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Grignano MA, Pisani S, Gregorini M, Rainaudo G, Avanzini MA, Croce S, Valsecchi C, Ceccarelli G, Islami T, Margiotta E, Portalupi V, De Mauri A, Stea ED, Pattonieri EF, Iadarola P, Viglio S, Conti B, Rampino T. Engineered ATP-Loaded Extracellular Vesicles Derived from Mesenchymal Stromal Cells: A Novel Strategy to Counteract Cell ATP Depletion in an In Vitro Model. Int J Mol Sci 2025; 26:3424. [PMID: 40244293 PMCID: PMC11990007 DOI: 10.3390/ijms26073424] [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: 03/03/2025] [Revised: 04/02/2025] [Accepted: 04/04/2025] [Indexed: 04/18/2025] Open
Abstract
The use of adenosine triphosphate (ATP) has shown promising effects in alleviating ischemic damage across various tissues. However, the penetration of ATP into kidney tubular cells presents a challenge due to their unique anatomical and physiological properties. In this study, we introduce a novel bioinspired drug delivery system utilizing extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) and engineered to carry ATP. ATP-loaded liposomes (ATP-LPs) and ATP-loaded EVs (ATP-EVs) were prepared using microfluidic technology, followed by characterization of their morphology (DLS, NTA, SEM, TEM), ATP content, and release rate at 37 °C (pH 7.4). Additionally, the delivery efficacy of ATP-LPs and ATP-EVs was evaluated in vitro on renal cells (HK2 cells) under chemically induced ischemia. The results indicated successful ATP enrichment in EVs, with ATP-EVs showing no significant changes in morphology or size compared to naïve EVs. Notably, ATP-EVs demonstrated superior ATP retention compared to ATP-LPs, protecting the ATP from degradation in the extracellular environment. In an ATP-depleted HK2 cell model, only ATP-EVs effectively restored ATP levels, preserving cell viability and reducing apoptotic gene expression (BCL2-BAX). This study is the first to successfully demonstrate the direct delivery of ATP into renal tubular cells in vitro using EVs as carriers.
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Affiliation(s)
- Maria Antonietta Grignano
- Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.A.G.); (M.G.); (G.R.); (T.I.); (E.M.); (V.P.); (A.D.M.); (E.D.S.); (E.F.P.); (T.R.)
| | - Silvia Pisani
- Department of Drug Sciences, University of Pavia, Viale Torquato Taramelli 12, 27100 Pavia, Italy;
| | - Marilena Gregorini
- Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.A.G.); (M.G.); (G.R.); (T.I.); (E.M.); (V.P.); (A.D.M.); (E.D.S.); (E.F.P.); (T.R.)
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Giorgia Rainaudo
- Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.A.G.); (M.G.); (G.R.); (T.I.); (E.M.); (V.P.); (A.D.M.); (E.D.S.); (E.F.P.); (T.R.)
| | - Maria Antonietta Avanzini
- Pediatric Haematology/Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.A.A.); (C.V.)
- Cell Factory and Center for Advanced Therapies, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Stefania Croce
- Cell Factory and Center for Advanced Therapies, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Chiara Valsecchi
- Pediatric Haematology/Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.A.A.); (C.V.)
- Cell Factory and Center for Advanced Therapies, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Gabriele Ceccarelli
- Human Anatomy Unit, Department of Public Health, Experimental Medicine and Forensic, University of Pavia, 27100 Pavia, Italy;
- Centre for Health Technologies (CHT), University of Pavia, 27100 Pavia, Italy
| | - Tefik Islami
- Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.A.G.); (M.G.); (G.R.); (T.I.); (E.M.); (V.P.); (A.D.M.); (E.D.S.); (E.F.P.); (T.R.)
| | - Elisabetta Margiotta
- Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.A.G.); (M.G.); (G.R.); (T.I.); (E.M.); (V.P.); (A.D.M.); (E.D.S.); (E.F.P.); (T.R.)
| | - Valentina Portalupi
- Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.A.G.); (M.G.); (G.R.); (T.I.); (E.M.); (V.P.); (A.D.M.); (E.D.S.); (E.F.P.); (T.R.)
| | - Andreana De Mauri
- Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.A.G.); (M.G.); (G.R.); (T.I.); (E.M.); (V.P.); (A.D.M.); (E.D.S.); (E.F.P.); (T.R.)
| | - Emma Diletta Stea
- Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.A.G.); (M.G.); (G.R.); (T.I.); (E.M.); (V.P.); (A.D.M.); (E.D.S.); (E.F.P.); (T.R.)
| | - Eleonora Francesca Pattonieri
- Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.A.G.); (M.G.); (G.R.); (T.I.); (E.M.); (V.P.); (A.D.M.); (E.D.S.); (E.F.P.); (T.R.)
| | - Paolo Iadarola
- Department of Biology and Biotechnologies “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy;
| | - Simona Viglio
- Lung Transplantation Unit, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy;
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Bice Conti
- Department of Drug Sciences, University of Pavia, Viale Torquato Taramelli 12, 27100 Pavia, Italy;
| | - Teresa Rampino
- Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.A.G.); (M.G.); (G.R.); (T.I.); (E.M.); (V.P.); (A.D.M.); (E.D.S.); (E.F.P.); (T.R.)
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
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Lu Y, Shi R, He W, An Q, Zhao J, Gao X, Zhang B, Zhang L, Xu K, Ma D. Cell therapy in Sjögren's syndrome: opportunities and challenges. Expert Rev Mol Med 2024; 26:e28. [PMID: 39438246 PMCID: PMC11505611 DOI: 10.1017/erm.2024.21] [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: 08/22/2023] [Revised: 06/26/2024] [Accepted: 07/09/2024] [Indexed: 10/25/2024]
Abstract
Sjögren's syndrome (SS) is a chronic autoimmune disease caused by immune system disorders. The main clinical manifestations of SS are dry mouth and eyes caused by the destruction of exocrine glands, such as the salivary and lacrimal glands, and systemic manifestations, such as interstitial pneumonia, interstitial nephritis and vasculitis. The pathogenesis of this condition is complex. However, this has not been fully elucidated. Treatment mainly consists of glucocorticoids, disease-modifying antirheumatic drugs and biological agents, which can only control inflammation but not repair the tissue. Therefore, identifying methods to regulate immune disorders and repair damaged tissues is imperative. Cell therapy involves the transplantation of autologous or allogeneic normal or bioengineered cells into the body of a patient to replace damaged cells or achieve a stronger immunomodulatory capacity to cure diseases, mainly including stem cell therapy and immune cell therapy. Cell therapy can reduce inflammation, relieve symptoms and promote tissue repair and regeneration of exocrine glands such as the salivary glands. It has broad application prospects and may become a new treatment strategy for patients with SS. However, there are various challenges in cell preparation, culture, storage and transportation. This article reviews the research status and prospects of cell therapies for SS.
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Affiliation(s)
- Yangyang Lu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic diseases), Taiyuan, China
- Shanxi Province Clinical Theranostics Technology Innovation Center for Immunologic and Rheumatic Diseases, Taiyuan, China
| | - Rongjing Shi
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic diseases), Taiyuan, China
- Shanxi Province Clinical Theranostics Technology Innovation Center for Immunologic and Rheumatic Diseases, Taiyuan, China
| | - Wenqin He
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic diseases), Taiyuan, China
- Shanxi Province Clinical Theranostics Technology Innovation Center for Immunologic and Rheumatic Diseases, Taiyuan, China
| | - Qi An
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic diseases), Taiyuan, China
- Shanxi Province Clinical Theranostics Technology Innovation Center for Immunologic and Rheumatic Diseases, Taiyuan, China
| | - Jingwen Zhao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic diseases), Taiyuan, China
- Shanxi Province Clinical Theranostics Technology Innovation Center for Immunologic and Rheumatic Diseases, Taiyuan, China
| | - Xinnan Gao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic diseases), Taiyuan, China
- Shanxi Province Clinical Theranostics Technology Innovation Center for Immunologic and Rheumatic Diseases, Taiyuan, China
| | - Baiyan Zhang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic diseases), Taiyuan, China
- Shanxi Province Clinical Theranostics Technology Innovation Center for Immunologic and Rheumatic Diseases, Taiyuan, China
| | - Liyun Zhang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic diseases), Taiyuan, China
- Shanxi Province Clinical Theranostics Technology Innovation Center for Immunologic and Rheumatic Diseases, Taiyuan, China
| | - Ke Xu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic diseases), Taiyuan, China
- Shanxi Province Clinical Theranostics Technology Innovation Center for Immunologic and Rheumatic Diseases, Taiyuan, China
| | - Dan Ma
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
- Shanxi Province Clinical Research Center for Dermatologic and Immunologic Diseases (Rheumatic diseases), Taiyuan, China
- Shanxi Province Clinical Theranostics Technology Innovation Center for Immunologic and Rheumatic Diseases, Taiyuan, China
- Shanxi Academy of Advanced Research and Innovation, Taiyuan, China
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Wrublewsky S, Schultz J, Ammo T, Bickelmann C, Metzger W, Später T, Pohlemann T, Menger MD, Laschke MW. Biofabrication of prevascularized spheroids for bone tissue engineering by fusion of microvascular fragments with osteoblasts. Front Bioeng Biotechnol 2024; 12:1436519. [PMID: 39318668 PMCID: PMC11419975 DOI: 10.3389/fbioe.2024.1436519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 08/29/2024] [Indexed: 09/26/2024] Open
Abstract
Introduction Spheroids are promising building blocks for scaffold-free bone tissue engineering. Their rapid vascularization is of major importance to guarantee their survival after transplantation. To achieve this, we herein introduce the biofabrication of prevascularized spheroids by fusion of adipose tissue-derived microvascular fragments (MVF) with osteoblasts (OB). Methods For this purpose, 200 MVF from donor mice and 5,000, 10,000 or 20,000 murine OB (MC3T3-E1) were co-cultured in a liquid overlay system for 3 days to generate OB + MVF spheroids. OB mono-culture spheroids served as controls. Results and discussion During the generation process, the diameters of all spheroids progressively decreased, resulting in compact, viable spheroids of homogeneous sizes. MVF promoted the maturation of spheroids containing 5,000 OB, as shown by an accelerated decline of cell proliferation due to contact inhibition. Moreover, MVF most effectively reassembled into new microvascular networks within these small spheroids when compared to the other spheroid types, indicating the most beneficial MVF to OB ratio. Accordingly, these spheroids also showed a high angiogenic sprouting activity in vitro. In contrast to OB spheroids, they further rapidly vascularized in vivo after transplantation into dorsal skinfold chambers. This was caused by the interconnection of incorporated MVF with surrounding blood vessels. These findings indicate that OB + MVF spheroids may be suitable for bone tissue engineering, which should be next tested in appropriate in vivo bone defect models.
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Affiliation(s)
- Selina Wrublewsky
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
| | - Jessica Schultz
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
- Department of Trauma, Hand, and Reconstructive Surgery, Saarland University, Homburg, Germany
| | - Tekoshin Ammo
- Department of Trauma, Hand, and Reconstructive Surgery, Saarland University, Homburg, Germany
| | - Caroline Bickelmann
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
| | - Wolfgang Metzger
- Department of Trauma, Hand, and Reconstructive Surgery, Saarland University, Homburg, Germany
| | - Thomas Später
- Department of Molecular, Cell and Systems Biology, University of California, Riverside, Riverside, CA, United States
| | - Tim Pohlemann
- Department of Trauma, Hand, and Reconstructive Surgery, Saarland University, Homburg, Germany
| | - Michael D. Menger
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
| | - Matthias W. Laschke
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany
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Zhuo H, Chen Y, Zhao G. Advances in application of hypoxia-preconditioned mesenchymal stem cell-derived exosomes. Front Cell Dev Biol 2024; 12:1446050. [PMID: 39239560 PMCID: PMC11375678 DOI: 10.3389/fcell.2024.1446050] [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: 06/12/2024] [Accepted: 08/12/2024] [Indexed: 09/07/2024] Open
Abstract
Mesenchymal stem cells (MSCs) primarily secrete physiologically functional exosomes via paracrine effects that act on various adjacent and distant cells, thus exerting their therapeutic effects. In recent years, hypoxic preconditioning, as a novel MSC culture mode, has emerged as a research hotspot. Many previous studies have shown the role and underlying regulatory mechanisms of hypoxic preconditioning in various diseases, which has provided sufficient reference materials for the MSC research field. Therefore, this review summarizes the progress in application of hypoxia-preconditioned MSC-derived exosomes that substantially increases and improves the biological activity of specific molecules, such as microRNA.
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Affiliation(s)
- Haitao Zhuo
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, China
| | - Yunfei Chen
- Department of Nuroscience, Mayo Clinic, Jacksonville, FL, United States
| | - Guifang Zhao
- Department of Pathology, Jilin Medical University, Jilin, China
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Ellakany AR, El Baz H, Shoheib ZS, Elzallat M, Ashour DS, Yassen NA. Stem cell-derived exosomes as a potential therapy for schistosomal hepatic fibrosis in experimental animals. Pathog Glob Health 2024; 118:429-449. [PMID: 37519008 PMCID: PMC11338202 DOI: 10.1080/20477724.2023.2240085] [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: 08/01/2023] Open
Abstract
Schistosomiasis is a neglected tropical disease. Egg-induced granuloma formation and tissue fibrosis are the main causes of the high morbidity and mortality of schistosomiasis. Mesenchymal stem cells (MSCs)-derived exosomes play an important role with a superior safety profile than MSCs in the treatment of liver fibrosis. Therefore, the aim of this study was to investigate the potential therapeutic effect of MSCs-derived exosomes on schistosomal hepatic fibrosis. Exosomes were isolated from bone marrow MSCs and characterized. A total of 85 mice were divided into four groups: group I (control group), group II (PZQ group) infected and treated with PZQ, group III (EXO group) infected and treated with MSCs-derived exosomes and group IV (PZQ+EXO group) infected and treated with both PZQ and MSCs-derived exosomes. Assessment of treatment efficacy was evaluated by histopathological and immunohistochemical examination of liver sections by proliferating cell nuclear antigen (PCNA) and nuclear factor-κB (NF-κB). The results showed significant reduction of the number and diameter of hepatic granulomas, hepatic fibrosis, upregulation of PCNA expression and reduction of NF-κB expression in EXO and PZQ+EXO groups as compared to other groups at all durations post infection. Additionally, more improvement was observed in PZQ+EXO group. In conclusion, MSCs-derived exosomes are a promising agent for the treatment of schistosomal hepatic fibrosis, and their combination with PZQ shows a synergistic action including antifibrotic and anti-inflammatory effects. However, further studies are required to establish their functional components and their mechanisms of action.
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Affiliation(s)
- Asmaa R. Ellakany
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Hanan El Baz
- Immunology Department, Theodor Bilharz Research Institute, Cairo, Egypt
| | - Zeinab S. Shoheib
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohamed Elzallat
- Immunology Department, Theodor Bilharz Research Institute, Cairo, Egypt
| | - Dalia S. Ashour
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Nabila A. Yassen
- Medical Parasitology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
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Krishnan I, Chan AML, Law JX, Ng MH, Jayapalan JJ, Lokanathan Y. Proteomic Analysis of Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Systematic Review. Int J Mol Sci 2024; 25:5340. [PMID: 38791378 PMCID: PMC11121203 DOI: 10.3390/ijms25105340] [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: 03/26/2024] [Revised: 04/29/2024] [Accepted: 05/01/2024] [Indexed: 05/26/2024] Open
Abstract
Numerous challenges remain within conventional cell-based therapy despite the growing trend of stem cells used to treat various life-debilitating diseases. These limitations include batch-to-batch heterogeneity, induced alloreactivity, cell survival and integration, poor scalability, and high cost of treatment, thus hindering successful translation from lab to bedside. However, recent pioneering technology has enabled the isolation and enrichment of small extracellular vesicles (EVs), canonically known as exosomes. EVs are described as a membrane-enclosed cargo of functional biomolecules not limited to lipids, nucleic acid, and proteins. Interestingly, studies have correlated the biological role of MSC-EVs to the paracrine activity of MSCs. This key evidence has led to rigorous studies on MSC-EVs as an acellular alternative. Using EVs as a therapy was proposed as a model leading to improvements through increased safety; enhanced bioavailability due to size and permeability; reduced heterogeneity by selective and quantifiable properties; and prolonged shelf-life via long-term freezing or lyophilization. Yet, the identity and potency of EVs are still relatively unknown due to various methods of preparation and to qualify the final product. This is reflected by the absence of regulatory strategies overseeing manufacturing, quality control, clinical implementation, and product registration. In this review, the authors review the various production processes and the proteomic profile of MSC-EVs.
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Affiliation(s)
- Illayaraja Krishnan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
| | - Alvin Man Lung Chan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
| | - Jia Xian Law
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
| | - Min Hwei Ng
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
| | | | - Yogeswaran Lokanathan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (A.M.L.C.); (J.X.L.); (M.H.N.)
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Zhang S, Wang S, Chen J, Cui Y, Lu X, Xiong S, Yue C, Yang B. Human dental pulp stem cell-derived exosomes decorated titanium scaffolds for promoting bone regeneration. Colloids Surf B Biointerfaces 2024; 235:113775. [PMID: 38330688 DOI: 10.1016/j.colsurfb.2024.113775] [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: 11/29/2023] [Revised: 01/21/2024] [Accepted: 01/31/2024] [Indexed: 02/10/2024]
Abstract
Exosomes, nanoscale extracellular vesicles crucial for intercellular communication, hold great promise as a therapeutic avenue in cell-free tissue regeneration. In this study, we identified and utilized exosomes to adorn anodized titanium scaffolds, inducing osteogenic differentiation in human dental pulp stem cells (hDPSCs). The osteogenesis of hDPSCs was stimulated by exosomes derived from hDPSCs that underwent various periods of osteogenic differentiation. After purification, these exosomes were loaded onto anodized titanium scaffolds. Notably, the scaffolds loaded with exosomes deriving from osteogenic differentiated hDPSCs demonstrated superior bone tissue regeneration compared to those loaded with exosomes deriving from hDPSCs within 10-week. RNA-sequencing analysis shed light on the underlying mechanism, revealing that the osteogenic exosomes carried specific cargo, which is due to upregulated miRNAs (Hsa-miR-29c-5p, Hsa-miR-378a-5p, Hsa-miR-10b-5p and Hsa-miR-9-3p) associated with osteogenesis. And down-regulated anti-osteogenic miRNA (Hsa-miR-31-3p, Hsa-miR-221-3p, Hsa-miR-183-5p and Hsa-miR-503-5p). In conclusion, the identification and utilization of exosomes derived from osteogenic differentiated stem cells offer a novel and promising strategy for achieving cell-free bone regeneration.
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Affiliation(s)
- Siqi Zhang
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Simeng Wang
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Jun Chen
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Yifan Cui
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Xugang Lu
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Shibing Xiong
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China
| | - Chongxia Yue
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterial & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China.
| | - Bangcheng Yang
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu 610064, People's Republic of China; National Engineering Research Center for Biomaterials, Chengdu 610064, People's Republic of China; College of Biomedical Engineering, Sichuan University, Chengdu 610064, People's Republic of China.
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Didamoony MA, Soubh AA, Atwa AM, Ahmed LA. Innovative preconditioning strategies for improving the therapeutic efficacy of extracellular vesicles derived from mesenchymal stem cells in gastrointestinal diseases. Inflammopharmacology 2023; 31:2973-2993. [PMID: 37874430 PMCID: PMC10692273 DOI: 10.1007/s10787-023-01350-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 09/20/2023] [Indexed: 10/25/2023]
Abstract
Gastrointestinal (GI) diseases have become a global health issue and an economic burden due to their wide distribution, late prognosis, and the inefficacy of recent available medications. Therefore, it is crucial to search for new strategies for their management. In the recent decades, mesenchymal stem cells (MSCs) therapy has attracted attention as a viable option for treating a myriad of GI disorders such as hepatic fibrosis (HF), ulcerative colitis (UC), acute liver injury (ALI), and non-alcoholic fatty liver disease (NAFLD) due to their regenerative and paracrine properties. Importantly, recent studies have shown that MSC-derived extracellular vesicles (MSC-EVs) are responsible for most of the therapeutic effects of MSCs. In addition, EVs have revealed several benefits over their parent MSCs, such as being less immunogenic, having a lower risk of tumour formation, being able to cross biological barriers, and being easier to store. MSC-EVs exhibited regenerative, anti-oxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic effects in different experimental models of GI diseases. However, a key issue with their clinical application is the maintenance of their stability and efficacy following in vivo transplantation. Preconditioning of MSC-EVs or their parent cells is one of the novel methods used to improve their effectiveness and stability. Herein, we discuss the application of MSC-EVs in several GI disorders taking into account their mechanism of action. We also summarise the challenges and restrictions that need to be overcome to promote their clinical application in the treatment of various GI diseases as well as the recent developments to improve their effectiveness. A representation of the innovative preconditioning techniques that have been suggested for improving the therapeutic efficacy of MSC-EVs in GI diseases. The pathological conditions in various GI disorders (ALI, UC, HF and NAFLD) create a harsh environment for EVs and their parents, increasing the risk of apoptosis and senescence of MSCs and thereby diminishing MSC-EVs yield and restricting their large-scale applications. Preconditioning with pharmacological agents or biological mediators can improve the therapeutic efficacy of MSC-EVs through their adaption to the lethal environment to which they are subjected. This can result in establishment of a more conducive environment and activation of numerous vital trajectories that act to improve the immunomodulatory, reparative and regenerative activities of the derived EVs, as a part of MSCs paracrine system. ALI, acute liver injury; GI diseases, gastrointestinal diseases; HF, hepatic fibrosis; HSP, heat shock protein; miRNA, microRNA; mRNA, messenger RNA; MSC-EVs, mesenchymal stem cell-derived extracellular vesicles; NAFLD, non-alcoholic fatty liver disease; UC, ulcerative colitis.
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Affiliation(s)
- Manar A Didamoony
- Faculty of Pharmacy, Pharmacology and Toxicology Department, Egyptian Russian University, Cairo, 11829, Egypt.
| | - Ayman A Soubh
- Faculty of Pharmacy, Pharmacology and Toxicology Department, Ahram Canadian University, 4th Industrial Zone, Banks Complex, 6th of October City, Giza, 12451, Egypt
| | - Ahmed M Atwa
- Faculty of Pharmacy, Pharmacology and Toxicology Department, Egyptian Russian University, Cairo, 11829, Egypt
| | - Lamiaa A Ahmed
- Faculty of Pharmacy, Pharmacology and Toxicology Department, Cairo University, Cairo, 11562, Egypt.
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9
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Peng Y, Jiang H, Zuo HD. Factors affecting osteogenesis and chondrogenic differentiation of mesenchymal stem cells in osteoarthritis. World J Stem Cells 2023; 15:548-560. [PMID: 37424946 PMCID: PMC10324504 DOI: 10.4252/wjsc.v15.i6.548] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/21/2023] [Accepted: 05/05/2023] [Indexed: 06/26/2023] Open
Abstract
Osteoarthritis (OA) is a common degenerative joint disease that often involves progressive cartilage degeneration and bone destruction of subchondral bone. At present, clinical treatment is mainly for pain relief, and there are no effective methods to delay the progression of the disease. When this disease progresses to the advanced stage, the only treatment option for most patients is total knee replacement surgery, which causes patients great pain and anxiety. As a type of stem cell, mesenchymal stem cells (MSCs) have multidirectional differentiation potential. The osteogenic differentiation and chondrogenic differentiation of MSCs can play vital roles in the treatment of OA, as they can relieve pain in patients and improve joint function. The differentiation direction of MSCs is accurately controlled by a variety of signaling pathways, so there are many factors that can affect the differentiation direction of MSCs by acting on these signaling pathways. When MSCs are applied to OA treatment, the microenvironment of the joints, injected drugs, scaffold materials, source of MSCs and other factors exert specific impacts on the differentiation direction of MSCs. This review aims to summarize the mechanisms by which these factors influence MSC differentiation to produce better curative effects when MSCs are applied clinically in the future.
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Affiliation(s)
- Yi Peng
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Hai Jiang
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Hou-Dong Zuo
- Medical Imaging Key Laboratory of Sichuan Province, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
- Department of Radiology, Chengdu Xinhua Hospital, Chengdu 610067, Sichuan Province, China
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10
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Gholami M, Ghorban K, Sadeghi M, Dadmanesh M, Rouzbahani NH, Dehnavi S. Mesenchymal stem cells and allergic airway inflammation; a therapeutic approach to induce immunoregulatory responses. Int Immunopharmacol 2023; 120:110367. [PMID: 37230032 DOI: 10.1016/j.intimp.2023.110367] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/07/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023]
Abstract
Allergic airway inflammations are among the essential disorders worldwide that are already considered a significant concern. Mesenchymal stem cells (MSCs) are stromal cells with regenerative potential and immunomodulatory characteristics and are widely administered for tissue repair as an immunoregulatory agent in different inflammatory diseases. The current review summarized primary studies conducted to evaluate the therapeutic potential of MSCs for allergic airway disorders. In this case, modulation of airway pathologic inflammation and infiltration of inflammatory cells were examined, and modulation of the Th1/Th2 cellular balance and humoral responses. Also, the effects of MSCs on the Th17/Treg ratio and inducing Treg immunoregulatory responses along with macrophage and dendritic cell function were evaluated.
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Affiliation(s)
- Mohammad Gholami
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Medical Microbiology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Khodayar Ghorban
- Department of Immunology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Mahvash Sadeghi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Dadmanesh
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Infectious Diseases, School Of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Negin Hosseini Rouzbahani
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Immunology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Sajad Dehnavi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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11
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Fu T, Zhu Q, Lou F, Cai S, Peng S, Xiao J. Advanced glycation end products inhibit the osteogenic differentiation potential of adipose-derived stem cells in mice through autophagy. Cell Signal 2023; 108:110694. [PMID: 37141927 DOI: 10.1016/j.cellsig.2023.110694] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/25/2023] [Accepted: 04/26/2023] [Indexed: 05/06/2023]
Abstract
BACKGROUND Diabetes mellitus (DM) microenvironment will accelerate the accumulation of Advanced glycation end products (AGEs), adipose-derived stem cells (ASCs) have poor osteogenesis in the DM microenvironment. Studies suggest autophagy plays a vital role in osteogenesis, but the mechanism of the altered osteogenic potential of ASCs has not been elucidated. Bone tissue engineering by ASCs is widely used in the treatment of bone defects with diabetic osteoporosis (DOP). Therefore, it is meaningful to explore the effect of AGEs on the osteogenic differentiation potential of ASCs and its potential mechanism for the repair of bone defects in DOP. MATERIALS AND METHODS ASCs in C57BL/6 mice were isolated, cultured, then treated with AGEs, subsequently, cell viability and proliferation were detected through Cell Counting Kit 8 assay. 3-Methyladenine (3-MA), an autophagic inhibitor used to inhibit autophagic levels. Rapamycin (Rapa), an autophagy activator that further activated autophagy levels by inhibiting mTOR.The osteogenesis and autophagy changes of ASCs were analyzed by flow cytometry, qPCR, western blot, immunofluorescence, alkaline phosphatase (ALP) and alizarin red staining. RESULTS AGEs reduced the autophagy level and osteogenic potential of ASCs. After 3-MA reduced autophagy, the osteogenic potential of ASCs also decreased. AGEs co-treatment with 3-MA, the levels of osteogenesis and autophagy reduced more significantly. When autophagy was activated by Rapa, it was found that it could rescue the reduced osteogenic potential of AGEs. CONCLUSIONS AGEs reduce the osteogenic differentiation potential of ASCs through autophagy, and may provide a reference for the treatment of bone defects with diabetes osteoporosis.
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Affiliation(s)
- Ting Fu
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China; Orofacial Reconstruction and Regeneration Laboratory, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China
| | - Qiang Zhu
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China; Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China
| | - Fangzhi Lou
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China; Orofacial Reconstruction and Regeneration Laboratory, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China
| | - Shuyu Cai
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China; Orofacial Reconstruction and Regeneration Laboratory, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China
| | - Shuanglin Peng
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China; Orofacial Reconstruction and Regeneration Laboratory, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China
| | - Jingang Xiao
- Department of Oral Implantology, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China; Orofacial Reconstruction and Regeneration Laboratory, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China; Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Southwest Medical University, Luzhou, China.
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12
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Lotfy A, AboQuella NM, Wang H. Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials. Stem Cell Res Ther 2023; 14:66. [PMID: 37024925 PMCID: PMC10079493 DOI: 10.1186/s13287-023-03287-7] [Citation(s) in RCA: 155] [Impact Index Per Article: 77.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 03/16/2023] [Indexed: 04/08/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) are widely utilized in cell therapy because of their robust immunomodulatory and regenerative properties. Their paracrine activity is one of the most important features that contribute to their efficacy. Recently, it has been demonstrated that the production of various factors via extracellular vesicles, especially exosomes, governs the principal efficacy of MSCs after infusion in experimental models. Compared to MSCs themselves, MSC-derived exosomes (MSC-Exos) have provided significant advantages by efficiently decreasing unfavorable adverse effects, such as infusion-related toxicities. MSC-Exos is becoming a promising cell-free therapeutic tool and an increasing number of clinical studies started to assess the therapeutic effect of MSC-Exos in different diseases. In this review, we summarized the ongoing and completed clinical studies using MSC-Exos for immunomodulation, regenerative medicine, gene delivery, and beyond. Additionally, we summarized MSC-Exos production methods utilized in these studies with an emphasis on MSCs source, MSC-Exos isolation methods, characterization, dosage, and route of administration. Lastly, we discussed the current challenges and future directions of exosome utilization in different clinical studies as a novel therapeutic strategy.
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Affiliation(s)
- Ahmed Lotfy
- Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA.
| | - Noha M AboQuella
- International Graduate Program Medical Neuroscience, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA
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13
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Ma D, Wu Z, Zhao X, Zhu X, An Q, Wang Y, Zhao J, Su Y, Yang B, Xu K, Zhang L. Immunomodulatory effects of umbilical mesenchymal stem cell-derived exosomes on CD4 + T cells in patients with primary Sjögren's syndrome. Inflammopharmacology 2023:10.1007/s10787-023-01189-x. [PMID: 37012581 DOI: 10.1007/s10787-023-01189-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 03/03/2023] [Indexed: 04/05/2023]
Abstract
BACKGROUND Primary Sjögren's syndrome (pSS) is an autoimmune disease that leads to the destruction of exocrine glands and multisystem lesions. Abnormal proliferation, apoptosis, and differentiation of CD4+ T cells are key factors in the pathogenesis of pSS. Autophagy is one of the important mechanisms to maintain immune homeostasis and function of CD4+ T cells. Human umbilical cord mesenchymal stem cell-derived exosomes (UCMSC-Exos) may simulate the immunoregulation of MSCs while avoiding the risks of MSCs treatment. However, whether UCMSC-Exos can regulate the functions of CD4+ T cells in pSS, and whether the effects via the autophagy pathway remains unclear. METHODS The study analyzed retrospectively the peripheral blood lymphocyte subsets in pSS patients, and explored the relationship between lymphocyte subsets and disease activity. Next, peripheral blood CD4+ T cells were sorted using immunomagnetic beads. The proliferation, apoptosis, differentiation, and inflammatory factors of CD4+ T cells were determined using flow cytometry. Autophagosomes of CD4+ T cells were detected using transmission electron microscopy, autophagy-related proteins and genes were detected using western blotting or RT-qPCR. RESULTS The study demonstrated that the peripheral blood CD4+ T cells decreased in pSS patients, and negatively correlated with disease activity. UCMSC-Exos inhibited excessive proliferation and apoptosis of CD4+ T cells in pSS patients, blocked them in the G0/G1 phase, inhibited them from entering the S phase, reduced the Th17 cell ratio, elevated the Treg ratio, inhibited IFN-γ, TNF-α, IL-6, IL-17A, and IL-17F secretion, and promoted IL-10 and TGF-β secretion. UCMSC-Exos reduced the elevated autophagy levels in the peripheral blood CD4+ T cells of patients with pSS. Furthermore, UCMSC-Exos regulated CD4+ T cell proliferation and early apoptosis, inhibited Th17 cell differentiation, promoted Treg cell differentiation, and restored the Th17/Treg balance in pSS patients through the autophagy pathway. CONCLUSIONS The study indicated that UCMSC-Exos exerts an immunomodulatory effect on the CD4+ T cells, and maybe as a new treatment for pSS.
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Affiliation(s)
- Dan Ma
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Zewen Wu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Xingxing Zhao
- Shanxi University of Chinese Medicine, Jinzhong, 030619, Shanxi, China
| | - Xueqing Zhu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Qi An
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Yajing Wang
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Jingwen Zhao
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Yazhen Su
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Baoqi Yang
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Ke Xu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Liyun Zhang
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China.
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14
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Hochmann S, Ou K, Poupardin R, Mittermeir M, Textor M, Ali S, Wolf M, Ellinghaus A, Jacobi D, Elmiger JAJ, Donsante S, Riminucci M, Schäfer R, Kornak U, Klein O, Schallmoser K, Schmidt-Bleek K, Duda GN, Polansky JK, Geissler S, Strunk D. The enhancer landscape predetermines the skeletal regeneration capacity of stromal cells. Sci Transl Med 2023; 15:eabm7477. [PMID: 36947595 DOI: 10.1126/scitranslmed.abm7477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Multipotent stromal cells are considered attractive sources for cell therapy and tissue engineering. Despite numerous experimental and clinical studies, broad application of stromal cell therapeutics is not yet emerging. A major challenge is the functional diversity of available cell sources. Here, we investigated the regenerative potential of clinically relevant human stromal cells from bone marrow (BMSCs), white adipose tissue, and umbilical cord compared with mature chondrocytes and skin fibroblasts in vitro and in vivo. Although all stromal cell types could express transcription factors related to endochondral ossification, only BMSCs formed cartilage discs in vitro that fully regenerated critical-size femoral defects after transplantation into mice. We identified cell type-specific epigenetic landscapes as the underlying molecular mechanism controlling transcriptional stromal differentiation networks. Binding sites of commonly expressed transcription factors in the enhancer and promoter regions of ossification-related genes, including Runt and bZIP families, were accessible only in BMSCs but not in extraskeletal stromal cells. This suggests an epigenetically predetermined differentiation potential depending on cell origin that allows common transcription factors to trigger distinct organ-specific transcriptional programs, facilitating forward selection of regeneration-competent cell sources. Last, we demonstrate that viable human BMSCs initiated defect healing through the secretion of osteopontin and contributed to transient mineralized bone hard callus formation after transplantation into immunodeficient mice, which was eventually replaced by murine recipient bone during final tissue remodeling.
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Affiliation(s)
- Sarah Hochmann
- Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020 Salzburg, Austria
| | - Kristy Ou
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), T Cell Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Rodolphe Poupardin
- Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020 Salzburg, Austria
| | - Michaela Mittermeir
- Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020 Salzburg, Austria
| | - Martin Textor
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute (JWI), Augustenburger Platz 1, 13353 Berlin, Germany
| | - Salaheddine Ali
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany
- Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
- Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
| | - Martin Wolf
- Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020 Salzburg, Austria
| | - Agnes Ellinghaus
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute (JWI), Augustenburger Platz 1, 13353 Berlin, Germany
| | - Dorit Jacobi
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute (JWI), Augustenburger Platz 1, 13353 Berlin, Germany
| | - Juri A J Elmiger
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute (JWI), Augustenburger Platz 1, 13353 Berlin, Germany
| | - Samantha Donsante
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy
| | - Mara Riminucci
- Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy
| | - Richard Schäfer
- Institute for Transfusion Medicine and Immunohematology, Goethe University Hospital, German Red Cross Blood Service Baden-Württemberg-Hessen gGmbH, 60323 Frankfurt am Main, Germany
- Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, 79106 Freiburg, Germany
| | - Uwe Kornak
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany
- Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
- Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
- Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany
| | - Oliver Klein
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany
| | | | - Katharina Schmidt-Bleek
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute (JWI), Augustenburger Platz 1, 13353 Berlin, Germany
| | - Georg N Duda
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute (JWI), Augustenburger Platz 1, 13353 Berlin, Germany
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
| | - Julia K Polansky
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), T Cell Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
- German Rheumatism Research Centre (DRFZ), 10117 Berlin, Germany
| | - Sven Geissler
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute (JWI), Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Center for Advanced Therapies (BECAT), Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Dirk Strunk
- Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020 Salzburg, Austria
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15
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Shi C, Zhang K, Zhao Z, Wang Y, Xu H, Wei W. Correlation between stem cell molecular phenotype and atherosclerotic plaque neointima formation and analysis of stem cell signal pathways. Front Cell Dev Biol 2023; 11:1080563. [PMID: 36711040 PMCID: PMC9877345 DOI: 10.3389/fcell.2023.1080563] [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: 10/26/2022] [Accepted: 01/02/2023] [Indexed: 01/14/2023] Open
Abstract
Vascular stem cells exist in the three-layer structure of blood vessel walls and play an indispensable role in angiogenesis under physiological conditions and vascular remodeling under pathological conditions. Vascular stem cells are mostly quiescent, but can be activated in response to injury and participate in endothelial repair and neointima formation. Extensive studies have demonstrated the differentiation potential of stem/progenitor cells to repair endothelium and participate in neointima formation during vascular remodeling. The stem cell population has markers on the surface of the cells that can be used to identify this cell population. The main positive markers include Stem cell antigen-1 (Sca1), Sry-box transcription factor 10 (SOX10). Stromal cell antigen 1 (Stro-1) and Stem cell growth factor receptor kit (c-kit) are still controversial. Different parts of the vessel have different stem cell populations and multiple markers. In this review, we trace the role of vascular stem/progenitor cells in the progression of atherosclerosis and neointima formation, focusing on the expression of stem cell molecular markers that occur during neointima formation and vascular repair, as well as the molecular phenotypic changes that occur during differentiation of different stem cell types. To explore the correlation between stem cell molecular markers and atherosclerotic diseases and neointima formation, summarize the differential changes of molecular phenotype during the differentiation of stem cells into smooth muscle cells and endothelial cells, and further analyze the signaling pathways and molecular mechanisms of stem cells expressing different positive markers participating in intima formation and vascular repair. Summarizing the limitations of stem cells in the prevention and treatment of atherosclerotic diseases and the pressing issues that need to be addressed, we provide a feasible scheme for studying the signaling pathways of vascular stem cells involved in vascular diseases.
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Affiliation(s)
- Chuanxin Shi
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Kefan Zhang
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhenyu Zhao
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yifan Wang
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haozhe Xu
- Department of Biotherapy, Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Wei
- Division of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China,*Correspondence: Wei Wei,
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16
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Jiang Z, Li N, Shao Q, Zhu D, Feng Y, Wang Y, Yu M, Ren L, Chen Q, Yang G. Light-controlled scaffold- and serum-free hard palatal-derived mesenchymal stem cell aggregates for bone regeneration. Bioeng Transl Med 2023; 8:e10334. [PMID: 36684075 PMCID: PMC9842060 DOI: 10.1002/btm2.10334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 04/10/2022] [Accepted: 04/18/2022] [Indexed: 01/25/2023] Open
Abstract
Cell aggregates that mimic in vivo cell-cell interactions are promising and powerful tools for tissue engineering. This study isolated a new, easily obtained, population of mesenchymal stem cells (MSCs) from rat hard palates named hard palatal-derived mesenchymal stem cells (PMSCs). The PMSCs were positive for CD90, CD44, and CD29 and negative for CD34, CD45, and CD146. They exhibited clonogenicity, self-renewal, migration, and multipotent differentiation capacities. Furthermore, this study fabricated scaffold-free 3D aggregates using light-controlled cell sheet technology and a serum-free method. PMSC aggregates were successfully constructed with good viability. Transplantation of the PMSC aggregates and the PMSC aggregate-implant complexes significantly enhanced bone formation and implant osseointegration in vivo, respectively. This new cell resource is easy to obtain and provides an alternative strategy for tissue engineering and regenerative medicine.
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Affiliation(s)
- Zhiwei Jiang
- Stomatology Hospital, School of StomatologyZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Oral DiseasesHangzhouZhejiangChina
- Key Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhouZhejiangChina
| | - Na Li
- Stomatology Hospital, School of StomatologyZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Oral DiseasesHangzhouZhejiangChina
- Key Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhouZhejiangChina
| | - Qin Shao
- Stomatology Hospital, School of StomatologyZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Oral DiseasesHangzhouZhejiangChina
- Key Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhouZhejiangChina
| | - Danji Zhu
- Stomatology Hospital, School of StomatologyZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Oral DiseasesHangzhouZhejiangChina
- Key Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhouZhejiangChina
| | - Yuting Feng
- Stomatology Hospital, School of StomatologyZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Oral DiseasesHangzhouZhejiangChina
- Key Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhouZhejiangChina
| | - Yang Wang
- Stomatology Hospital, School of StomatologyZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Oral DiseasesHangzhouZhejiangChina
- Key Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhouZhejiangChina
| | - Mengjia Yu
- Stomatology Hospital, School of StomatologyZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Oral DiseasesHangzhouZhejiangChina
- Key Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhouZhejiangChina
| | - Lingfei Ren
- Stomatology Hospital, School of StomatologyZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Oral DiseasesHangzhouZhejiangChina
- Key Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhouZhejiangChina
| | - Qianming Chen
- Stomatology Hospital, School of StomatologyZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Oral DiseasesHangzhouZhejiangChina
- Key Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhouZhejiangChina
| | - Guoli Yang
- Stomatology Hospital, School of StomatologyZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Oral DiseasesHangzhouZhejiangChina
- Key Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhouZhejiangChina
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17
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Kia V, Eshaghi-Gorji R, Mansour RN, Hassannia H, Hasanzadeh E, Gheibi M, Mellati A, Enderami SE. Mesenchymal Stromal Cells and their EVs as Potential Leads for SARSCoV2 Treatment. Curr Stem Cell Res Ther 2023; 18:35-53. [PMID: 35473518 DOI: 10.2174/1574888x17666220426115831] [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: 07/30/2021] [Revised: 12/17/2021] [Accepted: 01/28/2022] [Indexed: 11/22/2022]
Abstract
In December 2019, a betacoronavirus was isolated from pneumonia cases in China and rapidly turned into a pandemic of COVID-19. The virus is an enveloped positive-sense ssRNA and causes a severe respiratory syndrome along with a cytokine storm, which is the main cause of most complications. Therefore, treatments that can effectively control the inflammatory reactions are necessary. Mesenchymal Stromal Cells and their EVs are well-known for their immunomodulatory effects, inflammation reduction, and regenerative potentials. These effects are exerted through paracrine secretion of various factors. Their EVs also transport various molecules such as microRNAs to other cells and affect recipient cells' behavior. Scores of research and clinical trials have indicated the therapeutic potential of EVs in various diseases. EVs also seem to be a promising approach for severe COVID-19 treatment. EVs have also been used to develop vaccines since EVs are biocompatible nanoparticles that can be easily isolated and engineered. In this review, we have focused on the use of Mesenchymal Stromal Cells and their EVs for the treatment of COVID-19, their therapeutic capabilities, and vaccine development.
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Affiliation(s)
- Vahid Kia
- Department of Medical Biotechnology, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Reza Eshaghi-Gorji
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | | | - Hadi Hassannia
- Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Amol Faculty of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
| | - Elham Hasanzadeh
- Department of Tissue Engineering and Regenerative Medicine, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mobina Gheibi
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Amir Mellati
- Department of Tissue Engineering and Regenerative Medicine, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Seyed Ehsan Enderami
- Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Department of Medical Biotechnology, Faculty of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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18
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Di Stefano AB, Urrata V, Trapani M, Moschella F, Cordova A, Toia F. Systematic review on spheroids from adipose‐derived stem cells: Spontaneous or artefact state? J Cell Physiol 2022; 237:4397-4411. [PMID: 36209478 PMCID: PMC10091738 DOI: 10.1002/jcp.30892] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 09/16/2022] [Accepted: 09/22/2022] [Indexed: 11/09/2022]
Abstract
Three-dimensional (3D) cell cultures represent the spontaneous state of stem cells with specific gene and protein molecular expression that are more alike the in vivo condition. In vitro two-dimensional (2D) cell adhesion cultures are still commonly employed for various cellular studies such as movement, proliferation and differentiation phenomena; this procedure is standardized and amply used in laboratories, however their representing the original tissue has recently been subject to questioning. Cell cultures in 2D require a support/substrate (flasks, multiwells, etc.) and use of fetal bovine serum as an adjuvant that stimulates adhesion that most likely leads to cellular aging. A 3D environment stimulates cells to grow in suspended aggregates that are defined as "spheroids." In particular, adipose stem cells (ASCs) are traditionally observed in adhesion conditions, but a recent and vast literature offers many strategies that obtain 3D cell spheroids. These cells seem to possess a greater ability in maintaining their stemness and differentiate towards all mesenchymal lineages, as demonstrated in in vitro and in vivo studies compared to adhesion cultures. To date, standardized procedures that form ASC spheroids have not yet been established. This systematic review carries out an in-depth analysis of the 76 articles produced over the past 10 years and discusses the similarities and differences in materials, techniques, and purposes to standardize the methods aimed at obtaining ASC spheroids as already described for 2D cultures.
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Affiliation(s)
- Anna Barbara Di Stefano
- BIOPLAST‐Laboratory of BIOlogy and Regenerative Medicine‐PLASTic Surgery, Plastic and Reconstructive Surgery Unit, Department of Surgical, Oncological and Oral Sciences University of Palermo Palermo Italy
| | - Valentina Urrata
- BIOPLAST‐Laboratory of BIOlogy and Regenerative Medicine‐PLASTic Surgery, Plastic and Reconstructive Surgery Unit, Department of Surgical, Oncological and Oral Sciences University of Palermo Palermo Italy
| | - Marco Trapani
- BIOPLAST‐Laboratory of BIOlogy and Regenerative Medicine‐PLASTic Surgery, Plastic and Reconstructive Surgery Unit, Department of Surgical, Oncological and Oral Sciences University of Palermo Palermo Italy
| | - Francesco Moschella
- BIOPLAST‐Laboratory of BIOlogy and Regenerative Medicine‐PLASTic Surgery, Plastic and Reconstructive Surgery Unit, Department of Surgical, Oncological and Oral Sciences University of Palermo Palermo Italy
| | - Adriana Cordova
- BIOPLAST‐Laboratory of BIOlogy and Regenerative Medicine‐PLASTic Surgery, Plastic and Reconstructive Surgery Unit, Department of Surgical, Oncological and Oral Sciences University of Palermo Palermo Italy
- Department of Surgical, Oncological and Oral Sciences, Unit of Plastic and Reconstructive Surgery University of Palermo Palermo Italy
- Department of D.A.I. Chirurgico, Plastic and Reconstructive Unit Azienda Ospedaliera Universitaria Policlinico “Paolo Giaccone” Palermo Italy
| | - Francesca Toia
- BIOPLAST‐Laboratory of BIOlogy and Regenerative Medicine‐PLASTic Surgery, Plastic and Reconstructive Surgery Unit, Department of Surgical, Oncological and Oral Sciences University of Palermo Palermo Italy
- Department of Surgical, Oncological and Oral Sciences, Unit of Plastic and Reconstructive Surgery University of Palermo Palermo Italy
- Department of D.A.I. Chirurgico, Plastic and Reconstructive Unit Azienda Ospedaliera Universitaria Policlinico “Paolo Giaccone” Palermo Italy
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19
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Di SJ, Wu SY, Liu TJ, Shi YY. Stem cell therapy as a promising strategy in necrotizing enterocolitis. Mol Med 2022; 28:107. [PMID: 36068527 PMCID: PMC9450300 DOI: 10.1186/s10020-022-00536-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/29/2022] [Indexed: 11/10/2022] Open
Abstract
Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease that affects newborns, particularly preterm infants, and is associated with high morbidity and mortality. No effective therapeutic strategies to decrease the incidence and severity of NEC have been developed to date. Stem cell therapy has been explored and even applied in various diseases, including gastrointestinal disorders. Animal studies on stem cell therapy have made great progress, and the anti-inflammatory, anti-apoptotic, and intestinal barrier enhancing effects of stem cells may be protective against NEC clinically. In this review, we discuss the therapeutic mechanisms through which stem cells may function in the treatment of NEC.
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Affiliation(s)
- Si-Jia Di
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Si-Yuan Wu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Tian-Jing Liu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Yong-Yan Shi
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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20
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Sharifi M, Kheradmandi R, Salehi M, Alizadeh M, Ten Hagen TLM, Falahati M. Criteria, Challenges, and Opportunities for Acellularized Allogeneic/Xenogeneic Bone Grafts in Bone Repairing. ACS Biomater Sci Eng 2022; 8:3199-3219. [PMID: 35816626 DOI: 10.1021/acsbiomaterials.2c00194] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
As bone grafts become more commonly needed by patients and as donors become scarcer, acellularized bone grafts (ABGs) are becoming more popular for restorative purposes. While autogeneic grafts are reliable as a gold standard, allogeneic and xenogeneic ABGs have been shown to be of particular interest due to the limited availability of autogeneic resources and reduced patient well-being in long-term surgeries. Because of the complete similarity of their structures with native bone, excellent mechanical properties, high biocompatibility, and similarities of biological behaviors (osteoinductive and osteoconductive) with local bones, successful outcomes of allogeneic and xenogeneic ABGs in both in vitro and in vivo research have raised hopes of repairing patients' bone injuries in clinical applications. However, clinical trials have been delayed due to a lack of standardized protocols pertaining to acellularization, cell seeding, maintenance, and diversity of ABG evaluation criteria. This study sought to uncover these factors by exploring the bone structures, ossification properties of ABGs, sources, benefits, and challenges of acellularization approaches (physical, chemical, and enzymatic), cell loading, and type of cells used and effects of each of the above items on the regenerative technologies. To gain a perspective on the repair and commercialization of products before implementing new research activities, this study describes the differences between ABGs created by various techniques and methods applied to them. With a comprehensive understanding of ABG behavior, future research focused on treating bone defects could provide a better way to combine the treatment approaches needed to treat bone defects.
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Affiliation(s)
- Majid Sharifi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, 3614773955 Shahroud, Iran.,Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, 3614773955 Shahroud, Iran
| | - Rasoul Kheradmandi
- Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, 3614773955 Shahroud, Iran.,Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, 3614773955 Shahroud, Iran
| | - Majid Salehi
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, 3614773955 Shahroud, Iran.,Tissue Engineering and Stem Cells Research Center, Shahroud University of Medical Sciences, 3614773955 Shahroud, Iran
| | - Morteza Alizadeh
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, 3614773955 Shahroud, Iran
| | - Timo L M Ten Hagen
- Laboratory Experimental Oncology, Department of Pathology, Erasmus MC, 3015GD Rotterdam, The Netherlands
| | - Mojtaba Falahati
- Laboratory Experimental Oncology, Department of Pathology, Erasmus MC, 3015GD Rotterdam, The Netherlands
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21
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Sipos F, Műzes G. Disagreements in the therapeutic use of mesenchymal stem cell-derived secretome. World J Stem Cells 2022; 14:365-371. [PMID: 35949398 PMCID: PMC9244954 DOI: 10.4252/wjsc.v14.i6.365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 03/15/2022] [Accepted: 05/27/2022] [Indexed: 02/06/2023] Open
Abstract
In a recent article, the authors provide a detailed summary of the characteristics and biological functions of mesenchymal stem cells (MSCs), as well as a discussion on the potential mechanisms of action of MSC-based therapies. They describe the morphology, biogenesis, and current isolation techniques of exosomes, one of the most important fractions of the MSC-derived secretome. They also summarize the characteristics of MSC-derived exosomes and highlight their functions and therapeutic potential for tissue/organ regeneration and for kidney, liver, cardiovascular, neurological, and musculoskeletal diseases, as well as cutaneous wound healing. Despite the fact that MSCs are regarded as an important pillar of regenerative medicine, their regenerative potential has been demonstrated to be limited in a number of pathological conditions. The negative effects of MSC-based cell therapy have heightened interest in the therapeutic use of MSC-derived secretome. On the other hand, MSC-derived exosomes and microvesicles possess the potential to have a significant impact on disease development, including cancer. MSCs can interact with tumor cells and promote mutual exchange and induction of cellular markers by exchanging secretome. Furthermore, enzymes secreted into and activated within exosomes can result in tumor cells acquiring new properties. As a result, therapeutic applications of MSC-derived secretomes must be approached with extreme caution.
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Affiliation(s)
- Ferenc Sipos
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest 1088, Hungary.
| | - Györgyi Műzes
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest 1088, Hungary
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22
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Ren H, Guo Z, Liu Y, Song C. Stem Cell-derived Exosomal MicroRNA as Therapy for Vascular Age-related Diseases. Aging Dis 2022; 13:852-867. [PMID: 35656114 PMCID: PMC9116915 DOI: 10.14336/ad.2021.1110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 11/10/2021] [Indexed: 12/20/2022] Open
Abstract
Vascular age-related diseases describe a group of age-related chronic diseases that result in a considerable healthcare burden to society. Vascular aging includes structural changes and dysfunctions of endothelial cells (ECs) and smooth muscle cells (SMCs) in blood vessels. Compared with conventional treatment for vascular age-related diseases, stem cell (SC) therapy elicits better anti-aging effects viathe inhibition/delay ECs and SMCs from entering senescence. Exosomal noncoding RNA (ncRNAs) in vascular aging and stem cell-derived exosomal microRNAs (SCEV-miRNAs), especially in mesenchymal stem cells, have an important role in the development of age-related diseases. This review summarizes SCEV-miRNAs of diverse origins that may play a vital role in treating subclinical and clinical stages of vascular age-related disorders. We further explored possible age-related pathways and molecular targets of SCEV-miRNA, which are associated with dysfunctions of ECs and SMCs in the senescent stage. Moreover, the perspectives and difficulties of SCEV-miRNA clinical translation are discussed. This review aims to provide greater understanding of the biology of vascular aging and to identify critical therapeutic targets for SCEV-miRNAs. Though still in its infancy, the potential value of SCEV-miRNAs for vascular age-related diseases is clear.
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Affiliation(s)
- Hang Ren
- Department of Cardiovascular Internal Medicine, the Second Hospital of Jilin University, Changchun, China
| | - Ziyuan Guo
- Department of Cardiovascular Internal Medicine, the Second Hospital of Jilin University, Changchun, China
| | - Yang Liu
- Department of Cardiovascular Internal Medicine, the Second Hospital of Jilin University, Changchun, China
| | - Chunli Song
- Department of Cardiovascular Internal Medicine, the Second Hospital of Jilin University, Changchun, China
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23
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Sarvar DP, Effatpanah H, Akbarzadehlaleh P, Shamsasenjan K. Mesenchymal stromal cell-derived extracellular vesicles: novel approach in hematopoietic stem cell transplantation. Stem Cell Res Ther 2022; 13:202. [PMID: 35578300 PMCID: PMC9109321 DOI: 10.1186/s13287-022-02875-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 12/24/2021] [Indexed: 11/24/2022] Open
Abstract
Bone marrow mesenchymal stromal cells (MSCs) play a crucial role in the regulation of hematopoiesis. These cells affect the process through direct cell–cell contact, as well as releasing various trophic factors and extracellular vehicles (EVs) into the bone marrow microenvironment. MSC-derived EVs (MSC-EVs) are prominent intercellular communication tolls enriched with broad-spectrum bioactive factors such as proteins, cytokines, lipids, miRNAs, and siRNAs. They mimic some effects of MSCs by direct fusion with hematopoietic stem cells (HSC) membranes in the bone marrow (BM), thereby affecting HSC fate. MSC-EVs are attractive scope in cell-free therapy because of their unique capacity to repair BM tissue and regulate proliferation and differentiation of HSCs. These vesicles modulate the immune system responses and inhibit graft-versus-host disease following hematopoietic stem cell transplantation (HSCT). Recent studies have demonstrated that MSC-EVs play an influential role in the BM niches because of their unprecedented capacity to regulate HSC fate. Therefore, the existing paper intends to speculate upon the preconditioned MSC-EVs as a novel approach in HSCT.
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Affiliation(s)
| | | | - Parvin Akbarzadehlaleh
- Department of Pharmaceutical Biotechnology, Tabriz University of Medical Science, Tabriz, Iran
| | - Karim Shamsasenjan
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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24
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Liu P, Qin L, Liu C, Mi J, Zhang Q, Wang S, Zhuang D, Xu Q, Chen W, Guo J, Wu X. Exosomes Derived From Hypoxia-Conditioned Stem Cells of Human Deciduous Exfoliated Teeth Enhance Angiogenesis via the Transfer of let-7f-5p and miR-210-3p. Front Cell Dev Biol 2022; 10:879877. [PMID: 35557954 PMCID: PMC9086315 DOI: 10.3389/fcell.2022.879877] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 03/18/2022] [Indexed: 01/08/2023] Open
Abstract
Physiological root resorption of deciduous teeth is a normal phenomenon. How the angiogenesis process is regulated to provide adequate levels of oxygen and nutrients in hypoxic conditions when the dental pulp tissue is reduced at the stage of root resorption is not fully understood. In this study, we designed hypoxic preconditioning (2%) to mimic the physiological conditions. We isolated exosomes from hypoxic-preconditioned SHED (Hypo-exos) cells and from normally cultured SHED cells (Norm-exos). We found that treatment with Hypo-exos significantly enhanced the growth, migration and tube formation of endothelial cells in vitro compared with Norm-exos. We also performed matrigel plug assays in vivo and higher expression of VEGF and higher number of lumenal structures that stained positive for CD31 were found in the Hypo-exos treated group. To understand the potential molecular mechanism responsible for the positive effects of Hypo-exos, we performed exosomal miRNA sequencing and validated that Hypo-exos transferred both let-7f-5p and miR-210-3p to promote the tube formation of endothelial cells. Further study revealed that those two miRNAs regulate angiogenesis via the let-7f-5p/AGO1/VEGF and/or miR-210-3p/ephrinA3 signal pathways. Finally, we found that the increased release of exosomes regulated by hypoxia treatment may be related to Rab27a. Taking these data together, the present study demonstrates that exosomes derived from hypoxic-preconditioned SHED cells promote angiogenesis by transferring let-7f-5p and miR-210-3p, which suggests that they can potentially be developed as a novel therapeutic approach for pro-angiogenic therapy in tissue regeneration engineering.
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Affiliation(s)
- Panpan Liu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
- Department of Pediatrics Dentistry, Department of Preventive Dentistry, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Lihong Qin
- Department of Stomatology, Weihai Hospital of Traditional Chinese Medicine, Weihai, China
| | - Chang Liu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Jun Mi
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Qun Zhang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Shuangshuang Wang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Dexuan Zhuang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Qiuping Xu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Wenqian Chen
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Jing Guo
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
- Engineering Laboratory for Biomaterials and Tissue Regeneration, Ningbo Stomatology Hospital, Ningbo, China
- Savaid Stomatology School, Hangzhou Medical College, Hangzhou, China
- *Correspondence: Xunwei Wu, ; Jing Guo,
| | - Xunwei Wu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
- Engineering Laboratory for Biomaterials and Tissue Regeneration, Ningbo Stomatology Hospital, Ningbo, China
- Savaid Stomatology School, Hangzhou Medical College, Hangzhou, China
- *Correspondence: Xunwei Wu, ; Jing Guo,
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25
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A Novel Glucose-Sensitive Scaffold Accelerates Osteogenesis in Diabetic Conditions. BIOMED RESEARCH INTERNATIONAL 2022; 2022:4133562. [PMID: 35342759 PMCID: PMC8956406 DOI: 10.1155/2022/4133562] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 02/10/2022] [Accepted: 03/06/2022] [Indexed: 02/05/2023]
Abstract
Mandibular bone regeneration is still a big challenge in those diabetic patients with poorly controlled blood glucose. In this study, we prepared a novel glucose-sensitive controlled-release fiber scaffold (PVA-HTCC/PEO-rhBMP2-glucose oxidase (PHPB-G)), which contained the recombinant human bone morphogenetic protein 2 (rhBMP2) by coaxial cospinning and grafted with glucose oxidase (GOD). We presented evidence that PHPB-G could undergo a series of structural changes with the blood glucose and promoted bone regeneration in diabetic rat. PHPB-G expanded the voids in nanofibers when blood glucose levels elevated. More importantly, its slow-release rhBMP2 effectively promoted the healing of bone defects. These data suggested that the PHPB-G delivery system may provide a potential treatment strategy for patients with severe diabetic alveolar bone defects.
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26
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Zhang ZW, Wei P, Zhang GJ, Yan JX, Zhang S, Liang J, Wang XL. Intravenous infusion of the exosomes derived from human umbilical cord mesenchymal stem cells enhance neurological recovery after traumatic brain injury via suppressing the NF-κB pathway. Open Life Sci 2022; 17:189-201. [PMID: 35415238 PMCID: PMC8932398 DOI: 10.1515/biol-2022-0022] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 12/13/2021] [Accepted: 01/03/2022] [Indexed: 02/05/2023] Open
Abstract
Abstract
Traumatic brain injury (TBI) is a predominant cause of death and permanent disability globally. In recent years, much emphasis has been laid on treatments for TBI. Increasing evidence suggests that human umbilical cord mesenchymal stem cells (HUCMSCs) can improve neurological repair after TBI. However, the clinical use of HUCMSCs transplantation in TBI has been limited by immunological rejection, ethical issues, and the risk of tumorigenicity. Many studies have shown that HUCMSCs-derived exosomes may be an alternative approach for HUCMSCs transplantation. We hypothesized that exosomes derived from HUCMSCs could inhibit apoptosis after TBI, reduce neuroinflammation, and promote neurogenesis. A rat model of TBI was established to investigate the efficiency of neurological recovery with exosome therapy. We found that exosomes derived from HUCMSCs significantly ameliorated sensorimotor function and spatial learning in rats after TBI. Moreover, HUCMSCs-derived exosomes significantly reduced proinflammatory cytokine expression by suppressing the NF-κB signaling pathway. Furthermore, we found that HUCMSC-derived exosomes inhibited neuronal apoptosis, reduced inflammation, and promoted neuron regeneration in the injured cortex of rats after TBI. These results indicate that HUCMSCs-derived exosomes may be a promising therapeutic strategy for TBI.
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Affiliation(s)
- Zhen-Wen Zhang
- Department of Encephalopathy, Affiliated Hospital of Gansu University of Chinese Medicine , Lanzhou 730000 , Gansu , China
- Tianjin Key Laboratory of Neurotrauma Repair, Pingjin Hospital Brain Center, Characteristic Medical Center of PAPF , Tianjin 300162 , China
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine , Lanzhou 730000 , Gansu , China
| | - Pan Wei
- Department of Neurosurgery, The First People’s Hospital of Long Quan Yi District , Cheng Du 610000 , Si Chuan , China
| | - Gui-Jun Zhang
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University , Chengdu 610041 , Sichuan , China
| | - Jing-Xing Yan
- Department of Encephalopathy, Affiliated Hospital of Gansu University of Chinese Medicine , Lanzhou 730000 , Gansu , China
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine , Lanzhou 730000 , Gansu , China
| | - Sai Zhang
- Tianjin Key Laboratory of Neurotrauma Repair, Pingjin Hospital Brain Center, Characteristic Medical Center of PAPF , Tianjin 300162 , China
| | - Jin Liang
- Tianjin Key Laboratory of Neurotrauma Repair, Pingjin Hospital Brain Center, Characteristic Medical Center of PAPF , Tianjin 300162 , China
| | - Xiao-Li Wang
- Tianjin Key Laboratory of Neurotrauma Repair, Pingjin Hospital Brain Center, Characteristic Medical Center of PAPF , Tianjin 300162 , China
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27
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Optimization of a Tricalcium Phosphate-Based Bone Model Using Cell-Sheet Technology to Simulate Bone Disorders. Processes (Basel) 2022. [DOI: 10.3390/pr10030550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Bone diseases such as osteoporosis, delayed or impaired bone healing, and osteoarthritis still represent a social, financial, and personal burden for affected patients and society. Fully humanized in vitro 3D models of cancellous bone tissue are needed to develop new treatment strategies and meet patient-specific needs. Here, we demonstrate a successful cell-sheet-based process for optimized mesenchymal stromal cell (MSC) seeding on a β-tricalcium phosphate (TCP) scaffold to generate 3D models of cancellous bone tissue. Therefore, we seeded MSCs onto the β-TCP scaffold, induced osteogenic differentiation, and wrapped a single osteogenically induced MSC sheet around the pre-seeded scaffold. Comparing the wrapped with an unwrapped scaffold, we did not detect any differences in cell viability and structural integrity but a higher cell seeding rate with osteoid-like granular structures, an indicator of enhanced calcification. Finally, gene expression analysis showed a reduction in chondrogenic and adipogenic markers, but an increase in osteogenic markers in MSCs seeded on wrapped scaffolds. We conclude from these data that additional wrapping of pre-seeded scaffolds will provide a local niche that enhances osteogenic differentiation while repressing chondrogenic and adipogenic differentiation. This approach will eventually lead to optimized preclinical in vitro 3D models of cancellous bone tissue to develop new treatment strategies.
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28
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Dai K, Deng S, Yu Y, Zhu F, Wang J, Liu C. Construction of developmentally inspired periosteum-like tissue for bone regeneration. Bone Res 2022; 10:1. [PMID: 34975148 PMCID: PMC8720863 DOI: 10.1038/s41413-021-00166-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 05/19/2021] [Accepted: 06/08/2021] [Indexed: 12/15/2022] Open
Abstract
The periosteum, a highly vascularized thin tissue, has excellent osteogenic and bone regenerative abilities. The generation of periosteum-mimicking tissue has become a novel strategy for bone defect repair and regeneration, especially in critical-sized bone defects caused by trauma and bone tumor resection. Here, we utilized a bone morphogenetic protein-2 (BMP-2)-loaded scaffold to create periosteum-like tissue (PT) in vivo, mimicking the mesenchymal condensation during native long bone development. We found that BMP-2-induced endochondral ossification plays an indispensable role in the construction of PTs. Moreover, we confirmed that BMP-2-induced PTs exhibit a similar architecture to the periosteum and harbor abundant functional periosteum-like tissue-derived cells (PTDCs), blood vessels, and osteochondral progenitor cells. Interestingly, we found that the addition of chondroitin sulfate (CS), an essential component of the extracellular matrix (ECM), could further increase the abundance and enhance the function of recruited PTDCs from the PTs and finally increase the regenerative capacity of the PTs in autologous transplantation assays, even in old mice. This novel biomimetic strategy for generating PT through in vivo endochondral ossification deserves further clinical translation.
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Affiliation(s)
- Kai Dai
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, P. R. China.,Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China
| | - Shunshu Deng
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, P. R. China.,Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China
| | - Yuanman Yu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, P. R. China.,Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China
| | - Fuwei Zhu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, P. R. China.,Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China
| | - Jing Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, P. R. China. .,Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China.
| | - Changsheng Liu
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China. .,Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China. .,Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, P. R. China.
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29
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Rodrigues AA, Batista NA, Malmonge SM, Casarin SA, Agnelli JAM, Santos AR, Belangero WD. Osteogenic differentiation of rat bone mesenchymal stem cells cultured on poly (hydroxybutyrate-co-hydroxyvalerate), poly (ε-caprolactone) scaffolds. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2021; 32:138. [PMID: 34716801 PMCID: PMC8557177 DOI: 10.1007/s10856-021-06615-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 10/03/2021] [Indexed: 05/15/2023]
Abstract
Bioresorbable biomaterials can fill bone defects and act as temporary scaffold to recruit MSCs to stimulate their differentiation. Among the different bioresorbable polymers studied, this work focuses on poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) and poly(ε-caprolactone) (PCL). Were prepared blends of PHBV and PCL to obtain PHBV based biomaterials with good tenacity, important for bone tissue repair, associated with biocompatible properties of PCL. This study assesses the viability of Vero cells on scaffolds of PHBV, PCL, and their blends and the osteogenic differentiation of mesenchymal stem cells (MSCs). Materials were characterized in surface morphology, DSC and Impact Strength (IS). Vero cells and MSCs were assessed by MTT assay, cytochemical and SEM analysis. MSC osteogenic differentiation was evaluated through alizarin red staining and ALP activity. We found some roughness onto surface materials. DSC showed that the blends presented two distinct melting peaks, characteristic of immiscible blends. IS test confirmed that PHBV-PCL blends is an alternative for increase the tenacity of PHBV. MTT assay showed cells with high metabolic activities on extract toxicity test, but with low activity in the direct contact test. SEM analysis showed spreading cells with irregular and flattened morphology on different substrates. Cytochemical study revealed that MSCs maintained their morphology, although in smaller number for MSCs. The development of nodules of mineralized organic matrix in MSC cultures was identified by alizarin red staining and osteogenic differentiation was confirmed by the quantification of ALP activity. Thus, our scaffolds did not interfere on viability of Vero cells or the osteogenic differentiation of MSCs.
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Affiliation(s)
- Ana A Rodrigues
- Laboratório de Biomateriais em Ortopedia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil
| | - Nilza A Batista
- Laboratório de Biomateriais em Ortopedia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil
| | - Sônia M Malmonge
- Centro de Engenharia, Modelagem e Ciências Sociais Aplicadas (CECS), Universidade Federal do ABC, São Bernardo do Campo, SP, Brazil
| | - Suzan A Casarin
- Departamento de Engenharia de Materiais, Universidade Federal de São Carlos, São Carlos, SP, Brazil
| | - José Augusto M Agnelli
- Departamento de Engenharia de Materiais, Universidade Federal de São Carlos, São Carlos, SP, Brazil
| | - Arnaldo R Santos
- Centro de Ciências Naturais e Humanas (CCNH), Universidade Federal do ABC, São Bernardo do Campo, SP, Brazil.
| | - William D Belangero
- Laboratório de Biomateriais em Ortopedia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil
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30
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Le Q, Madhu V, Hart JM, Farber CR, Zunder ER, Dighe AS, Cui Q. Current evidence on potential of adipose derived stem cells to enhance bone regeneration and future projection. World J Stem Cells 2021; 13:1248-1277. [PMID: 34630861 PMCID: PMC8474721 DOI: 10.4252/wjsc.v13.i9.1248] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 05/22/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023] Open
Abstract
Injuries to the postnatal skeleton are naturally repaired through successive steps involving specific cell types in a process collectively termed “bone regeneration”. Although complex, bone regeneration occurs through a series of well-orchestrated stages wherein endogenous bone stem cells play a central role. In most situations, bone regeneration is successful; however, there are instances when it fails and creates non-healing injuries or fracture nonunion requiring surgical or therapeutic interventions. Transplantation of adult or mesenchymal stem cells (MSCs) defined by the International Society for Cell and Gene Therapy (ISCT) as CD105+CD90+CD73+CD45-CD34-CD14orCD11b-CD79αorCD19-HLA-DR- is being investigated as an attractive therapy for bone regeneration throughout the world. MSCs isolated from adipose tissue, adipose-derived stem cells (ADSCs), are gaining increasing attention since this is the most abundant source of adult stem cells and the isolation process for ADSCs is straightforward. Currently, there is not a single Food and Drug Administration (FDA) approved ADSCs product for bone regeneration. Although the safety of ADSCs is established from their usage in numerous clinical trials, the bone-forming potential of ADSCs and MSCs, in general, is highly controversial. Growing evidence suggests that the ISCT defined phenotype may not represent bona fide osteoprogenitors. Transplantation of both ADSCs and the CD105- sub-population of ADSCs has been reported to induce bone regeneration. Most notably, cells expressing other markers such as CD146, AlphaV, CD200, PDPN, CD164, CXCR4, and PDGFRα have been shown to represent osteogenic sub-population within ADSCs. Amongst other strategies to improve the bone-forming ability of ADSCs, modulation of VEGF, TGF-β1 and BMP signaling pathways of ADSCs has shown promising results. The U.S. FDA reveals that 73% of Investigational New Drug applications for stem cell-based products rely on CD105 expression as the “positive” marker for adult stem cells. A concerted effort involving the scientific community, clinicians, industries, and regulatory bodies to redefine ADSCs using powerful selection markers and strategies to modulate signaling pathways of ADSCs will speed up the therapeutic use of ADSCs for bone regeneration.
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Affiliation(s)
- Quang Le
- Department of Orthopaedic Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, United States
| | - Vedavathi Madhu
- Orthopaedic Surgery Research, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Joseph M Hart
- Department of Orthopaedic Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, United States
| | - Charles R Farber
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, United States
- Departments of Public Health Sciences and Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, United States
| | - Eli R Zunder
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, United States
| | - Abhijit S Dighe
- Department of Orthopaedic Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, United States
| | - Quanjun Cui
- Department of Orthopaedic Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, United States
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31
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Bray ER, Oropallo AR, Grande DA, Kirsner RS, Badiavas EV. Extracellular Vesicles as Therapeutic Tools for the Treatment of Chronic Wounds. Pharmaceutics 2021; 13:1543. [PMID: 34683836 PMCID: PMC8541217 DOI: 10.3390/pharmaceutics13101543] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/16/2021] [Accepted: 09/17/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic wounds develop when the orderly process of cutaneous wound healing is delayed or disrupted. Development of a chronic wound is associated with significant morbidity and financial burden to the individual and health-care system. Therefore, new therapeutic modalities are needed to address this serious condition. Mesenchymal stem cells (MSCs) promote skin repair, but their clinical use has been limited due to technical challenges. Extracellular vesicles (EVs) are particles released by cells that carry bioactive molecules (lipids, proteins, and nucleic acids) and regulate intercellular communication. EVs (exosomes, microvesicles, and apoptotic bodies) mediate key therapeutic effects of MSCs. In this review we examine the experimental data establishing a role for EVs in wound healing. Then, we explore techniques for designing EVs to function as a targeted drug delivery system and how EVs can be incorporated into biomaterials to produce a personalized wound dressing. Finally, we discuss the status of clinically deploying EVs as a therapeutic agent in wound care.
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Affiliation(s)
- Eric R. Bray
- Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (E.R.B.); (R.S.K.)
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Alisha R. Oropallo
- Comprehensive Wound Healing Center and Hyperbarics, Department of Vascular Surgery, Donald and Barbara Zucker School of Medicine, Hofstra/Northwell Health, Hempstead, NY 11549, USA; (A.R.O.); (D.A.G.)
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA
| | - Daniel A. Grande
- Comprehensive Wound Healing Center and Hyperbarics, Department of Vascular Surgery, Donald and Barbara Zucker School of Medicine, Hofstra/Northwell Health, Hempstead, NY 11549, USA; (A.R.O.); (D.A.G.)
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA
- Department of Orthopedic Surgery, Long Island Jewish Medical Center, Northwell Health, New Hyde Park, NY 11040, USA
| | - Robert S. Kirsner
- Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (E.R.B.); (R.S.K.)
| | - Evangelos V. Badiavas
- Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (E.R.B.); (R.S.K.)
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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32
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Chen Z, Ge Y, Zhou L, Li T, Yan B, Chen J, Huang J, Du W, Lv S, Tong P, Shan L. Pain relief and cartilage repair by Nanofat against osteoarthritis: preclinical and clinical evidence. Stem Cell Res Ther 2021; 12:477. [PMID: 34446107 PMCID: PMC8390235 DOI: 10.1186/s13287-021-02538-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/05/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Osteoarthritis (OA) is the most common joint degenerative disorder, with little effective therapy to date. Nanofat is a cocktail of cells obtained from fat tissue, which possesses regenerative capacity and has a potential in treating OA. This study aimed to determine the anti-OA efficacy of Nanofat from basic and clinical aspects and explore its action mode. METHODS Flow cytometry was performed to characterize Nanofat. A monoiodoacetate-induced OA rat model was employed for in vivo study. Cell viability and wound healing assays were conducted for in vitro study. Real-time PCR and Western blot assays were applied to explore the molecular action mode of Nanofat. Moreover, a retrospective analysis was conducted to determine the clinical efficacy and safety of Nanofat on knee OA patients. RESULTS The in vivo results showed that Nanofat significantly attenuated pain symptoms and protected cartilage ECM (Col2) from damage, and its effects were not significantly differed with adipose tissue-derived stem cells (both P > 0.05). The in vitro results showed that Nanofat promoted the cell viability and migration of chondrocytes and significantly restored the IL-1β-induced abnormal gene expressions of Col2, Aggrecan, Sox9, Adamts5, Mmp3, Mmp9 Mmp13, IL-6 and Col10 and protein expressions of Col2, MMP9, MMP13, and Sox9 of chondrocytes. The regulatory actions of Nanofat on these anabolic, catabolic, and hypertrophic molecules of chondrocytes were similar between two treatment routes: co-culture and conditioned medium, suggesting a paracrine-based mode of action of Nanofat. Moreover, the clinical data showed that Nanofat relieved pain and repaired damaged cartilage of OA patients, with no adverse events. CONCLUSION In sum, this study demonstrated the anti-OA efficacy as well as a paracrine-based action mode of Nanofat, providing novel knowledge of Nanofat and suggesting it as a promising and practical cell therapy for clinical treatment of OA.
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Affiliation(s)
- Zuxiang Chen
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Yanzhi Ge
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Li Zhou
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Ting Li
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, People's Republic of China
| | - Bo Yan
- Cell Resource Bank and Integrated Cell Preparation Center of Xiaoshan District, Hangzhou Regional Cell Preparation Center (Sanjiang Shangyu Biotechnology Co., Ltd), Hangzhou, People's Republic of China
| | - Junjie Chen
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Jiefeng Huang
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Wenxi Du
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Shuaijie Lv
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, People's Republic of China.
| | - Peijian Tong
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, People's Republic of China.
| | - Letian Shan
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, People's Republic of China.
- Cell Resource Bank and Integrated Cell Preparation Center of Xiaoshan District, Hangzhou Regional Cell Preparation Center (Sanjiang Shangyu Biotechnology Co., Ltd), Hangzhou, People's Republic of China.
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33
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Gupta A, Maffulli N, Rodriguez HC, Mistovich RJ, Delfino K, Cady C, Fauser AM, Cundiff ED, Martinez MA, Potty AG. Cell-free stem cell-derived extract formulation for treatment of knee osteoarthritis: study protocol for a preliminary non-randomized, open-label, multi-center feasibility and safety study. J Orthop Surg Res 2021; 16:514. [PMID: 34416898 PMCID: PMC8377854 DOI: 10.1186/s13018-021-02672-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 08/12/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Musculoskeletal conditions are highly prevalent, and knee OA is most common. Current treatment modalities have limitations and either fail to solve the underlying pathophysiology or are highly invasive. To address these limitations, attention has focused on the use of biologics. The efficacy of these devices is attributed to presence of growth factors (GFs), cytokines (CKs), and extracellular vesicles (EVs). With this in mind, we formulated a novel cell-free stem cell-derived extract (CCM) from human progenitor endothelial stem cells (hPESCs). A preliminary study demonstrated the presence of essential components of regenerative medicine, namely GFs, CKs, and EVs, including exosomes, in CCM. The proposed study aims to evaluate the safety and efficacy of intraarticular injection of the novel cell-free stem cell-derived extract (CCM) for the treatment of knee OA. METHODS AND ANALYSIS This is a non-randomized, open-label, multi-center, prospective study in which the safety and efficacy of intraarticular CCM in patients suffering from grade II/III knee OA will be evaluated. Up to 20 patients with grade II/III OA who meet the inclusion and exclusion criteria will be consented and screened to recruit 12 patients to receive treatment. The study will be conducted at up to 2 sites within the USA, and the 12 participants will be followed for 24 months. The study participants will be monitored for adverse reactions and assessed using Numeric Pain Rating Scale (NPRS), Patient-Reported Outcomes Measurement Information System (PROMIS) Score, Knee Injury and Osteoarthritis Outcome Score Jr. (KOOS Jr.), 36-ietm short form survey (SF-36), Single Assessment Numeric Evaluation (SANE), physical exams, plain radiography, and magnetic resonance imaging (MRI) with Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score for improvements in pain, function, satisfaction, and cartilage regeneration. DISCUSSION This prospective study will provide valuable information into the safety and efficacy of intraarticular administration of cell-free stem cell-derived extract (CCM) in patients suffering with grade II/III knee OA. The outcomes from this initial study of novel CCM will lay the foundation for a larger randomized, placebo-controlled, multi-center clinical trial of intraarticular CCM for symptomatic knee OA. TRIAL REGISTRATION Registered on July 21, 2021. ClinicalTrials.gov NCT04971798.
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Affiliation(s)
- Ashim Gupta
- General Therapeutics, 2956 Washington Blvd, Cleveland Heights, OH 44118 USA
- Future Biologics, Lawrenceville, GA USA
- South Texas Orthopedic Research Institute (STORI Inc.), Laredo, TX USA
- Veterans in Pain (V.I.P.), Los Angeles, CA USA
| | - Nicola Maffulli
- Department of Musculoskeletal Disorders, School of Medicine and Surgery, University of Salerno, Fisciano, Italy
- San Giovanni di Dio e Ruggi D’Aragona Hospital “Clinica Orthopedica” Department, Hospital of Salerno, Salerno, Italy
- Barts and the London School of Medicine and Dentistry, Centre for Sports and Exercise Medicine, Queen Mary University of London, London, UK
- School of Pharmacy and Bioengineering, Keele University School of Medicine, Stoke on Trent, UK
| | - Hugo C. Rodriguez
- Future Biologics, Lawrenceville, GA USA
- South Texas Orthopedic Research Institute (STORI Inc.), Laredo, TX USA
- School of Osteopathic Medicine, University of The Incarnate Word, San Antonio, TX USA
- Future Physicians of South Texas, San Antonio, TX USA
| | - R. Justin Mistovich
- General Therapeutics, 2956 Washington Blvd, Cleveland Heights, OH 44118 USA
- Department of Orthopaedics, School of Medicine, Case Western Reserve University, Cleveland, OH USA
| | - Kristin Delfino
- Southern Illinois University, School of Medicine, Springfield, IL USA
| | - Craig Cady
- General Therapeutics, 2956 Washington Blvd, Cleveland Heights, OH 44118 USA
- Bohlander Stem Cell Research Laboratory, Department of Biology, Bradley University, Peoria, IL USA
| | - Anne-Marie Fauser
- Bohlander Stem Cell Research Laboratory, Department of Biology, Bradley University, Peoria, IL USA
| | - Echo D. Cundiff
- General Therapeutics, 2956 Washington Blvd, Cleveland Heights, OH 44118 USA
| | | | - Anish G. Potty
- General Therapeutics, 2956 Washington Blvd, Cleveland Heights, OH 44118 USA
- South Texas Orthopedic Research Institute (STORI Inc.), Laredo, TX USA
- Barts and the London School of Medicine and Dentistry, Centre for Sports and Exercise Medicine, Queen Mary University of London, London, UK
- Laredo Sports Medicine Clinic, Laredo, TX USA
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Rauch A, Mandrup S. Transcriptional networks controlling stromal cell differentiation. Nat Rev Mol Cell Biol 2021; 22:465-482. [PMID: 33837369 DOI: 10.1038/s41580-021-00357-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2021] [Indexed: 02/02/2023]
Abstract
Stromal progenitors are found in many different tissues, where they play an important role in the maintenance of tissue homeostasis owing to their ability to differentiate into parenchymal cells. These progenitor cells are differentially pre-programmed by their tissue microenvironment but, when cultured and stimulated in vitro, these cells - commonly referred to as mesenchymal stromal cells (MSCs) - exhibit a marked plasticity to differentiate into many different cell lineages. Loss-of-function studies in vitro and in vivo have uncovered the involvement of specific signalling pathways and key transcriptional regulators that work in a sequential and coordinated fashion to activate lineage-selective gene programmes. Recent advances in omics and single-cell technologies have made it possible to obtain system-wide insights into the gene regulatory networks that drive lineage determination and cell differentiation. These insights have important implications for the understanding of cell differentiation, the contribution of stromal cells to human disease and for the development of cell-based therapeutic applications.
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Affiliation(s)
- Alexander Rauch
- Molecular Endocrinology & Stem Cell Research Unit (KMEB), Department of Endocrinology and Metabolism, Odense University Hospital and Department of Clinical Research, University of Southern Denmark, Odense, Denmark. .,Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark.
| | - Susanne Mandrup
- Center for Functional Genomics and Tissue Plasticity, Functional Genomics & Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
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Fracture Healing Research-Shift towards In Vitro Modeling? Biomedicines 2021; 9:biomedicines9070748. [PMID: 34203470 PMCID: PMC8301383 DOI: 10.3390/biomedicines9070748] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/18/2021] [Accepted: 06/23/2021] [Indexed: 01/07/2023] Open
Abstract
Fractures are one of the most frequently occurring traumatic events worldwide. Approximately 10% of fractures lead to bone healing disorders, resulting in strain for affected patients and enormous costs for society. In order to shed light into underlying mechanisms of bone regeneration (habitual or disturbed), and to develop new therapeutic strategies, various in vivo, ex vivo and in vitro models can be applied. Undeniably, in vivo models include the systemic and biological situation. However, transferability towards the human patient along with ethical concerns regarding in vivo models have to be considered. Fostered by enormous technical improvements, such as bioreactors, on-a-chip-technologies and bone tissue engineering, sophisticated in vitro models are of rising interest. These models offer the possibility to use human cells from individual donors, complex cell systems and 3D models, therefore bridging the transferability gap, providing a platform for the introduction of personalized precision medicine and finally sparing animals. Facing diverse processes during fracture healing and thus various scientific opportunities, the reliability of results oftentimes depends on the choice of an appropriate model. Hence, we here focus on categorizing available models with respect to the requirements of the scientific approach.
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Mesenchymal Stem Cell-Derived Extracellular Vesicles to the Rescue of Renal Injury. Int J Mol Sci 2021; 22:ijms22126596. [PMID: 34202940 PMCID: PMC8235408 DOI: 10.3390/ijms22126596] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/09/2021] [Accepted: 06/16/2021] [Indexed: 12/14/2022] Open
Abstract
Acute kidney injury (AKI) and chronic kidney disease (CKD) are rising in global prevalence and cause significant morbidity for patients. Current treatments are limited to slowing instead of stabilising or reversing disease progression. In this review, we describe mesenchymal stem cells (MSCs) and their constituents, extracellular vesicles (EVs) as being a novel therapeutic for CKD. MSC-derived EVs (MSC-EVs) are membrane-enclosed particles, including exosomes, which carry genetic information that mimics the phenotype of their cell of origin. MSC-EVs deliver their cargo of mRNA, miRNA, cytokines, and growth factors to target cells as a form of paracrine communication. This genetically reprograms pathophysiological pathways, which are upregulated in renal failure. Since the method of exosome preparation significantly affects the quality and function of MSC-exosomes, this review compares the methodologies for isolating exosomes from MSCs and their role in tissue regeneration. More specifically, it summarises the therapeutic efficacy of MSC-EVs in 60 preclinical animal models of AKI and CKD and the cargo of biomolecules they deliver. MSC-EVs promote tubular proliferation and angiogenesis, and inhibit apoptosis, oxidative stress, inflammation, the epithelial-to-mesenchymal transition, and fibrosis, to alleviate AKI and CKD. By reprogramming these pathophysiological pathways, MSC-EVs can slow or even reverse the progression of AKI to CKD, and therefore offer potential to transform clinical practice.
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Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles ameliorate collagen-induced arthritis via immunomodulatory T lymphocytes. Mol Immunol 2021; 135:36-44. [PMID: 33857817 DOI: 10.1016/j.molimm.2021.04.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 10/03/2020] [Accepted: 04/04/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Rheumatoid arthritis (RA) is an autoimmune disease for which there are currently no effective therapies. Although mesenchymal stem cells (MSCs) can prevent arthritis through immunomodulatory mechanisms, there are several associated risks. Alternatively, MSC-derived small extracellular vesicles (sEVs) can mimic the effects of MSCs, while reducing the risk of adverse events. However, few studies have examined sEVs in the context of RA. Here, we evaluate the immunomodulatory effects of human umbilical cord MSC (hUCMSC)-derived sEVs on T lymphocytes in a collagen-induced arthritis (CIA) rat model to elucidate the possible mechanism of sEVs in RA treatment. We then compare these mechanisms to those of MSCs and methotrexate (MTX). METHODS The arthritis index and synovial pathology were assessed. T lymphocyte proliferation and apoptosis, Th17 and Treg proportions, and interleukin (IL)-17, IL-10, and transforming growth factor (TGF)-β expression were detected using flow cytometry. Retinoic acid receptor-related orphan receptor gamma t (RORγt) and forkhead box P3 (FOXP3), which are master transcriptional regulators of Th17 and Treg differentiation, were also assessed using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS sEV treatment ameliorated arthritis and inhibited synovial hyperplasia in a dose-dependent manner. These effects were mediated by inhibiting T lymphocyte proliferation and promoting their apoptosis, while decreasing Th17 cell proportion and increasing that of Treg cells in the spleen, resulting in decreased serum IL-17, and enhanced IL-10 and TGF-β expression. Transcriptionally, sEVs decreased RORγt and increased FOXP3 expression in the spleen, and decreased RORγt and FOXP3 expression in the joints. In some aspects sEVs were more effective than MSCs and MTX in treating CIA. CONCLUSIONS hUCMSC-derived sEVs ameliorate CIA via immunomodulatory T lymphocytes, and might serve as a new therapy for RA.
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Rashid S, Qazi REM, Malick TS, Salim A, Khan I, Ilyas A, Haneef K. Effect of valproic acid on the hepatic differentiation of mesenchymal stem cells in 2D and 3D microenvironments. Mol Cell Biochem 2021; 476:909-919. [PMID: 33111212 DOI: 10.1007/s11010-020-03955-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 10/15/2020] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) have multi-lineage differentiation potential which make them an excellent source for cell-based therapies. Histone modification is one of the major epigenetic regulations that play central role in stem cell differentiation. Keeping in view their ability to maintain gene expression essential for successful differentiation, it was interesting to examine the effects of valproic acid (VPA), a histone deacetylase inhibitor, in the hepatic differentiation of MSCs within the 3D scaffold. MSCs were treated with the optimized concentration of VPA in the 3D collagen scaffold. Analyses of hepatic differentiation potential of treated MSCs were performed by qPCR, immunostaining and periodic acid Schiff assay. Our results demonstrate that MSCs differentiate into hepatic-like cells when treated with 5 mM VPA for 24 h. The VPA-treated MSCs have shown significant upregulation in the expression of hepatic genes, CK-18 (P < 0.05), TAT (P < 0.01), and AFP (P < 0.001), and hepatic proteins, AFP (P < 0.05) and ALB (P < 0.01). In addition, acetylation of histones (H3 and H4) was significantly increased (P < 0.001) in VPA-pretreated cells. Further analysis showed that VPA treatment significantly enhanced (P < 0.01) glycogen storage, an important functional aspect of hepatic cells. The present study revealed the effectiveness of VPA in hepatic differentiation within the 3D collagen scaffold. These hepatic-like cells may have an extended clinical applicability in future for successful liver regeneration.
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Affiliation(s)
- Saman Rashid
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, 75270, Pakistan
| | - Rida-E-Maria Qazi
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Tuba Shakil Malick
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Irfan Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Amber Ilyas
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, 75270, Pakistan
| | - Kanwal Haneef
- Dr. Zafar H. Zaidi Center for Proteomics, University of Karachi, Karachi, 75270, Pakistan.
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Küçükgüven MB, Çelebi-Saltik B. Stem Cell Based Exosomes: Are They Effective in Disease or Health? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1341:45-65. [PMID: 33782904 DOI: 10.1007/5584_2021_630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Exosomes are nano-sized vesicles involved in intercellular communication via delivery of molecules including lipids, nucleic acids, proteins, or other cellular components to distant or neighboring sites. Their ability to pass biological barriers, stability in physiological fluids without degradation, and distinctive affinity to target cells make exosomes very remarkable therapeutic vehicles. Virus-based approaches are some of the most widely used gene therapy methods; however, there are many issues need to be clarified such as high immunogenicity. Using of the exosomes procures the functional transfer of their cargo with minimal intervention from the immune system and it has been reported to be secure and well-tolerated. When the regenerative medicine is taken into consideration, stem cell-based approaches have been aimed to utilize but the general efficacy and safety profile of stem cell therapy has still not been enlightened. At this point, stem cell-derived exosomes exhibit a way to procure cell-free regenerative medicine with their unique characteristics. Exosomes are considered as appropriate and highly stable biological nano-vectors taking part in a wide variety of healthy and pathological processes for advanced targeted therapies. However, there are still crucial obstacles to achieve efficient isolation of large amount of specific and pure exosomes. Thus, large-scale exosome production under good manufacturing practice is required. The purpose of this review is to focus on stem cell-based exosomes for gene delivery and to introduce synthetic exosome-mimics as a potential alternative in the field of targeted gene therapies. Further, we aim to highlight the biobanking and large-scale manufacturing methods of exosomes.
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Affiliation(s)
- Meriç Bilgiç Küçükgüven
- Department of Oral and Maxillofacial Surgery, Hacettepe University Faculty of Dentistry, Ankara, Turkey.,Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, Ankara, Turkey.,Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey
| | - Betül Çelebi-Saltik
- Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, Ankara, Turkey. .,Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey.
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Costimulatory Effect of Rough Calcium Phosphate Coating and Blood Mononuclear Cells on Adipose-Derived Mesenchymal Stem Cells In Vitro as a Model of In Vivo Tissue Repair. MATERIALS 2020; 13:ma13194398. [PMID: 33023124 PMCID: PMC7579197 DOI: 10.3390/ma13194398] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/26/2020] [Accepted: 09/29/2020] [Indexed: 02/07/2023]
Abstract
Calcium phosphate (CaP) materials do not always induce ectopic vascularization and bone formation; the reasons remain unclear, and there are active discussions of potential roles for post-implantation hematoma, circulating immune and stem cells, and pericytes, but studies on adipose-derived stem cells (AMSCs) in this context are lacking. The rough (average surface roughness Ra = 2-5 µm) scaffold-like CaP coating deposited on pure titanium plates by the microarc oxidation method was used to investigate its subcutaneous vascularization in CBA/CaLac mice and in vitro effect on cellular and molecular crosstalk between human blood mononuclear cells (hBMNCs) and AMSCs (hAMSCs). Postoperative hematoma development on the CaP surface lasting 1-3 weeks may play a key role in the microvessel elongation and invasion into the CaP relief at the end of the 3rd week of injury and BMNC migration required for enhanced wound healing in mice. Satisfactory osteogenic and chondrogenic differentiation but poor adipogenic differentiation of hAMSCs on the rough CaP surface were detected in vitro by differential cell staining. The fractions of CD73+ (62%), CD90+ (0.24%), and CD105+ (0.41%) BMNCs may be a source of autologous circulating stem/progenitor cells for the subcutis reparation, but allogenic hBMNC participation is mainly related to the effects of CD4+ T cells co-stimulated with CaP coating on the in vitro recruitment of hAMSCs, their secretion of angiogenic and osteomodulatory molecules, and the increase in osteogenic features within the period of in vivo vascularization. Cellular and molecular crosstalk between BMNCs and AMSCs is a model of effective subcutis repair. Rough CaP surface enhanced angio- and osteogenic signaling between cells. We believe that preconditioning and/or co-transplantation of hAMSCs with hBMNCs may broaden their potential in applications related to post-implantation tissue repair and bone bioengineering caused by microarc CaP coating.
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Shanbhag S, Mohamed-Ahmed S, Lunde THF, Suliman S, Bolstad AI, Hervig T, Mustafa K. Influence of platelet storage time on human platelet lysates and platelet lysate-expanded mesenchymal stromal cells for bone tissue engineering. Stem Cell Res Ther 2020; 11:351. [PMID: 32962723 PMCID: PMC7510290 DOI: 10.1186/s13287-020-01863-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 06/25/2020] [Accepted: 07/29/2020] [Indexed: 12/20/2022] Open
Abstract
Background Human platelet lysate (HPL) is emerging as the preferred xeno-free supplement for the expansion of mesenchymal stromal cells (MSCs) for bone tissue engineering (BTE) applications. Due to a growing demand, the need for standardization and scaling-up of HPL has been highlighted. However, the optimal storage time of the source material, i.e., outdated platelet concentrates (PCs), remains to be determined. The present study aimed to determine the optimal storage time of PCs in terms of the cytokine content and biological efficacy of HPL. Methods Donor-matched bone marrow (BMSCs) and adipose-derived MSCs (ASCs) expanded in HPL or fetal bovine serum (FBS) were characterized based on in vitro proliferation, immunophenotype, and multi-lineage differentiation. Osteogenic differentiation was assessed at early (gene expression), intermediate [alkaline phosphatase (ALP) activity], and terminal stages (mineralization). Using a multiplex immunoassay, the cytokine contents of HPLs produced from PCs stored for 1–9 months were screened and a preliminary threshold of 4 months was identified. Next, HPLs were produced from PCs stored for controlled durations of 0, 1, 2, 3, and 4 months, and their efficacy was compared in terms of cytokine content and BMSCs’ proliferation and osteogenic differentiation. Results BMSCs and ASCs in both HPL and FBS demonstrated a characteristic immunophenotype and multi-lineage differentiation; osteogenic differentiation of BMSCs and ASCs was significantly enhanced in HPL vs. FBS. Multiplex network analysis of HPL revealed several interacting growth factors, chemokines, and inflammatory cytokines. Notably, stem cell growth factor (SCGF) was detected in high concentrations. A majority of cytokines were elevated in HPLs produced from PCs stored for ≤ 4 months vs. > 4 months. However, no further differences in PC storage times between 0 and 4 months were identified in terms of HPLs’ cytokine content or their effects on the proliferation, ALP activity, and mineralization of BMSCs from multiple donors. Conclusions MSCs expanded in HPL demonstrate enhanced osteogenic differentiation, albeit with considerable donor variation. HPLs produced from outdated PCs stored for up to 4 months efficiently supported the proliferation and osteogenic differentiation of MSCs. These findings may facilitate the standardization and scaling-up of HPL from outdated PCs for BTE applications.
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Affiliation(s)
- Siddharth Shanbhag
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Årstadveien 19, 5008, Bergen, Norway
| | - Samih Mohamed-Ahmed
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Årstadveien 19, 5008, Bergen, Norway
| | - Turid Helen Felli Lunde
- Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway
| | - Salwa Suliman
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Årstadveien 19, 5008, Bergen, Norway
| | - Anne Isine Bolstad
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Årstadveien 19, 5008, Bergen, Norway
| | - Tor Hervig
- Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway.,Laboratory of Immunology and Transfusion Medicine, Haugesund Hospital, Fonna Health Trust, Haugesund, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Kamal Mustafa
- Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Årstadveien 19, 5008, Bergen, Norway.
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Mendt M, Rezvani K, Shpall E. Mesenchymal stem cell-derived exosomes for clinical use. Bone Marrow Transplant 2020; 54:789-792. [PMID: 31431712 DOI: 10.1038/s41409-019-0616-z] [Citation(s) in RCA: 339] [Impact Index Per Article: 67.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Mesenchymal stem/stromal cells (MSCs) are commonly used as a source of cellular therapy due to their strong immunosuppressive and regenerative effects. One of the key mechanisms of MSC efficacy appears to derive from their paracrine activity. Recently, it has been shown that the secretion of different factors through extracellular vesicles known as exosomes, orchestrate the principle mechanisms of action of MSCs after infusion. The use of MSC-derived exosomes may provide considerable advantages over their counterpart live cells, potentially reducing undesirable side effects including infusional toxicities. In this review, we examine clinical trials of MSC-derived exosomes currently in progress for gene delivery, regenerative medicine, and immunomodulation. In addition, we summarize the limitations and clinical potential of this cell-free therapeutic strategy.
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Affiliation(s)
- Mayela Mendt
- Stem Cell Transplantation, MD Anderson Cancer Center, Houston, TX, USA
| | - Katayoun Rezvani
- Stem Cell Transplantation, MD Anderson Cancer Center, Houston, TX, USA
| | - Elizabeth Shpall
- Stem Cell Transplantation, MD Anderson Cancer Center, Houston, TX, USA.
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Ma ZJ, Yang JJ, Lu YB, Liu ZY, Wang XX. Mesenchymal stem cell-derived exosomes: Toward cell-free therapeutic strategies in regenerative medicine. World J Stem Cells 2020; 12:814-840. [PMID: 32952861 PMCID: PMC7477653 DOI: 10.4252/wjsc.v12.i8.814] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/23/2020] [Accepted: 06/27/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells with marked potential for regenerative medicine because of their strong immunosuppressive and regenerative abilities. The therapeutic effects of MSCs are based in part on their secretion of biologically active factors in extracellular vesicles known as exosomes. Exosomes have a diameter of 30-100 nm and mediate intercellular communication and material exchange. MSC-derived exosomes (MSC-Exos) have potential for cell-free therapy for diseases of, for instance, the kidney, liver, heart, nervous system, and musculoskeletal system. Hence, MSC-Exos are an alternative to MSC-based therapy for regenerative medicine. We review MSC-Exos and their therapeutic potential for a variety of diseases and injuries.
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Affiliation(s)
- Zhan-Jun Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Jing-Jing Yang
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yu-Bao Lu
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Zhao-Yang Liu
- Department of Medical Imaging, Shanxi Medical University, Jinzhong 030600, Shaanxi Province, China
| | - Xue-Xi Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, Gansu Province, China.
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Mesenchymal Stem/Progenitor Cells: The Prospect of Human Clinical Translation. Stem Cells Int 2020; 2020:8837654. [PMID: 33953753 PMCID: PMC8063852 DOI: 10.1155/2020/8837654] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/19/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/progenitor cells (MSCs) are key players in regenerative medicine, relying principally on their differentiation/regeneration potential, immunomodulatory properties, paracrine effects, and potent homing ability with minimal if any ethical concerns. Even though multiple preclinical and clinical studies have demonstrated remarkable properties for MSCs, the clinical applicability of MSC-based therapies is still questionable. Several challenges exist that critically hinder a successful clinical translation of MSC-based therapies, including but not limited to heterogeneity of their populations, variability in their quality and quantity, donor-related factors, discrepancies in protocols for isolation, in vitro expansion and premodification, and variability in methods of cell delivery, dosing, and cell homing. Alterations of MSC viability, proliferation, properties, and/or function are also affected by various drugs and chemicals. Moreover, significant safety concerns exist due to possible teratogenic/neoplastic potential and transmission of infectious diseases. Through the current review, we aim to highlight the major challenges facing MSCs' human clinical translation and shed light on the undergoing strategies to overcome them.
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45
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Palmroth A, Pitkänen S, Hannula M, Paakinaho K, Hyttinen J, Miettinen S, Kellomäki M. Evaluation of scaffold microstructure and comparison of cell seeding methods using micro-computed tomography-based tools. J R Soc Interface 2020; 17:20200102. [PMID: 32228403 PMCID: PMC7211473 DOI: 10.1098/rsif.2020.0102] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 03/16/2020] [Indexed: 12/24/2022] Open
Abstract
Micro-computed tomography (micro-CT) provides a means to analyse and model three-dimensional (3D) tissue engineering scaffolds. This study proposes a set of micro-CT-based tools firstly for evaluating the microstructure of scaffolds and secondly for comparing different cell seeding methods. The pore size, porosity and pore interconnectivity of supercritical CO2 processed poly(l-lactide-co-ɛ-caprolactone) (PLCL) and PLCL/β-tricalcium phosphate scaffolds were analysed using computational micro-CT models. The models were supplemented with an experimental method, where iron-labelled microspheres were seeded into the scaffolds and micro-CT imaged to assess their infiltration into the scaffolds. After examining the scaffold architecture, human adipose-derived stem cells (hASCs) were seeded into the scaffolds using five different cell seeding methods. Cell viability, number and 3D distribution were evaluated. The distribution of the cells was analysed using micro-CT by labelling the hASCs with ultrasmall paramagnetic iron oxide nanoparticles. Among the tested seeding methods, a forced fluid flow-based technique resulted in an enhanced cell infiltration throughout the scaffolds compared with static seeding. The current study provides an excellent set of tools for the development of scaffolds and for the design of 3D cell culture experiments.
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Affiliation(s)
- Aleksi Palmroth
- Biomaterials and Tissue Engineering Group, BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Korkeakoulunkatu 3, 33720 Tampere, Finland
| | - Sanna Pitkänen
- Adult Stem Cell Group, Tampere University, Tampere, Finland
- Research, Development and Innovation Centre, Tampere University Hospital, Tampere, Finland
| | - Markus Hannula
- Computational Biophysics and Imaging Group, BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Kaarlo Paakinaho
- Adult Stem Cell Group, Tampere University, Tampere, Finland
- Orton Orthopaedic Hospital, Helsinki, Finland
| | - Jari Hyttinen
- Computational Biophysics and Imaging Group, BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Susanna Miettinen
- Adult Stem Cell Group, Tampere University, Tampere, Finland
- Research, Development and Innovation Centre, Tampere University Hospital, Tampere, Finland
| | - Minna Kellomäki
- Biomaterials and Tissue Engineering Group, BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Korkeakoulunkatu 3, 33720 Tampere, Finland
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Gowen A, Shahjin F, Chand S, Odegaard KE, Yelamanchili SV. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Challenges in Clinical Applications. Front Cell Dev Biol 2020; 8:149. [PMID: 32226787 PMCID: PMC7080981 DOI: 10.3389/fcell.2020.00149] [Citation(s) in RCA: 235] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 02/24/2020] [Indexed: 12/12/2022] Open
Abstract
Stem cell therapy has garnered much attention and application in the past decades for the treatment of diseases and injuries. Mesenchymal stem cells (MSCs) are studied most extensively for their therapeutic roles, which appear to be derived from their paracrine activity. Recent studies suggest a critical therapeutic role for extracellular vesicles (EV) secreted by MSCs. EV are nano-sized membrane-bound vesicles that shuttle important biomolecules between cells to maintain physiological homeostasis. Studies show that EV from MSCs (MSC-EV) have regenerative and anti-inflammatory properties. The use of MSC-EV, as an alternative to MSCs, confers several advantages, such as higher safety profile, lower immunogenicity, and the ability to cross biological barriers, and avoids complications that arise from stem cell-induced ectopic tumor formation, entrapment in lung microvasculature, and immune rejection. These advantages and the growing body of evidence suggesting that MSC-EV display therapeutic roles contribute to the strong rationale for developing EV as an alternative therapeutic option. Despite the success in preclinical studies, use of MSC-EV in clinical settings will require careful consideration; specifically, several critical issues such as (i) production methods, (ii) quantification and characterization, (iii) pharmacokinetics, targeting and transfer to the target sites, and (iv) safety profile assessments need to be resolved. Keeping these issues in mind, the aim of this mini-review is to shed light on the challenges faced in MSC-EV research in translating successful preclinical studies to clinical platforms.
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Affiliation(s)
- Austin Gowen
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Farah Shahjin
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Subhash Chand
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Katherine E Odegaard
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Sowmya V Yelamanchili
- Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE, United States
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Kronemberger GS, Matsui RAM, Miranda GDASDCE, Granjeiro JM, Baptista LS. Cartilage and bone tissue engineering using adipose stromal/stem cells spheroids as building blocks. World J Stem Cells 2020; 12:110-122. [PMID: 32184936 PMCID: PMC7062040 DOI: 10.4252/wjsc.v12.i2.110] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 10/19/2019] [Accepted: 01/15/2020] [Indexed: 02/06/2023] Open
Abstract
Scaffold-free techniques in the developmental tissue engineering area are designed to mimic in vivo embryonic processes with the aim of biofabricating, in vitro, tissues with more authentic properties. Cell clusters called spheroids are the basis for scaffold-free tissue engineering. In this review, we explore the use of spheroids from adult mesenchymal stem/stromal cells as a model in the developmental engineering area in order to mimic the developmental stages of cartilage and bone tissues. Spheroids from adult mesenchymal stromal/stem cells lineages recapitulate crucial events in bone and cartilage formation during embryogenesis, and are capable of spontaneously fusing to other spheroids, making them ideal building blocks for bone and cartilage tissue engineering. Here, we discuss data from ours and other labs on the use of adipose stromal/stem cell spheroids in chondrogenesis and osteogenesis in vitro. Overall, recent studies support the notion that spheroids are ideal "building blocks" for tissue engineering by “bottom-up” approaches, which are based on tissue assembly by advanced techniques such as three-dimensional bioprinting. Further studies on the cellular and molecular mechanisms that orchestrate spheroid fusion are now crucial to support continued development of bottom-up tissue engineering approaches such as three-dimensional bioprinting.
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Affiliation(s)
- Gabriela S Kronemberger
- Laboratory of Tissue Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Post-graduate Program in Translational Biomedicine (Biotrans), Unigranrio, Campus I, Duque de Caxias, RJ 25250-020, Brazil
| | - Renata Akemi Morais Matsui
- Laboratory of Tissue Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Post-graduate Program in Biotechnology, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
| | - Guilherme de Almeida Santos de Castro e Miranda
- Laboratory of Tissue Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Federal University of Rio de Janeiro (UFRJ), Campus Duque de Caxias, Duque de Caxias, RJ 25250-020, Brazil
| | - José Mauro Granjeiro
- Laboratory of Tissue Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Post-graduate Program in Biotechnology, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Laboratory of Clinical Research in Odontology, Fluminense Federal University (UFF), Niterói 25255-030 Brazil
| | - Leandra Santos Baptista
- Laboratory of Tissue Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Post-graduate Program in Translational Biomedicine (Biotrans), Unigranrio, Campus I, Duque de Caxias, RJ 25250-020, Brazil
- Post-graduate Program in Biotechnology, National Institute of Metrology, Quality and Technology (INMETRO), Duque de Caxias, RJ 25250-020, Brazil
- Multidisciplinary Center for Biological Research (Numpex-Bio), Federal University of Rio de Janeiro (UFRJ) Campus Duque de Caxias, Duque de Caxias, RJ 25245-390, Brazil
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Yang S, Zhu B, Yin P, Zhao L, Wang Y, Fu Z, Dang R, Xu J, Zhang J, Wen N. Integration of Human Umbilical Cord Mesenchymal Stem Cells-Derived Exosomes with Hydroxyapatite-Embedded Hyaluronic Acid-Alginate Hydrogel for Bone Regeneration. ACS Biomater Sci Eng 2020; 6:1590-1602. [PMID: 33455380 DOI: 10.1021/acsbiomaterials.9b01363] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The treatment of bone defects has plagued clinicians. Exosomes, the naturally secreted nanovesicles by cells, exhibit great potential in bone defect regeneration to realize cell-free therapy. In this work, we successfully revealed that human umbilical cord mesenchymal stem cells-derived exosomes could effectively promote the proliferation, migration, and osteogenic differentiation of a murine calvariae preosteoblast cell line in vitro. Considering the long period of bone regeneration, to effectively exert the reparative effect of exosomes, we synthesized an injectable hydroxyapatite (HAP)-embedded in situ cross-linked hyaluronic acid-alginate (HA-ALG) hydrogel system to durably retain exosomes at the defect sites. Then, we combined the exosomes with the HAP-embedded in situ cross-linked HA-ALG hydrogel system to repair bone defects in rats in vivo. The results showed that the combination of exosomes and composite hydrogel could significantly enhance bone regeneration. Our experiment provides a new strategy for exosome-based therapy, which shows great potential in future tissue and organ repair.
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Affiliation(s)
- Shuo Yang
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Biao Zhu
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Peng Yin
- College of Chemical Engineering, Beijing University of Chemical Technology, Beijing 100029, China
| | - Lisheng Zhao
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Yizhu Wang
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Zhiguang Fu
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Ruijie Dang
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Juan Xu
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
| | - Jianjun Zhang
- College of Chemical Engineering, Beijing University of Chemical Technology, Beijing 100029, China
| | - Ning Wen
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, China
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Magnetic nanocomposite hydrogels and static magnetic field stimulate the osteoblastic and vasculogenic profile of adipose-derived cells. Biomaterials 2019; 223:119468. [DOI: 10.1016/j.biomaterials.2019.119468] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 08/20/2019] [Accepted: 09/01/2019] [Indexed: 11/18/2022]
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Filippi M, Nguyen DV, Garello F, Perton F, Bégin-Colin S, Felder-Flesch D, Power L, Scherberich A. Metronidazole-functionalized iron oxide nanoparticles for molecular detection of hypoxic tissues. NANOSCALE 2019; 11:22559-22574. [PMID: 31746914 DOI: 10.1039/c9nr08436c] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Being crucial under several pathological conditions, tumors, and tissue engineering, the MRI tracing of hypoxia within cells and tissues would be improved by the use of nanosystems allowing for direct recognition of low oxygenation and further treatment-oriented development. In the present study, we functionalized dendron-coated iron oxide nanoparticles (dendronized IONPs) with a bioreductive compound, a metronidazole-based ligand, to specifically detect the hypoxic tissues. Spherical IONPs with an average size of 10 nm were obtained and then decorated with the new metronidazole-conjugated dendron. The resulting nanoparticles (metro-NPs) displayed negligible effects on cell viability, proliferation, and metabolism, in both monolayer and 3D cell culture models, and a good colloidal stability in bio-mimicking media, as shown by DLS. Overtime quantitative monitoring of the IONP cell content revealed an enhanced intracellular retention of metro-NPs under anoxic conditions, confirmed by the in vitro MRI of cell pellets where a stronger negative contrast generation was observed in hypoxic primary stem cells and tumor cells after labeling with metro-NPs. Overall, these results suggest desirable properties in terms of interactions with the biological environment and capability of selective accumulation into the hypoxic tissue, and indicate that metro-NPs have considerable potential for the development of new nano-platforms especially in the field of anoxia-related diseases and tissue engineered models.
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Affiliation(s)
- Miriam Filippi
- Department of Biomedical Engineering, University of Basel, Gewerbestrasse 14, 4123, Allschwil, Basel, Switzerland.
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