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Wang YJ, Chen ZH, Shen YT, Wang KX, Han YM, Zhang C, Yang XM, Chen BQ. Stem cell therapy: A promising therapeutic approach for skeletal muscle atrophy. World J Stem Cells 2025; 17:98693. [DOI: 10.4252/wjsc.v17.i2.98693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 12/09/2024] [Accepted: 01/23/2025] [Indexed: 02/24/2025] Open
Abstract
Skeletal muscle atrophy results from disruptions in the growth and metabolism of striated muscle, leading to a reduction or loss of muscle fibers. This condition not only significantly impacts patients’ quality of life but also imposes substantial socioeconomic burdens. The complex molecular mechanisms driving skeletal muscle atrophy contribute to the absence of effective treatment options. Recent advances in stem cell therapy have positioned it as a promising approach for addressing this condition. This article reviews the molecular mechanisms of muscle atrophy and outlines current therapeutic strategies, focusing on mesenchymal stem cells, induced pluripotent stem cells, and their derivatives. Additionally, the challenges these stem cells face in clinical applications are discussed. A deeper understanding of the regenerative potential of various stem cells could pave the way for breakthroughs in the prevention and treatment of muscle atrophy.
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Affiliation(s)
- Ying-Jie Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Ze-Hao Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Yun-Tian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Ke-Xin Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Yi-Min Han
- Medical College, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Chen Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Xiao-Ming Yang
- Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong 226000, Jiangsu Province, China
- Research and Development Center for E-Learning, Ministry of Education, Beijing 100816, China
| | - Bing-Qian Chen
- Department of Orthopaedics, Changshu Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
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Park S, Rahaman KA, Kim YC, Jeon H, Han HS. Fostering tissue engineering and regenerative medicine to treat musculoskeletal disorders in bone and muscle. Bioact Mater 2024; 40:345-365. [PMID: 38978804 PMCID: PMC11228556 DOI: 10.1016/j.bioactmat.2024.06.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 05/26/2024] [Accepted: 06/11/2024] [Indexed: 07/10/2024] Open
Abstract
The musculoskeletal system, which is vital for movement, support, and protection, can be impaired by disorders such as osteoporosis, osteoarthritis, and muscular dystrophy. This review focuses on the advances in tissue engineering and regenerative medicine, specifically aimed at alleviating these disorders. It explores the roles of cell therapy, particularly Mesenchymal Stem Cells (MSCs) and Adipose-Derived Stem Cells (ADSCs), biomaterials, and biomolecules/external stimulations in fostering bone and muscle regeneration. The current research underscores the potential of MSCs and ADSCs despite the persistent challenges of cell scarcity, inconsistent outcomes, and safety concerns. Moreover, integrating exogenous materials such as scaffolds and external stimuli like electrical stimulation and growth factors shows promise in enhancing musculoskeletal regeneration. This review emphasizes the need for comprehensive studies and adopting innovative techniques together to refine and advance these multi-therapeutic strategies, ultimately benefiting patients with musculoskeletal disorders.
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Affiliation(s)
- Soyeon Park
- Biomaterials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea
| | - Khandoker Asiqur Rahaman
- Biomaterials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
| | - Yu-Chan Kim
- Biomaterials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea
| | - Hojeong Jeon
- Biomaterials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea
| | - Hyung-Seop Han
- Biomaterials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea
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Widodo W, Widyahening IS, Pratama IK, Kuncoro MW. Prospect of Mesenchymal Stem Cells in Enhancing Nerve Regeneration in Brachial Plexus Injury in Animals: A Systematic Review. THE ARCHIVES OF BONE AND JOINT SURGERY 2024; 12:149-158. [PMID: 38577510 PMCID: PMC10989726 DOI: 10.22038/abjs.2024.68053.3224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 01/14/2024] [Indexed: 04/06/2024]
Abstract
Objectives Brachial plexus injuries (BPI), although rare, often results in significant morbidity. Stem cell was thought to be one of BPI treatment modalities because of their nerve-forming regeneration potential. Although there is a possibility for the use of mesenchymal stem cells as one of BPI treatment, it is still limited on animal studies. Therefore, this systematic review aimed to analyze the role of mesenchymal stem cells in nerve regeneration in animal models of brachial plexus injury. Method This study is a systematic review with PROSPERO registration number CRD4202128321. Literature searching was conducted using keywords experimental, animal, brachial plexus injury, mesenchymal stem cell implantation, clinical outcomes, electrophysiological outcomes, and histologic outcomes. Searches were performed in the PubMed, Scopus, and ScienceDirect databases. The risk of bias was assessed using SYRCLE's risk of bias tool for animal studies. The data obtained were described and in-depth analysis was performed. Result Four studies were included in this study involving 183 animals from different species those are rats and rabbits. There was an increase in muscle weight and shortened initial onset time of muscle contraction in the group treated with stem cells. Electrophysiological results showed that mesenchymal stem cells exhibited higher (Compound muscle action potential) CMAP amplitude and shorter CMAP latency than control but not better than autograft. Histological outcomes showed an increase in axon density, axon number, and the formation of connections between nerve cells and target muscles. Conclusion Mesenchymal stem cell implantation to animals with brachial plexus injury showed its ability to regenerate nerve cells as evidenced by clinical, electrophysiological, and histopathological results. However, this systematic study involved experimental animals from various species so that the results cannot be uniformed, and conclusion should be drawn cautiously.
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Affiliation(s)
- Wahyu Widodo
- Department of Orthopaedic and Traumatology Cipto Mangunkusumo Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
| | - Indah Suci Widyahening
- Department of Community Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
| | - Irfan Kurnia Pratama
- Department of Orthopaedic and Traumatology Cipto Mangunkusumo Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
| | - Mohamad Walid Kuncoro
- Department of Orthopaedic and Traumatology Cipto Mangunkusumo Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
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Orthobiologic Interventions for Muscle Injuries. Phys Med Rehabil Clin N Am 2023; 34:181-198. [DOI: 10.1016/j.pmr.2022.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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5
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Świerczek-Lasek B, Tolak L, Bijoch L, Stefaniuk M, Szpak P, Kalaszczynska I, Streminska W, Ciemerych MA, Archacka K. Comparison of Muscle Regeneration after BMSC-Conditioned Medium, Syngeneic, or Allogeneic BMSC Injection. Cells 2022; 11:cells11182843. [PMID: 36139418 PMCID: PMC9497150 DOI: 10.3390/cells11182843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 09/05/2022] [Accepted: 09/07/2022] [Indexed: 11/16/2022] Open
Abstract
For many years optimal treatment for dysfunctional skeletal muscle characterized, for example, by impaired or limited regeneration, has been searched. Among the crucial factors enabling its development is finding the appropriate source of cells, which could participate in tissue reconstruction or serve as an immunomodulating agent (limiting immune response as well as fibrosis, that is, connective tissue formation), after transplantation to regenerating muscles. MSCs, including those derived from bone marrow, are considered for such applications in terms of their immunomodulatory properties, as their naive myogenic potential is rather limited. Injection of autologous (syngeneic) or allogeneic BMSCs has been or is currently being tested and compared in many potential clinical treatments. In the present study, we verified which approach, that is, the transplantation of either syngeneic or allogeneic BMSCs or the injection of BMSC-conditioned medium, would be the most beneficial for skeletal muscle regeneration. To properly assess the influence of the tested treatments on the inflammation, the experiments were carried out using immunocompetent mice, which allowed us to observe immune response. Combined analysis of muscle histology, immune cell infiltration, and levels of selected chemokines, cytokines, and growth factors important for muscle regeneration, showed that muscle injection with BMSC-conditioned medium is the most beneficial strategy, as it resulted in reduced inflammation and fibrosis development, together with enhanced new fiber formation, which may be related to, i.e., elevated level of IGF-1. In contrast, transplantation of allogeneic BMSCs to injured muscles resulted in a visible increase in the immune response, which hindered regeneration by promoting connective tissue formation. In comparison, syngeneic BMSC injection, although not detrimental to muscle regeneration, did not result in such significant improvement as CM injection.
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Affiliation(s)
- Barbara Świerczek-Lasek
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, Miecznikowa Str. 1, 02-096 Warsaw, Poland
| | - Lukasz Tolak
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, Miecznikowa Str. 1, 02-096 Warsaw, Poland
| | - Lukasz Bijoch
- Laboratory of Neuronal Plasticity, BRAINCITY, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteur Str. 3, 02-093 Warsaw, Poland
| | - Marzena Stefaniuk
- Laboratory of Neurobiology, BRAINCITY, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteur Str. 3, 02-093 Warsaw, Poland
| | - Patrycja Szpak
- Department of Histology and Embryology, Medical University of Warsaw, Banacha Str. 1b, 02-004 Warsaw, Poland
| | - Ilona Kalaszczynska
- Department of Histology and Embryology, Medical University of Warsaw, Banacha Str. 1b, 02-004 Warsaw, Poland
- Laboratory for Cell Research and Application, Medical University of Warsaw, Banacha Str. 1b, 02-097 Warsaw, Poland
| | - Władysława Streminska
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, Miecznikowa Str. 1, 02-096 Warsaw, Poland
| | - Maria A. Ciemerych
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, Miecznikowa Str. 1, 02-096 Warsaw, Poland
| | - Karolina Archacka
- Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, Miecznikowa Str. 1, 02-096 Warsaw, Poland
- Correspondence:
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The miR151 and miR5100 Transfected Bone Marrow Stromal Cells Increase Myoblast Fusion in IGFBP2 Dependent Manner. Stem Cell Rev Rep 2022; 18:2164-2178. [PMID: 35190967 PMCID: PMC9391248 DOI: 10.1007/s12015-022-10350-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2022] [Indexed: 12/12/2022]
Abstract
Background Bone marrow stromal cells (BMSCs) form a perivascular cell population in the bone marrow. These cells do not present naïve myogenic potential. However, their myogenic identity could be induced experimentally in vitro or in vivo. In vivo, after transplantation into injured muscle, BMSCs rarely fused with myofibers. However, BMSC participation in myofiber reconstruction increased if they were modified by NICD or PAX3 overexpression. Nevertheless, BMSCs paracrine function could play a positive role in skeletal muscle regeneration. Previously, we showed that SDF-1 treatment and coculture with myofibers increased BMSC ability to reconstruct myofibers. We also noticed that SDF-1 treatment changed selected miRNAs expression, including miR151 and miR5100. Methods Mouse BMSCs were transfected with miR151 and miR5100 mimics and their proliferation, myogenic differentiation, and fusion with myoblasts were analyzed. Results We showed that miR151 and miR5100 played an important role in the regulation of BMSC proliferation and migration. Moreover, the presence of miR151 and miR5100 transfected BMSCs in co-cultures with human myoblasts increased their fusion. This effect was achieved in an IGFBP2 dependent manner. Conclusions Mouse BMSCs did not present naïve myogenic potential but secreted proteins could impact myogenic cell differentiation. miR151 and miR5100 transfection changed BMSC migration and IGFBP2 and MMP12 expression in BMSCs. miR151 and miR5100 transfected BMSCs increased myoblast fusion in vitro. Graphical abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1007/s12015-022-10350-y.
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Fu C, Huang AH, Galatz LM, Han WM. Cellular and molecular modulation of rotator cuff muscle pathophysiology. J Orthop Res 2021; 39:2310-2322. [PMID: 34553789 DOI: 10.1002/jor.25179] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/04/2021] [Accepted: 09/07/2021] [Indexed: 02/04/2023]
Abstract
Rotator cuff (RC) tendon tears are common shoulder injuries that result in irreversible and persistent degeneration of the associated muscles, which is characterized by severe inflammation, atrophy, fibrosis, and fatty infiltration. Although RC muscle degeneration strongly dictates the overall clinical outcomes, strategies to stimulate RC muscle regeneration have largely been overlooked to date. In this review, we highlight the current understanding of the cellular processes that coordinate muscle regeneration, and the roles of muscle resident cells, including immune cells, fibroadipogenic progenitors, and muscle satellite cells in the pathophysiologic regulation of RC muscles following injury. This review also provides perspectives for potential therapies to alleviate the hallmarks of RC muscle degeneration to address current limitations in postsurgical recovery.
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Affiliation(s)
- Chengcheng Fu
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Alice H Huang
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.,Department of Orthopedic Surgery, Columbia University, New York City, New York, USA
| | - Leesa M Galatz
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Woojin M Han
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.,Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
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Alarcin E, Bal-Öztürk A, Avci H, Ghorbanpoor H, Dogan Guzel F, Akpek A, Yesiltas G, Canak-Ipek T, Avci-Adali M. Current Strategies for the Regeneration of Skeletal Muscle Tissue. Int J Mol Sci 2021; 22:5929. [PMID: 34072959 PMCID: PMC8198586 DOI: 10.3390/ijms22115929] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/21/2021] [Accepted: 05/26/2021] [Indexed: 12/11/2022] Open
Abstract
Traumatic injuries, tumor resections, and degenerative diseases can damage skeletal muscle and lead to functional impairment and severe disability. Skeletal muscle regeneration is a complex process that depends on various cell types, signaling molecules, architectural cues, and physicochemical properties to be successful. To promote muscle repair and regeneration, various strategies for skeletal muscle tissue engineering have been developed in the last decades. However, there is still a high demand for the development of new methods and materials that promote skeletal muscle repair and functional regeneration to bring approaches closer to therapies in the clinic that structurally and functionally repair muscle. The combination of stem cells, biomaterials, and biomolecules is used to induce skeletal muscle regeneration. In this review, we provide an overview of different cell types used to treat skeletal muscle injury, highlight current strategies in biomaterial-based approaches, the importance of topography for the successful creation of functional striated muscle fibers, and discuss novel methods for muscle regeneration and challenges for their future clinical implementation.
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Affiliation(s)
- Emine Alarcin
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Marmara University, 34854 Istanbul, Turkey;
| | - Ayca Bal-Öztürk
- Department of Analytical Chemistry, Faculty of Pharmacy, Istinye University, 34010 Istanbul, Turkey;
- Department of Stem Cell and Tissue Engineering, Institute of Health Sciences, Istinye University, 34010 Istanbul, Turkey
| | - Hüseyin Avci
- Department of Metallurgical and Materials Engineering, Eskisehir Osmangazi University, 26040 Eskisehir, Turkey;
- Cellular Therapy and Stem Cell Research Center, Eskisehir Osmangazi University, 26040 Eskisehir, Turkey
- AvciBio Research Group, Eskisehir Osmangazi University, 26040 Eskisehir, Turkey;
- Translational Medicine Research and Clinical Center, Eskisehir Osmangazi University, 26040 Eskisehir, Turkey
| | - Hamed Ghorbanpoor
- AvciBio Research Group, Eskisehir Osmangazi University, 26040 Eskisehir, Turkey;
- Department of Biomedical Engineering, Ankara Yildirim Beyazit University, 06010 Ankara, Turkey;
- Department of Biomedical Engineering, Eskisehir Osmangazi University, 26040 Eskisehir, Turkey
| | - Fatma Dogan Guzel
- Department of Biomedical Engineering, Ankara Yildirim Beyazit University, 06010 Ankara, Turkey;
| | - Ali Akpek
- Department of Bioengineering, Gebze Technical University, 41400 Gebze, Turkey; (A.A.); (G.Y.)
| | - Gözde Yesiltas
- Department of Bioengineering, Gebze Technical University, 41400 Gebze, Turkey; (A.A.); (G.Y.)
| | - Tuba Canak-Ipek
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany;
| | - Meltem Avci-Adali
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany;
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Sandonà M, Di Pietro L, Esposito F, Ventura A, Silini AR, Parolini O, Saccone V. Mesenchymal Stromal Cells and Their Secretome: New Therapeutic Perspectives for Skeletal Muscle Regeneration. Front Bioeng Biotechnol 2021; 9:652970. [PMID: 34095095 PMCID: PMC8172230 DOI: 10.3389/fbioe.2021.652970] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/01/2021] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are multipotent cells found in different tissues: bone marrow, peripheral blood, adipose tissues, skeletal muscle, perinatal tissues, and dental pulp. MSCs are able to self-renew and to differentiate into multiple lineages, and they have been extensively used for cell therapy mostly owing to their anti-fibrotic and immunoregulatory properties that have been suggested to be at the basis for their regenerative capability. MSCs exert their effects by releasing a variety of biologically active molecules such as growth factors, chemokines, and cytokines, either as soluble proteins or enclosed in extracellular vesicles (EVs). Analyses of MSC-derived secretome and in particular studies on EVs are attracting great attention from a medical point of view due to their ability to mimic all the therapeutic effects produced by the MSCs (i.e., endogenous tissue repair and regulation of the immune system). MSC-EVs could be advantageous compared with the parental cells because of their specific cargo containing mRNAs, miRNAs, and proteins that can be biologically transferred to recipient cells. MSC-EV storage, transfer, and production are easier; and their administration is also safer than MSC therapy. The skeletal muscle is a very adaptive tissue, but its regenerative potential is altered during acute and chronic conditions. Recent works demonstrate that both MSCs and their secretome are able to help myofiber regeneration enhancing myogenesis and, interestingly, can be manipulated as a novel strategy for therapeutic interventions in muscular diseases like muscular dystrophies or atrophy. In particular, MSC-EVs represent promising candidates for cell free-based muscle regeneration. In this review, we aim to give a complete picture of the therapeutic properties and advantages of MSCs and their products (MSC-derived EVs and secreted factors) relevant for skeletal muscle regeneration in main muscular diseases.
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Affiliation(s)
- Martina Sandonà
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Rome, Italy
| | - Lorena Di Pietro
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Federica Esposito
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Rome, Italy
| | - Alessia Ventura
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Rome, Italy
| | - Antonietta Rosa Silini
- Centro di Ricerca "E. Menni", Fondazione Poliambulanza - Istituto Ospedaliero, Brescia, Italy
| | - Ornella Parolini
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy.,Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, Italy
| | - Valentina Saccone
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Santa Lucia, Rome, Italy.,Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
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Bone Marrow-Mesenchymal Stromal Cell Secretome as Conditioned Medium Relieves Experimental Skeletal Muscle Damage Induced by Ex Vivo Eccentric Contraction. Int J Mol Sci 2021; 22:ijms22073645. [PMID: 33807453 PMCID: PMC8036477 DOI: 10.3390/ijms22073645] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 02/07/2023] Open
Abstract
Bone marrow-mesenchymal stem/stromal cells (MSCs) may offer promise for skeletal muscle repair/regeneration. Growing evidence suggests that the mechanisms underpinning the beneficial effects of such cells in muscle tissue reside in their ability to secrete bioactive molecules (secretome) with multiple actions. Hence, we examined the effects of MSC secretome as conditioned medium (MSC-CM) on ex vivo murine extensor digitorum longus muscle injured by forced eccentric contraction (EC). By combining morphological (light and confocal laser scanning microscopies) and electrophysiological analyses we demonstrated the capability of MSC-CM to attenuate EC-induced tissue structural damages and sarcolemnic functional properties’ modifications. MSC-CM was effective in protecting myofibers from apoptosis, as suggested by a reduced expression of pro-apoptotic markers, cytochrome c and activated caspase-3, along with an increase in the expression of pro-survival AKT factor. Notably, MSC-CM also reduced the EC-induced tissue redistribution and extension of telocytes/CD34+ stromal cells, distinctive cells proposed to play a “nursing” role for the muscle resident myogenic satellite cells (SCs), regarded as the main players of regeneration. Moreover, it affected SC functionality likely contributing to replenishment of the SC reservoir. This study provides the necessary groundwork for further investigation of the effects of MSC secretome in the setting of skeletal muscle injury and regenerative medicine.
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11
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Luo Z, Lin J, Sun Y, Wang C, Chen J. Bone Marrow Stromal Cell-Derived Exosomes Promote Muscle Healing Following Contusion Through Macrophage Polarization. Stem Cells Dev 2021; 30:135-148. [PMID: 33323007 DOI: 10.1089/scd.2020.0167] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Skeletal muscle contusion is among the most common injuries in traumatology and clinics of sports medicine. The injured muscle is vulnerable to re-injury owing to fibrosis formation. Given that the bone marrow stromal cell-derived exosomes (BMSC-Exos) displayed promising therapeutic effect for various tissues, we used BMSC-Exos to treat skeletal muscle contusion and investigated its effects on muscle healing. In this study, the in vivo model of skeletal muscle contusion was established by subjecting the tibialis anterior of young male mice to hit injury, and the in vitro inflammation model was established by lipopolysaccharide treatment on macrophages. Macrophage depletion model was built by intraperitoneal injection with clodronate-containing liposomes. Exosomes were isolated and purified from the supernatant of BMSCs using gradient centrifugation. Nanoparticle tracking analysis, transmission electron microscope, and western blot were used to identify the exosomes. HE stain, Masson stain, immunofluorescence, and biomechanical testing were carried out on the muscle tissue. In addition, enzyme-linked immunosorbent assay (ELISA) assays, real-time qPCR, flow cytometry, and PKH67 fluorescence trace were conducted in vitro. Intramuscular injection of BMSC-Exos to mice after muscle contusion alleviated inflammation level, reduced fibrosis size, promoted muscle regeneration, and improved biomechanical property. After macrophages depletion, the effects of BMSC-Exos were inhibited. In vitro, PKH-67 fluorescence was internalized into macrophages. BMSC-Exos promoted M2 macrophages polarization both in vivo and in vitro. At the same time, BMSC-Exos reduced the production of inflammatory cytokines under the inflammatory microenvironment and upregulated anti-inflammatory factors expression. In conclusion, BMSC-Exos attenuated muscle contusion injury and promoted muscle healing in mice by modifying the polarization status of macrophages and suppressing the inflammatory reaction.
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Affiliation(s)
- Zhiwen Luo
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Jinrong Lin
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Yaying Sun
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Chenghui Wang
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiwu Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
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Moussa MH, Hamam GG, Abd Elaziz AE, Rahoma MA, Abd El Samad AA, El-Waseef DAA, Hegazy MA. Comparative Study on Bone Marrow-Versus Adipose-Derived Stem Cells on Regeneration and Re-Innervation of Skeletal Muscle Injury in Wistar Rats. Tissue Eng Regen Med 2020; 17:887-900. [PMID: 33030680 DOI: 10.1007/s13770-020-00288-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/18/2020] [Accepted: 07/21/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Skeletal muscle injuries are frequent clinical challenges due to associated fibrosis and disability. Regenerative medicine is an emerging promising strategy for such cases. The aim of this study was to compare between the effects of bone marrow-mesenchymal stem cells (BM-MSCs) versus adipose tissue stromal cells (ADSCs) on regeneration and re-innervation of skeletal muscle laceration injury in Wistar rats at different time intervals. METHODS Six young male rats were used as a source of allogenic MSCs. Eighty-four adult female rats were divided into: Group I (control), Group II (Untreated Laceration): right gluteal muscle was lacerated and left for spontaneous healing, Group III (BM-MSCs): right gluteal muscle was lacerated with concomitant local intramuscular injection of 1 × 106 BM-MSCs in the lacerated muscle, Group IV (ADSCs): right gluteal muscle was lacerated with concomitant local intramuscular injection of 1 × 106 ADSCs in lacerated muscle. Rats were sacrificed after one, two and eight weeks. Muscles were processed to prepare sections stained with H&E, Mallory's trichrome and immune-histochemical staining (neurofilament light chain). RESULTS A significant increase in collagen fibers and failure of re-innervation were noticed in untreated laceration group. BM-MSCs-treated groups showed regeneration of muscle fibers but with increased collagen fibers. Meanwhile, ADSCs showed better regenerative effects evidenced by significant increase in the number of myotubes and significant decrease in collagen deposition. Re-innervation was noticed in MSCs-injected muscles after 8 weeks of laceration. CONCLUSION Both BM-MSCs and ADSCs improved regeneration of skeletal muscle laceration injury at short- and long-term durations. However, fibrosis was less in ADSCs-treated rats. Effective re-innervation of injured muscles occurred only at the long-term duration.
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Affiliation(s)
- Manal H Moussa
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, El-Khalyfa El-Mamoun Street Abbasya, Cairo, Egypt
| | - Ghada G Hamam
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, El-Khalyfa El-Mamoun Street Abbasya, Cairo, Egypt.
| | - Asmaa E Abd Elaziz
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, El-Khalyfa El-Mamoun Street Abbasya, Cairo, Egypt
| | - Marwa A Rahoma
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, El-Khalyfa El-Mamoun Street Abbasya, Cairo, Egypt
| | - Abeer A Abd El Samad
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, El-Khalyfa El-Mamoun Street Abbasya, Cairo, Egypt
| | - Dalia A A El-Waseef
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, El-Khalyfa El-Mamoun Street Abbasya, Cairo, Egypt
| | - Mohamed A Hegazy
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, El-Khalyfa El-Mamoun Street Abbasya, Cairo, Egypt
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13
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Sheveleva ON, Payushina OV, Butorina NN, Domaratskaya EI. The Myogenic Potential of Mesenchymal Stromal Cells and Their Effect on Skeletal Muscle Regeneration. BIOL BULL+ 2020. [DOI: 10.1134/s106235902005009x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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14
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Chiu CH, Chang TH, Chang SS, Chang GJ, Chen ACY, Cheng CY, Chen SC, Fu JF, Wen CJ, Chan YS. Application of Bone Marrow-Derived Mesenchymal Stem Cells for Muscle Healing After Contusion Injury in Mice. Am J Sports Med 2020; 48:1226-1235. [PMID: 32134689 DOI: 10.1177/0363546520905853] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Skeletal muscle injuries are very common in sports medicine. Conventional therapies have limited clinical efficacy. New treatment methods should be developed to allow athletes to return to play with better function. PURPOSE To evaluate the in vitro differentiation potential of bone marrow-derived mesenchymal stem cells and the in vivo histologic and physiologic effects of mesenchymal stem cell therapy on muscle healing after contusion injury. STUDY DESIGN Controlled laboratory study. METHODS Bone marrow cells were flushed from both femurs of 5-week-old C57BL/6 mice to establish immortalized mesenchymal stem cell lines. A total of 36 mice aged 8 to 10 weeks were used to develop a muscle contusion model and were divided into 6 groups (6 mice/group) on the basis of the different dosages of IM2 cells to be injected (0, 1.25 × 105, and 2.5 × 105 cells with/without F-127 in 100 μL of phosphate-buffered saline). Histological analysis of muscle regeneration was performed, and the fast-twitch and tetanus strength of the muscle contractions was measured 28 days after muscle contusion injury, after injections of different doses of mesenchymal stem cells with or without the F-127 scaffold beginning 14 days after contusion injury. RESULTS The mesenchymal stem cell-treated muscles exhibited numerous regenerating myofibers. All the groups treated with mesenchymal stem cells (1.25 × 105 cells, 2.5 × 105 cells, 1.25 × 105 cells plus F-127, and 2.5 × 105 cells plus F-127) exhibited a significantly higher number of regenerating myofibers (mean ± SD: 111.6 ± 14.77, 133.4 ± 21.44, 221.89 ± 32.65, and 241.5 ± 25.95, respectively) as compared with the control group and the control with F-127 (69 ± 18.79 and 63.2 ± 18.98). The physiologic evaluation of fast-twitch and tetanus strength did not reveal differences between the age-matched uninjured group and the groups treated with various doses of mesenchymal stem cells 28 days after contusion. Significant differences were found between the control group and the groups treated with various doses of mesenchymal stem cells after muscle contusion. CONCLUSION Mesenchymal stem cell therapy increased the number of regenerating myofibers and improved fast-twitch and tetanus muscle strength in a mouse model of muscle contusion. However, the rapid decay of transplanted mesenchymal stem cells suggests a paracrine effect of this action. Treatment with mesenchymal stem cells at various doses combined with the F-127 scaffold is a potential therapy for a muscle contusion. CLINICAL RELEVANCE Mesenchymal stem cell therapy has an effect on sports medicine because of its effects on myofiber regeneration and muscle strength after contusion injury.
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Affiliation(s)
- Chih-Hao Chiu
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Taoyuan
- Bone and Joint Research Center, Chang Gung Memorial Hospital, Linkou
| | - Tsan-Hsuan Chang
- Department of General Medicine, Tri-service General Hospital, Taipei
| | - Shih-Sheng Chang
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Taoyuan
- Bone and Joint Research Center, Chang Gung Memorial Hospital, Linkou
| | - Gwo-Jyh Chang
- Graduate Institute of Clinical and Medicinal Sciences, College of Medicine, Chang Gung University, Taoyuan
| | - Alvin Chao-Yu Chen
- Bone and Joint Research Center, Chang Gung Memorial Hospital, Linkou
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Linkou
| | - Chun-Ying Cheng
- Bone and Joint Research Center, Chang Gung Memorial Hospital, Linkou
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Linkou
| | - Su-Ching Chen
- Bone and Joint Research Center, Chang Gung Memorial Hospital, Linkou
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Linkou
| | - Jen-Fen Fu
- Department of Medical Research, Chang Gung Memorial Hospital, Linkou
- Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan
| | - Chih-Jen Wen
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Linkou
- College of Medicine, Chang Gung University, Taoyuan
| | - Yi-Sheng Chan
- Bone and Joint Research Center, Chang Gung Memorial Hospital, Linkou
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Linkou
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15
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Barisic D, Erb M, Follo M, Al-Mudaris D, Rolauffs B, Hart ML. Lack of a skeletal muscle phenotype in adult human bone marrow stromal cells following xenogeneic-free expansion. Stem Cell Res Ther 2020; 11:79. [PMID: 32087752 PMCID: PMC7036219 DOI: 10.1186/s13287-020-1587-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 01/22/2020] [Accepted: 02/05/2020] [Indexed: 02/07/2023] Open
Abstract
Background Many studies have elegantly shown that murine and rat bone marrow-derived mesenchymal stromal cells (bmMSCs) contribute to muscle regeneration and improve muscle function. Yet, the ability of transplanted human bmMSCs to manifest myogenic potential shows conflicting results. While human adipose- and umbilical cord-derived MSCs can be differentiated into a skeletal muscle phenotype using horse serum (HS), bmMSCs have only been shown to differentiate towards the skeletal muscle lineage using a complex mixture of cytokines followed by transfection with notch intracellular domain. Methods Since xenogeneic-free growth supplements are increasingly being used in the expansion of bmMSCs in clinical trials, we investigated the effects of human plasma and platelet lysate (P/PL) on the expression of neuromuscular markers and whether P/PL-expanded human bmMSCs could be differentiated towards a skeletal myogenic phenotype. Neuromuscular markers were measured using the highly sensitive droplet digital polymerase chain reaction for measuring the expression of Myf5, MyoD, MyoG, ACTA1, Desmin, GAP-43, and Coronin 1b transcripts, by performing immunofluorescence for the expression of Desmin, GAP-43, and MEF2, and flow cytometry for the expression of CD56/neural cell adhesion molecule (NCAM). Results Despite that bmMSCs expressed the myogenic regulatory factor (MRF) MEF2 after expansion in P/PL, bmMSCs cultured under such conditions did not express other essential MRFs including Myf5, MyoD, MyoG, or ACTA1 needed for myogenesis. Moreover, HS did not induce myogenesis of bmMSCs and hence did not induce the expression of any of these myogenic markers. P/PL, however, did lead to a significant increase in neurogenic GAP-43, as well as Desmin expression, and resulted in a high baseline expression of the neurogenic gene Coronin 1b which was sustained under further P/PL or HS culture conditions. Fetal bovine serum resulted in equally high levels of GAP-43 and Coronin 1b. Moreover, the proportion of CD56/NCAM-positive bmMSCs cultured in P/PL was 5.9 ± 2.1. Conclusions These data suggest that P/PL may prime a small portion of bmMSCs towards an early neural precursor cell type. Collectively, this shows that P/PL partially primes the cells towards a neurogenic phenotype, but does not prime adult human bmMSCs towards the skeletal muscle lineage.
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Affiliation(s)
- Dominik Barisic
- G.E.R.N. Center for Tissue Replacement, Regeneration and Neogenesis, Department of Orthopaedics and Trauma Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Marita Erb
- G.E.R.N. Center for Tissue Replacement, Regeneration and Neogenesis, Department of Orthopaedics and Trauma Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Marie Follo
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dahlia Al-Mudaris
- G.E.R.N. Center for Tissue Replacement, Regeneration and Neogenesis, Department of Orthopaedics and Trauma Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bernd Rolauffs
- G.E.R.N. Center for Tissue Replacement, Regeneration and Neogenesis, Department of Orthopaedics and Trauma Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Melanie L Hart
- G.E.R.N. Center for Tissue Replacement, Regeneration and Neogenesis, Department of Orthopaedics and Trauma Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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16
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Lin Y, Nan J, Shen J, Lv X, Chen X, Lu X, Zhang C, Xiang P, Wang Z, Li Z. Canagliflozin impairs blood reperfusion of ischaemic lower limb partially by inhibiting the retention and paracrine function of bone marrow derived mesenchymal stem cells. EBioMedicine 2020; 52:102637. [PMID: 31981975 PMCID: PMC6992997 DOI: 10.1016/j.ebiom.2020.102637] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 12/16/2019] [Accepted: 01/08/2020] [Indexed: 12/13/2022] Open
Abstract
Background Canagliflozin (CANA) administration increases the risk of lower limb amputation in the clinic. The present study aimed to investigate whether and how CANA interferes with the intracellular physiological processes of bone marrow derived mesenchymal stem cells (BM-MSCs) and its contribution to ischaemic lower limb. Methods The in vivo blood flow recovery in ischaemic lower limbs following CANA treatment was evaluated. The cellular function of BM-MSCs after CANA treatment were also assessed in vitro. In silico docking analysis and mutant substitution assay were conducted to confirm the interaction of CANA with glutamate dehydrogenase 1 (GDH1). Findings Following CANA treatment, attenuated angiogenesis and hampered blood flow recovery in the ischaemic region were detected in diabetic and non-diabetic mice, and inhibition of the proliferation and migration of BM-MSCs were also observed. CANA was involved in mitochondrial respiratory malfunction in BM-MSCs and the inhibition of ATP production, cytochrome c release and vessel endothelial growth factor A (VEGFA) secretion, which may contribute to reductions in the tissue repair capacity of BM-MSCs. The detrimental effects of CANA on MSCs result from the inhibition of GDH1 by CANA (evidenced by in silico docking analysis and H199A-GDH1/N392A-GDH1 mutant substitution). Interpretation Our work highlights that the inhibition of GDH1 activity by CANA interferes with the metabolic activity of the mitochondria, and this interference deteriorates the retention of and VEGFA secretion by MSCs. Funding National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province and Wenzhou Science and Technology Bureau Foundation.
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Affiliation(s)
- Yinuo Lin
- Wenzhou Municipal Key Cardiovascular Research Laboratory, Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Jinliang Nan
- Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Jian Shen
- Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Xinhuang Lv
- Research Institute of Experimental Neurobiology, Department of Neurology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Xiao Chen
- Wenzhou Municipal Key Cardiovascular Research Laboratory, Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Xingmei Lu
- Department of Pathology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Chi Zhang
- Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Pingping Xiang
- Provincial Key Cardiovascular Research Laboratory, Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Zhiting Wang
- Wenzhou Municipal Key Cardiovascular Research Laboratory, Department of Cardiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
| | - Zhengzheng Li
- Research Institute of Experimental Neurobiology, Department of Neurology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
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Hernández-Álvarez D, Mena-Montes B, Toledo-Pérez R, Pedraza-Vázquez G, López-Cervantes SP, Morales-Salazar A, Hernández-Cruz E, Lazzarini-Lechuga R, Vázquez-Cárdenas RR, Vilchis-DeLaRosa S, Posadas-Rodríguez P, Santín-Márquez R, Rosas-Carrasco O, Ibañez-Contreras A, Alarcón-Aguilar A, López-Díazguerrero NE, Luna-López A, Königsberg M. Long-Term Moderate Exercise Combined with Metformin Treatment Induces an Hormetic Response That Prevents Strength and Muscle Mass Loss in Old Female Wistar Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:3428543. [PMID: 31814870 PMCID: PMC6877950 DOI: 10.1155/2019/3428543] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 09/18/2019] [Indexed: 12/18/2022]
Abstract
Sarcopenia is a syndrome characterized by a progressive and generalized skeletal muscle mass and strength loss, as well as a poor physical performance, which as strongly been associated with aging. Sedentary lifestyle in the elderly contributes to this condition; however, physical activity improves health, reducing morbidity and mortality. Recent studies have shown that metformin (MTF) can also prevent muscle damage promoting muscular performance. To date, there is great controversy if MTF treatment combined with exercise training improves or nullifies the benefits provided by physical activity. This study is aimed at evaluating the effect of long-term moderate exercise combined with MTF treatment on body composition, strength, redox state, and survival rate during the life of female Wistar rats. In this study, rats performed moderate exercise during 20 of their 24 months of life and were treated with MTF for one year or for 6 months, i.e., from 12 to 24 months old and 18 to 24 months old. The body composition (percentage of fat, bone, and lean mass) was determined using a dual-energy X-ray absorption scanner (DXA), and grip strength was determined using a dynamometer. Likewise, medial and tibial nerve somatosensory evoked potentials were evaluated and the redox state was measured by HPLC, calculating the GSH/GSSG ratio in the gastrocnemius muscle. Our results suggest- that the MTF administration, both in the sedentary and the exercise groups, might activate a mechanism that is directly related to the induction of the hormetic response through the redox state modulation. MTF treatment does not eliminate the beneficial effects of exercise throughout life, and although MTF does not increase muscle mass, it increases longevity.
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Affiliation(s)
- David Hernández-Álvarez
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
- Posgrado en Ciencias Biológicas, Universidad Autónoma Metropolitana, Ciudad de México 09340, Mexico
| | - Beatriz Mena-Montes
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
- Instituto Nacional de Geriatría, SSA, Ciudad de México 10200, Mexico
- Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | - Rafael Toledo-Pérez
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
- Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | - Gibrán Pedraza-Vázquez
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
- Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | - Stefanie Paola López-Cervantes
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
- Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | - Alfredo Morales-Salazar
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | - Edith Hernández-Cruz
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | - Roberto Lazzarini-Lechuga
- Departamento de Biología de la Reproducción, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | - Roman Royer Vázquez-Cárdenas
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | - Silvia Vilchis-DeLaRosa
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | - Pedro Posadas-Rodríguez
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
- Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | - Roberto Santín-Márquez
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
- Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | | | | | - Adriana Alarcón-Aguilar
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | | | | | - Mina Königsberg
- Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
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Grabowska I, Zimowska M, Maciejewska K, Jablonska Z, Bazga A, Ozieblo M, Streminska W, Bem J, Brzoska E, Ciemerych MA. Adipose Tissue-Derived Stromal Cells in Matrigel Impacts the Regeneration of Severely Damaged Skeletal Muscles. Int J Mol Sci 2019; 20:E3313. [PMID: 31284492 PMCID: PMC6651806 DOI: 10.3390/ijms20133313] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/28/2019] [Accepted: 07/01/2019] [Indexed: 02/07/2023] Open
Abstract
In case of large injuries of skeletal muscles the pool of endogenous stem cells, i.e., satellite cells, might be not sufficient to secure proper regeneration. Such failure in reconstruction is often associated with loss of muscle mass and excessive formation of connective tissue. Therapies aiming to improve skeletal muscle regeneration and prevent fibrosis may rely on the transplantation of different types of stem cell. Among such cells are adipose tissue-derived stromal cells (ADSCs) which are relatively easy to isolate, culture, and manipulate. Our study aimed to verify applicability of ADSCs in the therapies of severely injured skeletal muscles. We tested whether 3D structures obtained from Matrigel populated with ADSCs and transplanted to regenerating mouse gastrocnemius muscles could improve the regeneration. In addition, ADSCs used in this study were pretreated with myoblasts-conditioned medium or anti-TGFβ antibody, i.e., the factors modifying their ability to proliferate, migrate, or differentiate. Analyses performed one week after injury allowed us to show the impact of 3D cultured control and pretreated ADSCs at muscle mass and structure, as well as fibrosis development immune response of the injured muscle.
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Affiliation(s)
- Iwona Grabowska
- Department of Cytology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland
| | - Malgorzata Zimowska
- Department of Cytology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland
| | - Karolina Maciejewska
- Department of Cytology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland
| | - Zuzanna Jablonska
- Department of Cytology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland
| | - Anna Bazga
- Department of Cytology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland
| | - Michal Ozieblo
- Department of Cytology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland
| | - Wladyslawa Streminska
- Department of Cytology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland
| | - Joanna Bem
- Department of Cytology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland
| | - Edyta Brzoska
- Department of Cytology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland
| | - Maria A Ciemerych
- Department of Cytology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland.
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Marcinczyk M, Dunn A, Haas G, Madsen J, Scheidt R, Patel K, Talovic M, Garg K. The Effect of Laminin-111 Hydrogels on Muscle Regeneration in a Murine Model of Injury. Tissue Eng Part A 2019; 25:1001-1012. [PMID: 30426851 PMCID: PMC9839345 DOI: 10.1089/ten.tea.2018.0200] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
IMPACT STATEMENT Extremity injuries make up the most common survivable injuries in vehicular accidents and modern military conflicts. A majority of these injuries involve volumetric muscle loss (VML). The potential for donor site morbidity may limit the clinical use of autologous muscle grafts for VML injuries. Treatments that can improve the regeneration of functional muscle tissue are critically needed to improve limb salvage and reduce the rate of delayed amputations. The development of a laminin-111-enriched fibrin hydrogel will offer a potentially transformative and "off-the-shelf" clinically relevant therapy for functional skeletal muscle regeneration.
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Affiliation(s)
- Madison Marcinczyk
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, St. Louis, Missouri
| | - Andrew Dunn
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, St. Louis, Missouri
| | - Gabriel Haas
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, St. Louis, Missouri
| | - Josh Madsen
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, St. Louis, Missouri
| | - Robert Scheidt
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, St. Louis, Missouri
| | - Krishna Patel
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, St. Louis, Missouri
| | - Muhamed Talovic
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, St. Louis, Missouri
| | - Koyal Garg
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, St. Louis, Missouri.,Address correspondence to: Koyal Garg, PhD, Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, 3507 Lindell Boulevard, St. Louis, MO 63103
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20
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Dunn A, Talovic M, Patel K, Patel A, Marcinczyk M, Garg K. Biomaterial and stem cell-based strategies for skeletal muscle regeneration. J Orthop Res 2019; 37:1246-1262. [PMID: 30604468 DOI: 10.1002/jor.24212] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 12/13/2018] [Indexed: 02/04/2023]
Abstract
Adult skeletal muscle can regenerate effectively after mild physical or chemical insult. Muscle trauma or disease can overwhelm this innate capacity for regeneration and result in heightened inflammation and fibrotic tissue deposition resulting in loss of structure and function. Recent studies have focused on biomaterial and stem cell-based therapies to promote skeletal muscle regeneration following injury and disease. Many stem cell populations besides satellite cells are implicated in muscle regeneration. These stem cells include but are not limited to mesenchymal stem cells, adipose-derived stem cells, hematopoietic stem cells, pericytes, fibroadipogenic progenitors, side population cells, and CD133+ stem cells. However, several challenges associated with their isolation, availability, delivery, survival, engraftment, and differentiation have been reported in recent studies. While acellular scaffolds offer a relatively safe and potentially off-the-shelf solution to cell-based therapies, they are often unable to stimulate host cell migration and activity to a level that would result in clinically meaningful regeneration of traumatized muscle. Combining stem cells and biomaterials may offer a viable therapeutic strategy that may overcome the limitations associated with these therapies when they are used in isolation. In this article, we review the stem cell populations that can stimulate muscle regeneration in vitro and in vivo. We also discuss the regenerative potential of combination therapies that utilize both stem cell and biomaterials for the treatment of skeletal muscle injury and disease. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1246-1262, 2019.
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Affiliation(s)
- Andrew Dunn
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, Saint Louis, Missouri
| | - Muhamed Talovic
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, Saint Louis, Missouri
| | - Krishna Patel
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, Saint Louis, Missouri
| | - Anjali Patel
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, Saint Louis, Missouri
| | - Madison Marcinczyk
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, Saint Louis, Missouri
| | - Koyal Garg
- Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, Saint Louis, Missouri
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Pantelic MN, Larkin LM. Stem Cells for Skeletal Muscle Tissue Engineering. TISSUE ENGINEERING PART B-REVIEWS 2018; 24:373-391. [PMID: 29652595 DOI: 10.1089/ten.teb.2017.0451] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Volumetric muscle loss (VML) is a debilitating condition wherein muscle loss overwhelms the body's normal physiological repair mechanism. VML is particularly common among military service members who have sustained war injuries. Because of the high social and medical cost associated with VML and suboptimal current surgical treatments, there is great interest in developing better VML therapies. Skeletal muscle tissue engineering (SMTE) is a promising alternative to traditional VML surgical treatments that use autogenic tissue grafts, and rather uses isolated stem cells with myogenic potential to generate de novo skeletal muscle tissues to treat VML. Satellite cells are the native precursors to skeletal muscle tissue, and are thus the most commonly studied starting source for SMTE. However, satellite cells are difficult to isolate and purify, and it is presently unknown whether they would be a practical source in clinical SMTE applications. Alternative myogenic stem cells, including adipose-derived stem cells, bone marrow-derived mesenchymal stem cells, perivascular stem cells, umbilical cord mesenchymal stem cells, induced pluripotent stem cells, and embryonic stem cells, each have myogenic potential and have been identified as possible starting sources for SMTE, although they have yet to be studied in detail for this purpose. These alternative stem cell varieties offer unique advantages and disadvantages that are worth exploring further to advance the SMTE field toward highly functional, safe, and practical VML treatments. The following review summarizes the current state of satellite cell-based SMTE, details the properties and practical advantages of alternative myogenic stem cells, and offers guidance to tissue engineers on how alternative myogenic stem cells can be incorporated into SMTE research.
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Affiliation(s)
- Molly N Pantelic
- 1 Department of Molecular and Integrative Physiology, University of Michigan , Ann Arbor, Michigan
| | - Lisa M Larkin
- 1 Department of Molecular and Integrative Physiology, University of Michigan , Ann Arbor, Michigan.,2 Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan
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Rahim S, Rahim F, Shirbandi K, Haghighi BB, Arjmand B. Sports Injuries: Diagnosis, Prevention, Stem Cell Therapy, and Medical Sport Strategy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1084:129-144. [PMID: 30539427 DOI: 10.1007/5584_2018_298] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sports injuries diagnosis, prevention, and treatment are the most important issues of sports medicine. Fortunately, sports injuries are often treated effectively, and people with damage recover and return to the sport in a satisfactory condition. Meanwhile, many sports injuries and complications can be prevented. In general, sports injuries include acute or chronic injuries. Given increasing in popularity, sports medicine doctors use stem cells to treat a wide variety of sports injuries, including damage to tendons, ligaments, muscles, and cartilage. Stem cell therapy to an injured area could be done through direct surgical application, stem-cell-bearing sutures, and injection. Stem cell therapy holds potential for repair and functional plasticity following sports injuries compared to traditional methods; however, the mechanism of stem cell therapy for sports injuries remains largely unknown. Medical imaging technologies provide the hope to ample the knowledge concerning basic stem cell biology in real time when transplanted into sport-induced damaged organs. Using stem cell treatment might restore continuity and regeneration and promote growth back the organ targets. Besides, using a noninvasive medical imaging method would have the long-time monitoring advantage to the stem cells transplanting individual. The multimodality imaging technique allows for studying acute pathological events following sports injuries; therefore, the use of imaging techniques in medicine permits the straight examination of dynamic regenerative events of specific stem cells following a sports injury in people.
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Affiliation(s)
- Sadegh Rahim
- Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Fakher Rahim
- Department of Molecular Medicine, Health research institute, Research Center of Thalassemia & Hemoglobinopathy, Health research institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. .,Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Kiarash Shirbandi
- Allied Health Sciences School, Radiology Department, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.,Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Shehata AS, Al-Ghonemy NM, Ahmed SM, Mohamed SR. Effect of mesenchymal stem cells on induced skeletal muscle chemodenervation atrophy in adult male albino rats. Int J Biochem Cell Biol 2017; 85:135-148. [PMID: 28232107 DOI: 10.1016/j.biocel.2017.01.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Revised: 01/25/2017] [Accepted: 01/29/2017] [Indexed: 12/11/2022]
Abstract
The present research was conducted to evaluate the effect of bone marrow derived mesenchymal stem cells (BM-MSCs) as a potential therapeutic tool for improvement of skeletal muscle recovery after induced chemodenervation atrophy by repeated local injection of botulinum toxin-A in the right tibialis anterior muscle of adult male albino rats. Forty five adult Wistar male albino rats were classified into control and experimental groups. Experimental group was further subdivided into 3 equal subgroups; induced atrophy, BM-MSCs treated and recovery groups. Biochemical analysis of serum LDH, CK and Real-time PCR for Bcl-2, caspase 3 and caspase 9 was measured. Skeletal muscle sections were stained with H and E, Mallory trichrome, and Immunohistochemical reaction for Bax and CD34. Improvement in the skeletal muscle histological structure was noticed in BM-MSCs treated group, however, in the recovery group, some sections showed apparent transverse striations and others still affected. Immunohistochemical reaction of Bax protein showed strong positive immunoreaction in the cytoplasm of muscle fibers in the induced atrophy group. BM-MSCs treated group showed weak positive reaction while the recovery group showed moderate reaction in the cytoplasm of muscle fibers. Immunohistochemical reaction for CD34 revealed occasional positive CD34 stained cells in the induced atrophy group. In BM-MSCs treated group, multiple positive CD34 stained cells were detected. However, recovery group showed some positive CD34 stained cells at the periphery of the muscle fibers. Marked improvement in the regenerative capacity of skeletal muscles after BM-MSCs therapy. Hence, stem cell therapy provides a new hope for patients suffering from myopathies and severe injuries.
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Affiliation(s)
| | | | - Samah M Ahmed
- Faculty of Medicine, Zagazig University, Zagazig, Egypt.
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24
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Deshpande RS, Spector AA. Modeling Stem Cell Myogenic Differentiation. Sci Rep 2017; 7:40639. [PMID: 28106095 PMCID: PMC5247743 DOI: 10.1038/srep40639] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 12/09/2016] [Indexed: 01/04/2023] Open
Abstract
The process of stem cell myogenesis (transformation into skeletal muscle cells) includes several stages characterized by the expression of certain combinations of myogenic factors. The first part of this process is accompanied by cell division, while the second part is mainly associated with direct differentiation. The mechanical cues are known to enhance stem cell myogenesis, and the paper focuses on the stem cell differentiation under the condition of externally applied strain. The process of stem cell myogenic differentiation is interpreted as the interplay among transcription factors, targeted proteins and strain-generated signaling molecule, and it is described by a kinetic multi-stage model. The model parameters are optimally adjusted by using the available data from the experiment with adipose-derived stem cells subjected to the application of cyclic uniaxial strains of the magnitude of 10%. The modeling results predict the kinetics of the process of myogenic differentiation, including the number of cells in each stage of differentiation and the rates of differentiation from one stage to another for different strains from 4% to 16%. The developed model can help better understand the process of myogenic differentiation and the effects of mechanical cues on stem cell use in muscle therapies.
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Affiliation(s)
- Rajiv S Deshpande
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Alexander A Spector
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA
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Passipieri JA, Christ GJ. The Potential of Combination Therapeutics for More Complete Repair of Volumetric Muscle Loss Injuries: The Role of Exogenous Growth Factors and/or Progenitor Cells in Implantable Skeletal Muscle Tissue Engineering Technologies. Cells Tissues Organs 2016; 202:202-213. [PMID: 27825153 DOI: 10.1159/000447323] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2016] [Indexed: 11/19/2022] Open
Abstract
Despite the robust regenerative capacity of skeletal muscle, there are a variety of congenital and acquired conditions in which the volume of skeletal muscle loss results in major permanent functional and cosmetic deficits. These latter injuries are referred to as volumetric muscle loss (VML) injuries or VML-like conditions, and they are characterized by the simultaneous absence of multiple tissue components (i.e., nerves, vessels, muscles, satellite cells, and matrix). There are currently no effective treatment options. Regenerative medicine/tissue engineering technologies hold great potential for repair of these otherwise irrecoverable VML injuries. In this regard, three-dimensional scaffolds have been used to deliver sustained amounts of growth factors into a variety of injury models, to modulate host cell recruitment and extracellular matrix remodeling. However, this is a nascent field of research, and more complete functional improvements require more precise control of the spatiotemporal distribution of critical growth factors over a physiologically relevant range. This is especially true for VML injuries where incorporation of a cellular component into the scaffolds might provide not only a source of new tissue formation but also additional signals for host cell migration, recruitment, and survival. To this end, we review the major features of muscle repair and regeneration for largely recoverable injuries, and then discuss recent cell- and/or growth factor-based approaches to repair the more profound and irreversible VML and VML-like injuries. The underlying supposition is that more rationale incorporation of exogenous growth factors and/or cellular components will be required to optimize the regenerative capacity of implantable therapeutics for VML repair.
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