chronic cardiomyopathy. Despite pharmacological progress, effective cardiac repair represents an unmet clinical need, with heart transplantation being the only option for end-stage heart failure. The functional profiling of the biological activity of extracellular vesicles (EVs) has recently attracted increasing interest in the field of translational research for cardiac regenerative medicine. The cardioprotective and cardioactive potential of human progenitor stem/cell-derived EVs has been reported in several preclinical studies, and EVs have been suggested as promising paracrine therapy candidates for future clinical translation. Nevertheless, some compelling aspects must be properly addressed, including optimizing delivery strategies to meet patient needs and enhancing targeting specificity to the cardiac tissue. Therefore, in this review, we will discuss the most relevant aspects of the therapeutic potential of EVs released by human progenitors for cardiovascular disease, with a specific focus on the strategies that have been recently implemented to improve myocardial targeting and administration routes.
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Affiliation(s)
- Laura Guerricchio
- Biology Unit, Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy;
| | - Lucio Barile
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, CH-6500 Bellinzona, Switzerland;
- Euler Institute, Faculty of Biomedical Sciences, Università della Svizzera Italiana, CH-6900 Lugano, Switzerland
| | - Sveva Bollini
- Biology Unit, Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy;
- Cellular Oncology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
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