|
1
|
You N, Liu G, Yu M, Chen W, Fei X, Sun T, Han M, Qin Z, Wei Z, Wang D. Reconceptualizing Endothelial-to-mesenchymal transition in atherosclerosis: Signaling pathways and prospective targeting strategies. J Adv Res 2025:S2090-1232(24)00627-1. [PMID: 39756576 DOI: 10.1016/j.jare.2024.12.049] [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: 09/15/2024] [Revised: 12/27/2024] [Accepted: 12/28/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND The modification of endothelial cells (ECs) biological function under pathogenic conditions leads to the expression of mesenchymal stromal cells (MSCs) markers, defined as endothelial-to-mesenchymal transition (EndMT). Invisible in onset and slow in progression, atherosclerosis (AS) is a potential contributor to various atherosclerotic cardiovascular diseases (ASCVD). By triggering AS, EndMT, the "initiator" of AS, induces the progression of ASCVD such as coronary atherosclerotic heart disease (CHD) and ischemic cerebrovascular disease (ICD), with serious clinical complications such as myocardial infarction (MI) and stroke. In-depth research of the pathomechanisms of EndMT and identification of potential targeted therapeutic strategies hold considerable research value for the prevention and treatment of ASCVD-associated with delayed EndMT. Although previous studies have progressively unraveled the complexity of EndMT and its pathogenicity triggered by alterations in vascular microenvironmental factors, systematic descriptions of the most recent pathogenic roles of EndMT in the progression of AS, targeted therapeutic strategies, and their future research directions are scarce. AIM OF REVIEW We aim to provide new researchers with comprehensive knowledge of EndMT in AS. We exhaustively review the latest research advancements in the field and provide a theoretical basis for investigating EndMT, a biological process with sophisticated mechanisms. KEY SCIENTIFIC CONCEPTS OF REVIEW This review summarized that altered hemodynamics with microenvironmental crosstalk consisting of inflammatory responses or glycolysis, oxidative stress, lactate or acetyl-CoA (Ac-CoA), fatty acid oxidation (FAO), intracellular iron overload, and transcription factors, including ELK1 and STAT3, modulate the EndMT and affect AS progression. In addition, we provide new paradigms for the development of promising therapeutic agents against these disease-causing processes and indicate promising directions and challenges that need to be addressed to elucidate the EndMT process.
Collapse
Affiliation(s)
- Nanlin You
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
| | - Guohao Liu
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Mengchen Yu
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Wenbo Chen
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Xiaoyao Fei
- Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Infection and Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Tao Sun
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Mengtao Han
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Zhen Qin
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Zhaosheng Wei
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Donghai Wang
- Department of Neurosurgery, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, Shandong 253032, China.
| |
Collapse
|
|
2
|
Verma M, Asakura Y, Wang X, Zhou K, Ünverdi M, Kann AP, Krauss RS, Asakura A. Endothelial cell signature in muscle stem cells validated by VEGFA-FLT1-AKT1 axis promoting survival of muscle stem cell. eLife 2024; 13:e73592. [PMID: 38842166 PMCID: PMC11216748 DOI: 10.7554/elife.73592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 06/05/2024] [Indexed: 06/07/2024] Open
Abstract
Endothelial and skeletal muscle lineages arise from common embryonic progenitors. Despite their shared developmental origin, adult endothelial cells (ECs) and muscle stem cells (MuSCs; satellite cells) have been thought to possess distinct gene signatures and signaling pathways. Here, we shift this paradigm by uncovering how adult MuSC behavior is affected by the expression of a subset of EC transcripts. We used several computational analyses including single-cell RNA-seq (scRNA-seq) to show that MuSCs express low levels of canonical EC markers in mice. We demonstrate that MuSC survival is regulated by one such prototypic endothelial signaling pathway (VEGFA-FLT1). Using pharmacological and genetic gain- and loss-of-function studies, we identify the FLT1-AKT1 axis as the key effector underlying VEGFA-mediated regulation of MuSC survival. All together, our data support that the VEGFA-FLT1-AKT1 pathway promotes MuSC survival during muscle regeneration, and highlights how the minor expression of select transcripts is sufficient for affecting cell behavior.
Collapse
Affiliation(s)
- Mayank Verma
- Department of Pediatrics & Neurology, Division of Pediatric Neurology, The University of Texas Southwestern Medical CenterDallasUnited States
- Stem Cell Institute, University of Minnesota Medical SchoolMinneapolisUnited States
- Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical SchoolMinneapolisUnited States
- Department of Neurology, University of Minnesota Medical SchoolMinneapolisUnited States
| | - Yoko Asakura
- Stem Cell Institute, University of Minnesota Medical SchoolMinneapolisUnited States
- Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical SchoolMinneapolisUnited States
- Department of Neurology, University of Minnesota Medical SchoolMinneapolisUnited States
| | - Xuerui Wang
- Stem Cell Institute, University of Minnesota Medical SchoolMinneapolisUnited States
- Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical SchoolMinneapolisUnited States
- Department of Neurology, University of Minnesota Medical SchoolMinneapolisUnited States
| | - Kasey Zhou
- Stem Cell Institute, University of Minnesota Medical SchoolMinneapolisUnited States
- Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical SchoolMinneapolisUnited States
- Department of Neurology, University of Minnesota Medical SchoolMinneapolisUnited States
| | - Mahmut Ünverdi
- Stem Cell Institute, University of Minnesota Medical SchoolMinneapolisUnited States
- Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical SchoolMinneapolisUnited States
- Department of Neurology, University of Minnesota Medical SchoolMinneapolisUnited States
| | - Allison P Kann
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Graduate School of Biomedical Sciencesf, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Robert S Krauss
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Graduate School of Biomedical Sciencesf, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Atsushi Asakura
- Stem Cell Institute, University of Minnesota Medical SchoolMinneapolisUnited States
- Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical SchoolMinneapolisUnited States
- Department of Neurology, University of Minnesota Medical SchoolMinneapolisUnited States
| |
Collapse
|
|
3
|
Dar A, Li A, Petrigliano FA. Lineage tracing reveals a novel PDGFRβ + satellite cell subset that contributes to myo-regeneration of chronically injured rotator cuff muscle. Sci Rep 2024; 14:9668. [PMID: 38671006 PMCID: PMC11053018 DOI: 10.1038/s41598-024-58926-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 04/04/2024] [Indexed: 04/28/2024] Open
Abstract
Massive rotator cuff (RC) tendon tears are associated with progressive fibro-adipogenesis and muscle atrophy that altogether cause shoulder muscle wasting. Platelet derived growth factor β (PDGFRβ) lineage cells, that co-express PDGFRα have previously been shown to directly contribute to scar formation and fat accumulation in a mouse model of irreversible tendon and nerve transection (TTDN). Conversely, PDGFRβ+ lineage cells have also been shown to be myogenic in cultures and in other models of skeletal muscle injury. We therefore hypothesized that PDGFRβ demarcates two distinct RC residing subpopulations, fibro-adipogenic and myogenic, and aimed to elucidate the identity of the PDGFRβ myogenic precursors and evaluate their contribution, if any, to RC myo-regeneration. Lineage tracing revealed increasing contribution of PDGFRβ+ myo-progenitors to the formation of GFP+ myofibers, which were the most abundant myofiber type in regenerated muscle at 2 weeks post-TTDN. Muscle regeneration preceded muscle atrophy and both advanced from the lateral site of tendon transection to the farthest medial region. GFP+/PDGFRβ+Sca-1-lin-CXCR4+Integrin-β1+ marked a novel subset of satellite cells with confirmed myogenic properties. Further studies are warranted to identify the existence of PDGFRβ+ satellite cells in human and other mouse muscles and to define their myo-regenerative potential following acute and chronic muscle injury.
Collapse
Affiliation(s)
- Ayelet Dar
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| | - Angela Li
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Frank A Petrigliano
- Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| |
Collapse
|
|
4
|
Dewi L, Liao YC, Jean WH, Huang KC, Huang CY, Chen LK, Nicholls A, Lai LF, Kuo CH. Cordyceps sinensis accelerates stem cell recruitment to human skeletal muscle after exercise. Food Funct 2024; 15:4010-4020. [PMID: 38501161 DOI: 10.1039/d3fo03770c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2024]
Abstract
Cordyceps sinensis is a parasitic fungus known to induce immune responses. The impact of Cordyceps supplementation on stem cell homing and expansion to human skeletal muscle after exercise remains unexplored. In this study, we examined how pre-exercise Cordyceps supplementation influences cell infiltration, CD34+ cell recruitment, and Pax7+ cell expansion in human skeletal muscle after high-intensity interval exercise (HIIE) on a cycloergometer. A randomized, double-blind, placebo-controlled crossover study was conducted with 14 young adults (age: 24 ± 0.8 years). A placebo (1 g cornstarch) and Cordyceps (1 g Cordyceps sinensis) were administered before exercise (at 120% maximal aerobic power). Multiple biopsies were taken from the vastus lateralis for muscle tissue analysis before and after HIIE. This exercise regimen doubled the VEGF mRNA in the muscle at 3 h post-exercise (P = 0.006). A significant necrotic cell infiltration (+284%, P = 0.05) was observed 3 h after HIIE and resolved within 24 h. This response was substantially attenuated by Cordyceps supplementation. Moreover, we observed increases in CD34+ cells at 24 h post-exercise, notably accelerated by Cordyceps supplementation to 3 h (+51%, P = 0.002). This earlier response contributed to a four-fold expansion in Pax7+ cell count, as demonstrated by immunofluorescence double staining (CD34+/Pax7+) (P = 0.01). In conclusion, our results provide the first human evidence demonstrating the accelerated resolution of exercise-induced muscle damage by Cordyceps supplementation. This effect is associated with earlier stem cell recruitment into the damaged sites for muscle regeneration.
Collapse
Affiliation(s)
- Luthfia Dewi
- Laboratory of Exercise Biochemistry, University of Taipei, Tianmu Campus, Taipei, Taiwan.
- Department of Nutrition, Universitas Muhammadiyah Semarang, Semarang, Indonesia
| | - Yu-Chieh Liao
- Laboratory of Exercise Biochemistry, University of Taipei, Tianmu Campus, Taipei, Taiwan.
| | - Wei-Horng Jean
- Department of Anaesthesiology, Far East Memorial Hospital, No. 21, Sec. 2, Nanya S. Rd, Banciao Dist., New Taipei, Taiwan
| | - Kuo-Chin Huang
- Department of Family Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Liang-Kung Chen
- Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, Taipei, Taiwan
- Taipei Municipal Gan-Dau Hospital (Managed by Taipei Veterans General Hospital), Taipei, Taiwan
| | - Andrew Nicholls
- Laboratory of Exercise Biochemistry, University of Taipei, Tianmu Campus, Taipei, Taiwan.
| | - Li-Fan Lai
- Laboratory of Exercise Biochemistry, University of Taipei, Tianmu Campus, Taipei, Taiwan.
| | - Chia-Hua Kuo
- Laboratory of Exercise Biochemistry, University of Taipei, Tianmu Campus, Taipei, Taiwan.
- School of Physical Education and Sports Science, Soochow University, Suzhou, China
- Department of Kinesiology and Health, College of William and Mary, Williamsburg VA, USA
| |
Collapse
|
|
5
|
Ripamonti U, Duarte R. Mechanistic insights into the spontaneous induction of bone formation. BIOMATERIALS ADVANCES 2024; 158:213795. [PMID: 38335762 DOI: 10.1016/j.bioadv.2024.213795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 12/19/2023] [Accepted: 02/01/2024] [Indexed: 02/12/2024]
Abstract
The grand discovery of morphogens, or "form-generating substances", revealed that tissue morphogenesis is initiated by soluble molecular signals or morphogens primarily belonging to the transforming growth factor-β (TGF-β) supergene family. The regenerative potential of bone rests on its extracellular matrix, which is the repository of several morphogens that tightly control cellular differentiating pathways, cellular matrix deposition and remodeling. Alluringly, the matrix also contains specific factors transferred from the heterotopic implanted bone matrices initiating "Tissue Induction", as provocatively described in Nature in 1945. Later, it was found that selected genes and gene products of the TGF-β supergene family singly, synchronously, and synergistically mastermind the induction of bone formation. This review describes the phenomenon of the spontaneous and/or intrinsic osteoinductivity of calcium phosphate-based biomaterials and titanium' constructs without the applications of soluble osteogenetic molecular signals. The review shows the spontaneous induction of bone formation initiated by Ca++ activating stem cell differentiation and up-regulation of bone morphogenetic proteins genes. Expressed gene products are embedded into the concavities of the calcium phosphate-based substrata, initiating bone formation as a secondary response. Pure titanium's substrata do not initiate the spontaneous induction of bone formation. The induction of bone is solely dependent on acid, alkali and heat treatments to form apatite layers on the treated titanium surfaces. The induction of bone formation is achieved exclusively by apatite-based biomaterial surfaces. The hydroxyapatite, in its various forms and geometric configurations, finely tunes the induction of bone formation in heterotopic sites. Cellular differentiation by fine-tuning of the cellular molecular machinery is initiated by specific geometric modularity of the hydroxyapatite substrata that push cellular buttons that start the ripple-like cascade of "Tissue Induction", generating newly formed ossicles with bone marrow in heterotopic extraskeletal sites. The highlighted mechanistic insights into the spontaneous induction of bone formation are a research platform invocating selected molecular elements to construct the induction of bone formation.
Collapse
Affiliation(s)
- Ugo Ripamonti
- Bone Research Laboratory, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
| | - Raquel Duarte
- Bone Research Laboratory, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Internal Medicine Research Laboratory, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| |
Collapse
|
|
6
|
Bouche Djatche WH, Zhu H, Ma W, Li Y, Li Z, Zhao H, Liu Z, Qiao H. Potential of mesenchymal stem cell-derived conditioned medium/secretome as a therapeutic option for ocular diseases. Regen Med 2023; 18:795-807. [PMID: 37702008 DOI: 10.2217/rme-2023-0089] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2023] Open
Abstract
Research has shown that the therapeutic effect of mesenchymal stem cells (MSCs) is partially due to its secreted factors as opposed to the implantation of the cells into the treated tissue or tissue replacement. MSC secretome, especially in the form of conditioned medium (MSC-CM) is now being explored as an alternative to MSCs transplantation. Despite the observed benefits of MSC-CM, only a few clinical trials have evaluated it and other secretome components in the treatment of eye diseases. This review provides insight into the potential therapeutic use of MSC-CM in eye conditions, such as corneal diseases, dry eye, glaucoma, retinal diseases and uveitis. We discuss the current evidence, some limitations, and the progress that remains to be achieved before clinical translation becomes possible.
Collapse
Affiliation(s)
| | - Huimin Zhu
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
| | - Wenlei Ma
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
| | - Yue Li
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
| | - Ziang Li
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
| | - Hong Zhao
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
| | - Zhizhen Liu
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
| | - Hua Qiao
- School of Basic Medicine, Shanxi Medical University, Taiyuan, 030001, China
| |
Collapse
|
|
7
|
Rodrigues CR, Moga S, Singh B, Aulakh GK. CD34 Protein: Its expression and function in inflammation. Cell Tissue Res 2023; 393:443-454. [PMID: 37450038 DOI: 10.1007/s00441-023-03811-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 07/06/2023] [Indexed: 07/18/2023]
Abstract
CD34 has spear-headed the field of basic research and clinical transplantation since the first reports of its expression on hematopoietic stem cells (HSCs). Expressed in mice, humans, rats and other species, CD34 has been used for more than 40 years as a hematopoietic stem and progenitor cell marker. It was later found that muscle satellite cells and epidermal precursors can also be identified with the aid of CD34. Despite the usefulness of CD34 as a marker of HSCs, its overall purpose in animal physiology has remained unclear. This review recaptures CD34 structure, evolutionary conservation, proposed functions, and role in lung inflammation, to describe current research findings and to provide guidance for future studies on CD34.
Collapse
Affiliation(s)
- Carolina Rego Rodrigues
- Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, SK, S7N5B4, Canada
| | - Sahib Moga
- Faculty of Science, The University of Ottawa, 75 Laurier Ave. E, Ottawa, ON, K1N 6N5, Canada
| | - Baljit Singh
- Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, SK, S7N5B4, Canada
| | - Gurpreet Kaur Aulakh
- Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, SK, S7N5B4, Canada.
| |
Collapse
|
|
8
|
Johnson AL, Kamal M, Parise G. The Role of Supporting Cell Populations in Satellite Cell Mediated Muscle Repair. Cells 2023; 12:1968. [PMID: 37566047 PMCID: PMC10417507 DOI: 10.3390/cells12151968] [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: 06/29/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/12/2023] Open
Abstract
Skeletal muscle has a high capacity to repair and remodel in response to damage, largely through the action of resident muscle stem cells, termed satellite cells. Satellite cells are required for the proper repair of skeletal muscle through a process known as myogenesis. Recent investigations have observed relationships between satellite cells and other cell types and structures within the muscle microenvironment. These findings suggest that the crosstalk between inflammatory cells, fibrogenic cells, bone-marrow-derived cells, satellite cells, and the vasculature is essential for the restoration of muscle homeostasis. This review will discuss the influence of the cells and structures within the muscle microenvironment on satellite cell function and muscle repair.
Collapse
Affiliation(s)
| | | | - Gianni Parise
- Department of Kinesiology, McMaster University, Hamilton, ON L8S 4L8, Canada
| |
Collapse
|
|
9
|
Radu P, Zurzu M, Paic V, Bratucu M, Garofil D, Tigora A, Georgescu V, Prunoiu V, Pasnicu C, Popa F, Surlin P, Surlin V, Strambu V. CD34-Structure, Functions and Relationship with Cancer Stem Cells. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59050938. [PMID: 37241170 DOI: 10.3390/medicina59050938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 05/08/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023]
Abstract
The CD34 protein was identified almost four decades ago as a biomarker for hematopoietic stem cell progenitors. CD34 expression of these stem cells has been exploited for therapeutic purposes in various hematological disorders. In the last few decades, studies have revealed the presence of CD34 expression on other types of cells with non-hematopoietic origins, such as interstitial cells, endothelial cells, fibrocytes, and muscle satellite cells. Furthermore, CD34 expression may also be found on a variety of cancer stem cells. Nowadays, the molecular functions of this protein have been involved in a variety of cellular functions, such as enhancing proliferation and blocking cell differentiation, enhanced lymphocyte adhesion, and cell morphogenesis. Although a complete understanding of this transmembrane protein, including its developmental origins, its stem cell connections, and other functions, is yet to be achieved. In this paper, we aimed to carry out a systematic analysis of the structure, functions, and relationship with cancer stem cells of CD34 based on the literature overview.
Collapse
Affiliation(s)
- Petru Radu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
- Tenth Department of Surgery, University of Medicine and Pharmacy "Carol Davila" Bucharest, 050474 Bucharest, Romania
| | - Mihai Zurzu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
- Tenth Department of Surgery, University of Medicine and Pharmacy "Carol Davila" Bucharest, 050474 Bucharest, Romania
| | - Vlad Paic
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
- Tenth Department of Surgery, University of Medicine and Pharmacy "Carol Davila" Bucharest, 050474 Bucharest, Romania
| | - Mircea Bratucu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
- Tenth Department of Surgery, University of Medicine and Pharmacy "Carol Davila" Bucharest, 050474 Bucharest, Romania
| | - Dragos Garofil
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
- Tenth Department of Surgery, University of Medicine and Pharmacy "Carol Davila" Bucharest, 050474 Bucharest, Romania
| | - Anca Tigora
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Valentin Georgescu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
| | - Virgiliu Prunoiu
- Tenth Department of Surgery, University of Medicine and Pharmacy "Carol Davila" Bucharest, 050474 Bucharest, Romania
- Oncological Institute "Prof. Dr. Alexandru Trestioreanu", 022328 Bucharest, Romania
| | - Costin Pasnicu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
- Tenth Department of Surgery, University of Medicine and Pharmacy "Carol Davila" Bucharest, 050474 Bucharest, Romania
| | - Florian Popa
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
- Tenth Department of Surgery, University of Medicine and Pharmacy "Carol Davila" Bucharest, 050474 Bucharest, Romania
| | - Petra Surlin
- Department of Periodontology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Valeriu Surlin
- Sixth Department of Surgery, University of Medicine and Pharmacy of Craiova, Craiova Emergency Clinical 7 Hospital, 200642 Craiova, Romania
| | - Victor Strambu
- General Surgery Department, Carol Davila Nephrology Hospital Bucharest, 020021 Bucharest, Romania
- Tenth Department of Surgery, University of Medicine and Pharmacy "Carol Davila" Bucharest, 050474 Bucharest, Romania
| |
Collapse
|
|
10
|
Shao X, Lin X, Zhu S, Zhou H, Lu Z, Zhang Y, Wang J. Human Muscle-Derived Cells Are Capable of Tenogenic Differentiation and Contribution to Tendon Repair. Am J Sports Med 2023; 51:786-797. [PMID: 36734484 DOI: 10.1177/03635465221147486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND It has been reported that the harvested hamstring tendon for autograft could be regenerated with well-oriented fibers and uniformly distributed spindle-shaped cells after removal. However, which cell type might participate in the repair process remains unknown. PURPOSE To investigate the tenogenic differentiation potential of human muscle-derived cells (MDCs) both in vitro and in vivo. STUDY DESIGN Controlled laboratory study. METHODS Primary human MDCs and tenocytes were isolated from discarded materials during a peroneus longus tendon-harvesting procedure. Expression of tenogenic genes were evaluated and compared among MDCs, MDCs with tenogenic induction, and tenocytes. RNA sequencing was performed to evaluate the expression profile of differentiated MDCs. Human MDCs were implanted in a tendon injury model to investigate the in vivo tenogenic differentiation potential. Histologic and functional analyses were performed to evaluate the function of MDCs for tendon repair. RESULTS The relative expression levels (in fold change) of tenogenic genes Col I, MKX, SCX, THBS4, and TNC in MDCs were significantly upregulated 11.5 ± 1.3, 957.1 ± 63.7, 19.1 ± 2.8, 61.9 ± 4.8, and 10.2 ± 2.8 after tenogenic induction, respectively. The expression profile of tenogenically differentiated MDCs was much closer to primary tenocytes. Activation of TGF-β/Smad3 signaling significantly promoted the tenogenic differentiation ability of MDCs. Transplanted human MDCs were identified in regenerated tendon and expressed tenogenic genes. As for biomechanical properties, the failure loads in the Matrigel, transplantation, and uninjured groups were 7.2 ± 0.5, 11.6 ± 0.3, and 13.9 ± 0.7 N, while the stiffness values were 4.4 ± 1.3 × 103, 7.6 ± 0.8 × 103, and 10.9 ± 1.1 × 103 N/m. Plantarflexion force, histologic morphology, and motor function were also significantly improved after MDC transplantation in a tendon injury model. CONCLUSION There exist cells with tenogenic differentiation potential in human skeletal muscles. Activation of TGF-β/Smad3 signaling plays an important role in tenogenic differentiation for human MDCs. Human MDCs contribute to structural and functional repair for the injured tendon. MDCs are a potential cell source to participate in the repair process after tendon injury. CLINICAL RELEVANCE The MDCs could be a promising cell source to repair tendon injury.
Collapse
Affiliation(s)
- Xiexiang Shao
- Department of Orthopaedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xingzuan Lin
- Department of Orthopaedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Siyuan Zhu
- Department of Orthopaedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Zhou
- Department of Orthopaedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenfei Lu
- Department of Sports Medicine, Wuxi Hospital of Traditional Chinese Medicine, Wuxi, China
| | - Yuanyuan Zhang
- Centre Testing International Medical Laboratory, Shanghai, China
| | - Jianhua Wang
- Department of Orthopaedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
11
|
Pax7 + Satellite Cells in Human Skeletal Muscle After Exercise: A Systematic Review and Meta-analysis. Sports Med 2023; 53:457-480. [PMID: 36266373 DOI: 10.1007/s40279-022-01767-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/08/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND Skeletal muscle has extraordinary regenerative capabilities against challenge, mainly owing to its resident muscle stem cells, commonly identified by Pax7+, which expediently donate nuclei to the regenerating multinucleated myofibers. This local reserve of stem cells in damaged muscle tissues is replenished by undifferentiated bone marrow stem cells (CD34+) permeating into the surrounding vascular system. OBJECTIVE The purpose of the study was to provide a quantitative estimate for the changes in Pax7+ muscle stem cells (satellite cells) in humans following an acute bout of exercise until 96 h, in temporal relation to circulating CD34+ bone marrow stem cells. A subgroup analysis of age was also performed. METHODS Four databases (Web of Science, PubMed, Scopus, and BASE) were used for the literature search until February 2022. Pax7+ cells in human skeletal muscle were the primary outcome. Circulating CD34+ cells were the secondary outcome. The standardized mean difference (SMD) was calculated using a random-effects meta-analysis. Subgroup analyses were conducted to examine the influence of age, training status, type of exercise, and follow-up time after exercise. RESULTS The final search identified 20 studies for Pax7+ cells comprising a total of 370 participants between the average age of 21 and 74 years and 26 studies for circulating CD34+ bone marrow stem cells comprising 494 participants between the average age of 21 and 67 years. Only one study assessed Pax7+ cells immediately after aerobic exercise and showed a 32% reduction in exercising muscle followed by a fast repletion to pre-exercise level within 3 h. A large effect on increasing Pax7+ cell content in skeletal muscles was observed 24 h after resistance exercise (SMD = 0.89, p < 0.001). Pax7+ cells increased to ~ 50% above pre-exercise level 24-72 h after resistance exercise. For a subgroup analysis of age, a large effect (SMD = 0.81, p < 0.001) was observed on increasing Pax7+ cells in exercised muscle among adults aged > 50 years, whereas adults at younger age presented a medium effect (SMD = 0.64, p < 0.001). Both resistance exercise and aerobic exercise showed a medium overall effect in increasing circulating CD34+ cells (SMD = 0.53, p < 0.001), which declined quickly to the pre-exercise baseline level after exercise within 6 h. CONCLUSIONS An immediate depletion of Pax7+ cells in exercising skeletal muscle concurrent with a transient release of CD34+ cells suggest a replenishment of the local stem cell reserve from bone marrow. A protracted Pax7+ cell expansion in the muscle can be observed during 24-72 h after resistance exercise. This result provides a scientific basis for exercise recommendations on weekly cycles allowing for adequate recovery time. Exercise-induced Pax7+ cell expansion in muscle remains significant at higher age, despite a lower stem cell reserve after age 50 years. More studies are required to confirm whether Pax7+ cell increment can occur after aerobic exercise. CLINICAL TRIAL REGISTRATION Registered at the International Prospective Register of Systematic Reviews (PROSPERO) [identification code CRD42021265457].
Collapse
|
|
12
|
Ostrovidov S, Ramalingam M, Bae H, Orive G, Fujie T, Shi X, Kaji H. Latest developments in engineered skeletal muscle tissues for drug discovery and development. Expert Opin Drug Discov 2023; 18:47-63. [PMID: 36535280 DOI: 10.1080/17460441.2023.2160438] [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] [Indexed: 12/24/2022]
Abstract
INTRODUCTION With the advances in skeletal muscle tissue engineering, new platforms have arisen with important applications in biology studies, disease modeling, and drug testing. Current developments highlight the quest for engineering skeletal muscle tissues with higher complexity . These new human skeletal muscle tissue models will be powerful tools for drug discovery and development and disease modeling. AREAS COVERED The authors review the latest advances in in vitro models of engineered skeletal muscle tissues used for testing drugs with a focus on the use of four main cell culture techniques: Cell cultures in well plates, in microfluidics, in organoids, and in bioprinted constructs. Additional information is provided on the satellite cell niche. EXPERT OPINION In recent years, more sophisticated in vitro models of skeletal muscle tissues have been fabricated. Important developments have been made in stem cell research and in the engineering of human skeletal muscle tissue. Some platforms have already started to be used for drug testing, notably those based on the parameters of hypertrophy/atrophy and the contractibility of myotubes. More developments are expected through the use of multicellular types and multi-materials as matrices . The validation and use of these models in drug testing should now increase.
Collapse
Affiliation(s)
- Serge Ostrovidov
- Department of Biomechanics, Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Murugan Ramalingam
- Institute of Tissue Regeneration Engineering, Dankook University, Cheonan, Republic of Korea.,Department of Nanobiomedical Science, BK21 PLUS NBM Global Research Center for Regenerative Medicine Research Center, Dankook University, Cheonan, Republic of Korea.,School of Basic Medical Science, Chengdu University, Chengdu, Sichuan, China.,Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, Republic of Korea.,Department of Metallurgical and Materials Engineering, Atilim University, Ankara, Turkey
| | - Hojae Bae
- KU Convergence Science and Technology Institute, Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Hwayang-dong, Kwangjin-gu, Seoul, Republic of Korea
| | - Gorka Orive
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.,Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain.,Biomaterials and Nanomedicine (CIBER-BBN), Biomedical Research Networking Centre in Bioengineering, Vitoria-Gasteiz, Spain
| | - Toshinori Fujie
- Department of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
| | - Xuetao Shi
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, Guangdong, China
| | - Hirokazu Kaji
- Department of Biomechanics, Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| |
Collapse
|
|
13
|
Lu A, Tseng C, Guo P, Gao Z, Whitney KE, Kolonin MG, Huard J. The role of the aging microenvironment on the fate of PDGFRβ lineage cells in skeletal muscle repair. Stem Cell Res Ther 2022; 13:405. [PMID: 35932084 PMCID: PMC9356493 DOI: 10.1186/s13287-022-03072-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: 05/18/2022] [Accepted: 07/20/2022] [Indexed: 11/20/2022] Open
Abstract
Background During aging, perturbation of muscle progenitor cell (MPC) constituents leads to progressive loss of muscle mass and accumulation of adipose and fibrotic tissue. Mesenchymal stem cells (MSCs) give rise to adipocytes and fibroblasts that accumulate in injured and pathological skeletal muscle through constitutive activation of platelet-derived growth factor receptors (PDGFRs). Although the role of the PDGFRα has been widely explored, there is a paucity of evidence demonstrating the role of PDGFRβ in aged skeletal muscle. Methods In this study, we investigated the role of PDGFRβ lineage cells in skeletal muscle during aging by using Cre/loxP lineage tracing technology. The PDGFR-Cre mice were crossed with global double-fluorescent Cre reporter mice (mTmG) that indelibly marks PDGFRβ lineage cells. Those cells were analyzed and compared at different ages in the skeletal muscle of the mice. Results Our results demonstrated that PDGFRβ lineage cells isolated from the muscles of young mice are MPC-like cells that exhibited satellite cell morphology, expressed Pax7, and undergo myogenic differentiation producing myosin heavy chain expressing myotubes. Conversely, the PDGFRβ lineage cells isolated from muscles of old mice displayed MSC morphology with a reduced myogenic differentiation potential while expressing adipogenic and fibrotic differentiation markers. PDGFRβ lineage cells also gave rise to newly regenerated muscle fibers in young mice after muscle injury, but their muscle regenerative process is reduced in old mice. Conclusions Our data suggest that PDGFRβ lineage cells function as MPCs in young mice, while the same PDGFRβ lineage cells from old mice undergo a fate switch participating in adipose and fibrotic tissue infiltration in aged muscle. The inhibition of fate-switching in PDGFRβ lineage cells may represent a potential approach to prevent fibrosis and fatty infiltration in skeletal muscle during the aging process.
Collapse
Affiliation(s)
- Aiping Lu
- Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, 181 West Meadow Drive, Suite 1000, Vail, CO, 81657, USA.
| | - Chieh Tseng
- M.D. Anderson Cancer Center, The University of Texas Health Science Center, Houston, TX, 77030, USA
| | - Ping Guo
- Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, 181 West Meadow Drive, Suite 1000, Vail, CO, 81657, USA
| | - Zhanguo Gao
- Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, 77030, USA
| | - Kaitlyn E Whitney
- Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, 181 West Meadow Drive, Suite 1000, Vail, CO, 81657, USA
| | - Mikhail G Kolonin
- Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, 77030, USA
| | - Johnny Huard
- Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, 181 West Meadow Drive, Suite 1000, Vail, CO, 81657, USA.
| |
Collapse
|
|
14
|
Systematic identification of cell-fate regulatory programs using a single-cell atlas of mouse development. Nat Genet 2022; 54:1051-1061. [PMID: 35817981 DOI: 10.1038/s41588-022-01118-8] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 06/01/2022] [Indexed: 12/21/2022]
Abstract
Waddington's epigenetic landscape is a metaphor frequently used to illustrate cell differentiation. Recent advances in single-cell genomics are altering our understanding of the Waddington landscape, yet the molecular mechanisms of cell-fate decisions remain poorly understood. We constructed a cell landscape of mouse lineage differentiation during development at the single-cell level and described both lineage-common and lineage-specific regulatory programs during cell-type maturation. We also found lineage-common regulatory programs that are broadly active during the development of invertebrates and vertebrates. In particular, we identified Xbp1 as an evolutionarily conserved regulator of cell-fate determinations across different species. We demonstrated that Xbp1 transcriptional regulation is important for the stabilization of the gene-regulatory networks for a wide range of mouse cell types. Our results offer genetic and molecular insights into cellular gene-regulatory programs and will serve as a basis for further advancing the understanding of cell-fate decisions.
Collapse
|
|
15
|
Craig DJ, James AW, Wang Y, Tavian M, Crisan M, Péault BM. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:35-43. [PMID: 35641167 PMCID: PMC8895497 DOI: 10.1093/stcltm/szab001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 12/30/2020] [Indexed: 11/17/2022] Open
Abstract
The vascular wall is comprised of distinct layers controlling angiogenesis, blood flow, vessel anchorage within organs, and cell and molecule transit between blood and tissues. Moreover, some blood vessels are home to essential stem-like cells, a classic example being the existence in the embryo of hemogenic endothelial cells at the origin of definitive hematopoiesis. In recent years, microvascular pericytes and adventitial perivascular cells were observed to include multi-lineage progenitor cells involved not only in organ turnover and regeneration but also in pathologic remodeling, including fibrosis and atherosclerosis. These perivascular mesodermal elements were identified as native forerunners of mesenchymal stem cells. We have presented in this brief review our current knowledge on vessel wall-associated tissue remodeling cells with respect to discriminating phenotypes, functional diversity in health and disease, and potential therapeutic interest.
Collapse
Affiliation(s)
- David J Craig
- Center for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
- Center for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Aaron W James
- Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
| | - Yiyun Wang
- Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
| | | | - Mihaela Crisan
- Center for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
- Center for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Bruno M Péault
- Center for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
- Orthopaedic Hospital Research Center and Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA
- Corresponding author: Bruno Péault, PhD, Orthopaedic Hospital Research Center, David Geffen School of Medicine, University of California at Los Angeles, 615 Charles E. Young Drive South, Los Angeles, CA 90095-7358, USA.
| |
Collapse
|
|
16
|
Lu A, Guo P, Pan H, Tseng C, Sinha KM, Yang F, Scibetta A, Cui Y, Huard M, Zhong L, Ravuri S, Huard J. Enhancement of myogenic potential of muscle progenitor cells and muscle healing during pregnancy. FASEB J 2021; 35:e21378. [PMID: 33565161 DOI: 10.1096/fj.202001914r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 12/10/2020] [Accepted: 01/04/2021] [Indexed: 11/11/2022]
Abstract
The decline of muscle regenerative potential with age has been attributed to a diminished responsiveness of muscle progenitor cells (MPCs). Heterochronic parabiosis has been used as a model to study the effects of aging on stem cells and their niches. These studies have demonstrated that, by exposing old mice to a young systemic environment, aged progenitor cells can be rejuvenated. One interesting idea is that pregnancy represents a unique biological model of a naturally shared circulatory system between developing and mature organisms. To test this hypothesis, we evaluated the muscle regeneration potential of pregnant mice using a cardiotoxin (CTX) injury mouse model. Our results indicate that the pregnant mice demonstrate accelerated muscle healing compared to nonpregnant control mice following muscle injury based on improved muscle histology, superior muscle regeneration, and a reduction in inflammation and necrosis. Additionally, we found that MPCs isolated from pregnant mice display a significant improvement of myogenic differentiation capacity in vitro and muscle regeneration in vivo when compared to the MPCs from nonpregnant mice. Furthermore, MPCs from nonpregnant mice display enhanced myogenic capacity when cultured in the presence of serum obtained from pregnant mice. Our proteomics data from these studies provides potential therapeutic targets to enhance the myogenic potential of progenitor cells and muscle repair.
Collapse
Affiliation(s)
- Aiping Lu
- Steadman Philippon Research Institute, Vail, CO, USA
| | - Ping Guo
- Steadman Philippon Research Institute, Vail, CO, USA
| | - Haiying Pan
- Department of Orthopaedic Surgery, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Chieh Tseng
- Department of Orthopaedic Surgery, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Krishna M Sinha
- Department of Orthopaedic Surgery, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Fan Yang
- Department of Traumatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Alex Scibetta
- Steadman Philippon Research Institute, Vail, CO, USA
| | - Yan Cui
- Department of Orthopaedic Surgery, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | | | - Ling Zhong
- Department of Orthopaedic Surgery, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | | | - Johnny Huard
- Department of Orthopaedic Surgery, The University of Texas Health Science Center at Houston, Houston, TX, USA
| |
Collapse
|
|
17
|
Xu J, Wang Y, Gomez-Salazar MA, Hsu GCY, Negri S, Li Z, Hardy W, Ding L, Peault B, James AW. Bone-forming perivascular cells: Cellular heterogeneity and use for tissue repair. STEM CELLS (DAYTON, OHIO) 2021; 39:1427-1434. [PMID: 34252260 DOI: 10.1002/stem.3436] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/31/2021] [Accepted: 06/25/2021] [Indexed: 11/11/2022]
Abstract
Mesenchymal progenitor cells are broadly distributed across perivascular niches-an observation conserved between species. One common histologic zone with a high frequency of mesenchymal progenitor cells within mammalian tissues is the tunica adventitia, the outer layer of blood vessel walls populated by cells with a fibroblastic morphology. The diversity and functions of (re)generative cells present in this outermost perivascular niche are under intense investigation; we have reviewed herein our current knowledge of adventitial cell potential with a somewhat narrow focus on bone formation. Antigens of interest to functionally segregate adventicytes are discussed, including CD10, CD107a, aldehyde dehydrogenase isoforms, and CD140a among others. Purified adventicytes (such as CD10+ , CD107alow , and CD140a+ cells) have stronger osteogenic potential and promote bone formation in vivo. Recent bone tissue engineering applications of adventitial cells are also presented. A better understanding of perivascular progenitor cell subsets may represent a beneficial advance for future efforts in tissue repair and bioengineering.
Collapse
Affiliation(s)
- Jiajia Xu
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Yiyun Wang
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA
| | | | | | - Stefano Negri
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Zhao Li
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Winters Hardy
- UCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, Los Angeles, California, USA
| | - Lijun Ding
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Drum Tower Hospital of Nanjing University Medical School, Nanjing, People's Republic of China.,Clinical Center for Stem Cell Research, Drum Tower Hospital of Nanjing University Medical School, Nanjing, People's Republic of China.,Center For Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK
| | - Bruno Peault
- UCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, Los Angeles, California, USA.,Center For Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK
| | - Aaron W James
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA
| |
Collapse
|
|
18
|
Lee S, Heo J, Ahn EK, Kim JH, Kim YH, Chang HK, Lee SJ, Kim J, Park SJ. Conditioned secretome of adipose-derived stem cells improves dextran sulfate sodium-induced colitis in mice. World J Gastroenterol 2021; 27:3342-3356. [PMID: 34163116 PMCID: PMC8218368 DOI: 10.3748/wjg.v27.i23.3342] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/05/2021] [Accepted: 05/19/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) is related to uncontrolled immune response. Currently, there is no successful treatment for significant improvement in IBD. Stem cells display their therapeutic effects through their repopulating capacity or secreting factors.
AIM To investigate the effects of conditioned mouse adipose-derived stem cells (mADSCs) secretome on colitis-induced mice.
METHODS mADSCs were isolated from adipose tissue of C57BL/6 mice. Conditioned mADSCs secrectome was obtained by culturing of mADSCs with lipopolysaccharides (LPS, 1 μg/mL) for 24 h. Acute colitis was induced by 2% dextran sulfate sodium (DSS) drinking water for 7 d and then normal drinking water for 4 d. The mice were treated with normal culture medium (NM group), conditioned mADSCs secretome (CM group) or mADSCs (SC group). The length of colon and histopatholgy of colon tissues were evaluated. The mRNA expression levels of inflammatory cytokines in colon tissue and the serum interleukin (IL)-6 levels were determined.
RESULTS The isolated mADSCs maintained the mADSCs specific gene expression profiles during experiment. The conditioned mADSCs secretome released by the treatment of mADSCs with LPS contained mainly inflammatory chemokines, colony-stimulating factors and inflammatory cytokines. The loss of body weight and reduction in colon length were ameliorated in the CM group. The conditioned mADSCs secretome reduced the histological score in colon tissue. The expression of IL-1b and IL-6 mRNAs in colon tissues significantly inhibited in the CM group compared to SC group and NM group, respectively. The elevation of serum IL-6 levels was also ameliorated in the CM group. These results indicate that the conditioned mADSCs secretome suppressed the synthesis of inflammatory cytokines in damaged colon tissue and the elevation of serum IL-6 concentration in DSS-induced mice
CONCLUSION Conditioned mADSCs secretome might play regenerative roles by the suppression of IL-6 in serum and tissue during acute colitis, and may be more effective than stem cells themselves in the regeneration of colon tissue.
Collapse
Affiliation(s)
- Seunghun Lee
- Department of Colorectal Surgery, Kosin University College of Medicine, Busan 49267, South Korea
| | - Jeonghoon Heo
- Department of Molecular Biology and Immunology, Kosin University College of Medicine, Busan 49267, South Korea
| | - Eun-Kyung Ahn
- Department of Molecular Biology and Immunology, Kosin University College of Medicine, Busan 49267, South Korea
| | - Jae Hyun Kim
- Department of Gastroenterology, Kosin University College of Medicine, Busan 49267, South Korea
| | - Young-Ho Kim
- Department of Molecular Biology and Immunology, Kosin University College of Medicine, Busan 49267, South Korea
| | - Hee-Kyung Chang
- Department of Pathology, Kosin University College of Medicine, Busan 49267, South Korea
| | - Sang-Joon Lee
- Department of Ophthalmology, Kosin University College of Medicine, Busan 49267, South Korea
| | - Jongsik Kim
- Department of Anatomy, Kosin University College of Medicine, Busan 49267, South Korea
| | - Seun-Ja Park
- Department of Gastroenterology, Kosin University College of Medicine, Busan 49267, South Korea
| |
Collapse
|
|
19
|
Ausems CRM, van Engelen BGM, van Bokhoven H, Wansink DG. Systemic cell therapy for muscular dystrophies : The ultimate transplantable muscle progenitor cell and current challenges for clinical efficacy. Stem Cell Rev Rep 2021; 17:878-899. [PMID: 33349909 PMCID: PMC8166694 DOI: 10.1007/s12015-020-10100-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/01/2020] [Indexed: 01/07/2023]
Abstract
The intrinsic regenerative capacity of skeletal muscle makes it an excellent target for cell therapy. However, the potential of muscle tissue to renew is typically exhausted and insufficient in muscular dystrophies (MDs), a large group of heterogeneous genetic disorders showing progressive loss of skeletal muscle fibers. Cell therapy for MDs has to rely on suppletion with donor cells with high myogenic regenerative capacity. Here, we provide an overview on stem cell lineages employed for strategies in MDs, with a focus on adult stem cells and progenitor cells resident in skeletal muscle. In the early days, the potential of myoblasts and satellite cells was explored, but after disappointing clinical results the field moved to other muscle progenitor cells, each with its own advantages and disadvantages. Most recently, mesoangioblasts and pericytes have been pursued for muscle cell therapy, leading to a handful of preclinical studies and a clinical trial. The current status of (pre)clinical work for the most common forms of MD illustrates the existing challenges and bottlenecks. Besides the intrinsic properties of transplantable cells, we discuss issues relating to cell expansion and cell viability after transplantation, optimal dosage, and route and timing of administration. Since MDs are genetic conditions, autologous cell therapy and gene therapy will need to go hand-in-hand, bringing in additional complications. Finally, we discuss determinants for optimization of future clinical trials for muscle cell therapy. Joined research efforts bring hope that effective therapies for MDs are on the horizon to fulfil the unmet clinical need in patients.
Collapse
Affiliation(s)
- C Rosanne M Ausems
- Donders lnstitute for Brain Cognition and Behavior, Department of Human Genetics, Radboud University Medical Center, 6525, GA, Nijmegen, The Netherlands
- Donders lnstitute for Brain Cognition and Behavior, Department of Neurology, Radboud University Medical Center, 6525, GA, Nijmegen, The Netherlands
- Radboud Institute for Molecular Life Sciences, Department of Cell Biology, Radboud University Medical Center, 6525, GA, Nijmegen, The Netherlands
| | - Baziel G M van Engelen
- Donders lnstitute for Brain Cognition and Behavior, Department of Neurology, Radboud University Medical Center, 6525, GA, Nijmegen, The Netherlands
| | - Hans van Bokhoven
- Donders lnstitute for Brain Cognition and Behavior, Department of Human Genetics, Radboud University Medical Center, 6525, GA, Nijmegen, The Netherlands.
| | - Derick G Wansink
- Radboud Institute for Molecular Life Sciences, Department of Cell Biology, Radboud University Medical Center, 6525, GA, Nijmegen, The Netherlands.
| |
Collapse
|
|
20
|
Abstract
BACKGROUND This manuscript is a review of the literature investigating the use of mesenchymal stem cells (MSCs) being applied in the setting of spinal fusion surgery. We mention the rates of pseudarthrosis, discuss current bone grafting options, and examine the preclinical and clinical outcomes of utilizing MSCs to assist in successfully fusing the spine. METHODS A thorough literature review was conducted to look at current and previous preclinical and clinical studies using stem cells for spinal fusion augmentation. Searches for PubMed/MEDLINE and ClinicalTrials.gov through January 2021 were conducted for literature mentioning stem cells and spinal fusion. RESULTS All preclinical and clinical studies investigating MSC use in spinal fusion were examined. We found 19 preclinical and 17 clinical studies. The majority of studies, both preclinical and clinical, were heterogeneous in design due to different osteoconductive scaffolds, cells, and techniques used. Preclinical studies showed promising outcomes in animal models when using appropriate osteoconductive scaffolds and factors for osteogenic differentiation. Similarly, clinical studies have promising outcomes but differ in their methodologies, surgical techniques, and materials used, making it difficult to adequately compare between the studies. CONCLUSION MSCs may be a promising option to use to augment grafting for spinal fusion surgery. MSCs must be used with appropriate osteoconductive scaffolds. Cell-based allografts and the optimization of their use have yet to be fully elucidated. Further studies are necessary to determine the efficacy of MSCs with different osteoconductive scaffolds and growth/osteogenic differentiation factors. LEVEL OF EVIDENCE 3.
Collapse
Affiliation(s)
- Stephen R Stephan
- Department of Orthopaedic Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Linda E Kanim
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Hyun W Bae
- Department of Orthopaedic Surgery, Cedars-Sinai Medical Center, Los Angeles, California.,Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| |
Collapse
|
|
21
|
Starosta A, Konieczny P. Therapeutic aspects of cell signaling and communication in Duchenne muscular dystrophy. Cell Mol Life Sci 2021; 78:4867-4891. [PMID: 33825942 PMCID: PMC8233280 DOI: 10.1007/s00018-021-03821-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 02/26/2021] [Accepted: 03/23/2021] [Indexed: 12/11/2022]
Abstract
Duchenne muscular dystrophy (DMD) is a devastating chromosome X-linked disease that manifests predominantly in progressive skeletal muscle wasting and dysfunctions in the heart and diaphragm. Approximately 1/5000 boys and 1/50,000,000 girls suffer from DMD, and to date, the disease is incurable and leads to premature death. This phenotypic severity is due to mutations in the DMD gene, which result in the absence of functional dystrophin protein. Initially, dystrophin was thought to be a force transducer; however, it is now considered an essential component of the dystrophin-associated protein complex (DAPC), viewed as a multicomponent mechanical scaffold and a signal transduction hub. Modulating signal pathway activation or gene expression through epigenetic modifications has emerged at the forefront of therapeutic approaches as either an adjunct or stand-alone strategy. In this review, we propose a broader perspective by considering DMD to be a disease that affects myofibers and muscle stem (satellite) cells, as well as a disorder in which abrogated communication between different cell types occurs. We believe that by taking this systemic view, we can achieve safe and holistic treatments that can restore correct signal transmission and gene expression in diseased DMD tissues.
Collapse
Affiliation(s)
- Alicja Starosta
- Faculty of Biology, Institute of Human Biology and Evolution, Adam Mickiewicz University, ul. Uniwersytetu Poznańskiego 6, 61-614, Poznań, Poland
| | - Patryk Konieczny
- Faculty of Biology, Institute of Human Biology and Evolution, Adam Mickiewicz University, ul. Uniwersytetu Poznańskiego 6, 61-614, Poznań, Poland.
| |
Collapse
|
|
22
|
Aerobic exercise induces tumor suppressor p16 INK4a expression of endothelial progenitor cells in human skeletal muscle. Aging (Albany NY) 2020; 12:20226-20234. [PMID: 33104519 PMCID: PMC7655215 DOI: 10.18632/aging.103763] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 07/07/2020] [Indexed: 12/28/2022]
Abstract
Aerobic exercise induces oxidative stress and DNA damage, nevertheless, lowers cancer incidence. It remains unclear how genetic stability is maintained under this condition. Here, we examined the dynamic change of the tumor suppressor p16INK4a in cells of skeletal muscle among young men following 60-min of aerobic cycling at 70% maximal oxygen consumption (V̇O2max). Rg1 (5 mg, an immunostimulant ginsenoside) and placebo (PLA) were supplemented 1 h before exercise. Data from serial muscle biopsies shows unchanged p16INK4a+ cells after exercise followed by a considerable increase (+21-fold) in vastus lateralis muscle 3 h later. This increase was due to the accumulation of endothelial progenitor cells (p16INK4a+/CD34+) surrounding myofibers and other infiltrated nucleated cells (p16INK4a+/CD34-) in necrotic myofibers. During the Rg1 trial, acute increases of p16INK4a+ cells in the muscle occurred immediately after exercise (+3-fold) and reversed near baseline 3 h later. Rg1 also lowered IL-10 mRNA relative to PLA 3 h after exercise. Post-exercise increases in VEGF mRNA and CD163+ macrophages were similar for PLA and Rg1 trials. Conclusion: The marked increases in p16INK4a protein expression of endothelial progenitor cells in skeletal muscle implicates a protective mechanism for maintaining genetic stability against aerobic exercise. Rg1 accelerates resolution of the exercise-induced stress response.
Collapse
|
|
23
|
Pre-Clinical Cell Therapeutic Approaches for Repair of Volumetric Muscle Loss. Bioengineering (Basel) 2020; 7:bioengineering7030097. [PMID: 32825213 PMCID: PMC7552602 DOI: 10.3390/bioengineering7030097] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/04/2020] [Accepted: 08/18/2020] [Indexed: 01/15/2023] Open
Abstract
Extensive damage to skeletal muscle tissue due to volumetric muscle loss (VML) is beyond the inherent regenerative capacity of the body, and results in permanent functional debilitation. Current clinical treatments fail to fully restore native muscle function. Recently, cell-based therapies have emerged as a promising approach to promote skeletal muscle regeneration following injury and/or disease. Stem cell populations, such as muscle stem cells, mesenchymal stem cells and induced pluripotent stem cells (iPSCs), have shown a promising capacity for muscle differentiation. Support cells, such as endothelial cells, nerve cells or immune cells, play a pivotal role in providing paracrine signaling cues for myogenesis, along with modulating the processes of inflammation, angiogenesis and innervation. The efficacy of cell therapies relies on the provision of instructive microenvironmental cues and appropriate intercellular interactions. This review describes the recent developments of cell-based therapies for the treatment of VML, with a focus on preclinical testing and future trends in the field.
Collapse
|
|
24
|
Tamaki T. Biomedical applications of muscle-derived stem cells: from bench to bedside. Expert Opin Biol Ther 2020; 20:1361-1371. [PMID: 32643444 DOI: 10.1080/14712598.2020.1793953] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Skeletal muscle-derived stem cells (Sk-MDSCs) are considered promising sources of adult stem cell therapy. Skeletal muscle comprises approximately 40-50% of the total body mass with marked potential for postnatal adaptive response, such as muscle hypertrophy, hyperplasia, atrophy, and regenerative capacity. This strongly suggests that skeletal muscle contains various stem/progenitor cells related to muscle-nerve-vascular tissues, which would support the above postnatal events even in adulthood. AREA COVERED The focus of this review is the therapeutic potential of the Sk-MDSCs as an adult stem cell autograft. For this purpose, the validity of cell isolation and purification, tissue reconstitution capacity in vivo after transplantation, comparison of the results of basic mouse and preclinical human studies, potential problematic and beneficial aspects, and effective usage have been discussed following the history of clinical applications. EXPERT OPINION Although the clinical application of Sk-MDSCs began as a therapy for the systemic disease of Duchenne muscular dystrophy, here, through the unique local injection method, therapy for severely damaged peripheral nerves, particularly the long-gap nerve transection, has been introduced. The beneficial aspects of the use of Sk-MDSCs as the source of local tissue transplantation therapy have also been discussed.
Collapse
Affiliation(s)
- Tetsuro Tamaki
- Muscle Physiology and Cell Biology Unit, Department of Physiology, Tokai University School of Medicine , Isehara, Kanagawa ,Japan
| |
Collapse
|
|
25
|
High-Dimensional Single-Cell Quantitative Profiling of Skeletal Muscle Cell Population Dynamics during Regeneration. Cells 2020; 9:cells9071723. [PMID: 32708412 PMCID: PMC7407527 DOI: 10.3390/cells9071723] [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: 04/17/2020] [Revised: 06/03/2020] [Accepted: 07/14/2020] [Indexed: 12/15/2022] Open
Abstract
The interstitial space surrounding the skeletal muscle fibers is populated by a variety of mononuclear cell types. Upon acute or chronic insult, these cell populations become activated and initiate finely-orchestrated crosstalk that promotes myofiber repair and regeneration. Mass cytometry is a powerful and highly multiplexed technique for profiling single-cells. Herein, it was used to dissect the dynamics of cell populations in the skeletal muscle in physiological and pathological conditions. Here, we characterized an antibody panel that could be used to identify most of the cell populations in the muscle interstitial space. By exploiting the mass cytometry resolution, we provided a comprehensive picture of the dynamics of the major cell populations that sensed and responded to acute damage in wild type mice and in a mouse model of Duchenne muscular dystrophy. In addition, we revealed the intrinsic heterogeneity of many of these cell populations.
Collapse
|
|
26
|
Ma J, Sanchez-Duffhues G, Goumans MJ, ten Dijke P. TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering. Front Cell Dev Biol 2020; 8:260. [PMID: 32373613 PMCID: PMC7187792 DOI: 10.3389/fcell.2020.00260] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/27/2020] [Indexed: 12/12/2022] Open
Abstract
Endothelial to mesenchymal transition (EndMT) is a complex biological process that gives rise to cells with multipotent potential. EndMT is essential for the formation of the cardiovascular system during embryonic development. Emerging results link EndMT to the postnatal onset and progression of fibrotic diseases and cancer. Moreover, recent reports have emphasized the potential for EndMT in tissue engineering and regenerative applications by regulating the differentiation status of cells. Transforming growth factor β (TGF-β) engages in many important physiological processes and is a potent inducer of EndMT. In this review, we first summarize the mechanisms of the TGF-β signaling pathway as it relates to EndMT. Thereafter, we discuss the pivotal role of TGF-β-induced EndMT in the development of cardiovascular diseases, fibrosis, and cancer, as well as the potential application of TGF-β-induced EndMT in tissue engineering.
Collapse
Affiliation(s)
- Jin Ma
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
- Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| | | | - Marie-José Goumans
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - Peter ten Dijke
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
- Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| |
Collapse
|
|
27
|
Gomez-Salazar M, Gonzalez-Galofre ZN, Casamitjana J, Crisan M, James AW, Péault B. Five Decades Later, Are Mesenchymal Stem Cells Still Relevant? Front Bioeng Biotechnol 2020; 8:148. [PMID: 32185170 PMCID: PMC7058632 DOI: 10.3389/fbioe.2020.00148] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 02/13/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells are culture-derived mesodermal progenitors isolatable from all vascularized tissues. In spite of multiple fundamental, pre-clinical and clinical studies, the native identity and role in tissue repair of MSCs have long remained elusive, with MSC selection in vitro from total cell suspensions essentially unchanged as a mere primary culture for half a century. Recent investigations have helped understand the tissue origin of these progenitor cells, and uncover alternative effects of MSCs on tissue healing via growth factor secretion and interaction with the immune system. In this review, we describe current trends in MSC biology and discuss how these may improve the use of these therapeutic cells in tissue engineering and regenerative medicine.
Collapse
Affiliation(s)
- Mario Gomez-Salazar
- MRC Centre for Regenerative Medicine and Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | - Zaniah N Gonzalez-Galofre
- MRC Centre for Regenerative Medicine and Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | - Joan Casamitjana
- MRC Centre for Regenerative Medicine and Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | - Mihaela Crisan
- MRC Centre for Regenerative Medicine and Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | - Aaron W James
- Orthopaedic Hospital Research Center and Broad Stem Cell Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Pathology, Johns Hopkins University, Baltimore, MD, United States
| | - Bruno Péault
- MRC Centre for Regenerative Medicine and Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom.,Orthopaedic Hospital Research Center and Broad Stem Cell Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| |
Collapse
|
|
28
|
Dong Y, Li Y, Zhang C, Chen H, Liu L, Chen S. Effects of SW033291 on the myogenesis of muscle-derived stem cells and muscle regeneration. Stem Cell Res Ther 2020; 11:76. [PMID: 32085799 PMCID: PMC7035785 DOI: 10.1186/s13287-020-1574-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 01/17/2020] [Accepted: 01/27/2020] [Indexed: 12/15/2022] Open
Abstract
Background The unmet medical needs in repairing large muscle defects promote the development of tissue regeneration strategy. The use of bioactive molecules in combination with biomaterial scaffold has become an area of great interest. SW033291, a small-molecule inhibitor targeting 15-hydroxyprostaglandin dehydrogenase (15-PDGH) and subsequently elevating the production of prostaglandin E2 (PGE2), has been proved to accelerate the recovery and potentiate the regeneration of multiple tissues including the bone, liver, and colon. The limited understanding of the potential therapeutic effects on myogenesis motivated us to investigate the role of SW033291 in regulating muscle-derived stem cell (MDSC) myogenic differentiation and MDSC-mediated muscle regeneration. Methods The characteristics of rat MDSCs, including cell-specific markers and myogenic differentiation potential, were determined. MDSCs were incubated with SW033291 to evaluate PGE2 production and cytotoxicity. The effects of SW033291 on MDSC myogenic differentiation were assessed by quantitative real-time polymerase chain reaction (qPCR), western blot, and immunocytochemistry. The fibrin gel containing MDSCs and SW033291 was used for muscle regeneration in a tibialis anterior muscle defect model. Results Our data demonstrated that MDSCs were well-tolerated to SW033291 and treatment with SW033291 significantly promoted the production of PGE2 by MDSCs. In vitro analysis showed that SW033291 enhanced the myogenic differentiation and myotube formation by upregulating a series of myogenic markers. Additionally, the activation of PI3K/Akt pathway was involved in the mechanism underlying these promotive effects. Then, in situ casting of fibrin gel containing MDSCs and SW033291 was used to repair the tibialis anterior muscle defect; the addition of SW033291 significantly promoted myofiber formation within the defect region with mild immune response, less fibrosis, and sufficient vascularization. Conclusion SW033291 acted as a positive regulator of MDSC myogenic differentiation, and incorporating the compound with MDSCs in fibrin gel could serve as an effective method to repair large skeletal muscle defects.
Collapse
Affiliation(s)
- Yuanqiang Dong
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Yuan Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Chuan Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Haibin Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Lijia Liu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.
| | - Simeng Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.
| |
Collapse
|
|
29
|
Iseoka H, Miyagawa S, Saito A, Harada A, Sawa Y. Role and therapeutic effects of skeletal muscle-derived non-myogenic cells in a rat myocardial infarction model. Stem Cell Res Ther 2020; 11:69. [PMID: 32070429 PMCID: PMC7029551 DOI: 10.1186/s13287-020-1582-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 01/25/2020] [Accepted: 02/04/2020] [Indexed: 11/10/2022] Open
Abstract
Background Transplantation of skeletal myoblast sheets is a promising strategy for the treatment of heart failure, and its therapeutic effects have already been proven in both animal disease models and clinical trials. Myoblast sheets reportedly demonstrate their therapeutic effects by producing many paracrine factors. Although the quality of processed cells for transplantation can be evaluated by the positive ratio of CD56, a myoblast marker, it is unclear which cell populations from isolated cells produce paracrine factors that have an impact on therapeutic effects, and whether these therapeutic effects are closely correlated with CD56-positive cells isolated from the skeletal muscle is also unclear. Therefore, we hypothesized that CD56-negative cells as well as CD56-positive cells isolated from the skeletal muscle produce paracrine factors and have therapeutic effects in skeletal muscle-derived cell sheet therapy for heart failure. Methods Cell surface and intracellular markers of CD56-negative non-myogenic cells (NMCs) and CD56-positive myoblasts were evaluated. We also analyzed cytokine expression, tube formation ability, and stem cell mobilization in both cell populations. Finally, we assessed the therapeutic effects of the cell populations in a rat myocardial infarction model. Results Analysis of cell surface and intracellular markers revealed that CD56-negative NMCs expressed fibroblast markers and a higher level of mesenchymal cell markers, such as CD49b and CD140a, than myoblasts. Both NMCs and myoblasts expressed various cytokines in vitro with different expression patterns. In addition, NMCs induced tube formation (control vs. myoblasts vs. NMCs: 100 ± 11.2 vs. 142 ± 8.3 vs. 198 ± 7.4%) and stem cell mobilization (control vs. myoblasts vs. NMCs: 100 ± 6.8 vs. 210 ± 22.9 vs. 351 ± 36.0%) to a higher degree in vitro than did myoblasts. The effect of NMCs and myoblasts on the improvement of cardiac function and suppression of myocardial fibrosis in rat myocardial infarction model was comparable. Conclusion These results indicate that NMCs exhibit therapeutic effects in skeletal muscle-derived cell sheet therapy for heart failure. Thus, accurate parameters correlating with therapeutic effects need to be further explored.
Collapse
Affiliation(s)
- Hiroko Iseoka
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Yamadaoka, 2-2, Suita, Osaka, 565-0871, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Yamadaoka, 2-2, Suita, Osaka, 565-0871, Japan
| | - Atsuhiro Saito
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Yamadaoka, 2-2, Suita, Osaka, 565-0871, Japan
| | - Akima Harada
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Yamadaoka, 2-2, Suita, Osaka, 565-0871, Japan
| | - Yoshiki Sawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Yamadaoka, 2-2, Suita, Osaka, 565-0871, Japan.
| |
Collapse
|
|
30
|
Soto-Avellaneda A, Morrison BE. Central nervous system and peripheral cell labeling by vascular endothelial cadherin-driven lineage tracing in adult mice. Neural Regen Res 2020; 15:1856-1866. [PMID: 32246634 PMCID: PMC7513977 DOI: 10.4103/1673-5374.280317] [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] [Indexed: 12/27/2022] Open
Abstract
Understanding the contribution of endothelial cells to the progenitor pools of adult tissues has the potential to inform therapies for human disease. To address whether endothelial cells transdifferentiate into non-vascular cell types, we performed cell lineage tracing analysis using transgenic mice engineered to express a fluorescent marker following activation by tamoxifen in vascular endothelial cadherin promoter-expressing cells (VEcad-CreERT2; B6 Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze). Activation of target-cell labeling following 1.5 months of ad libitum feeding with tamoxifen-laden chow in 4–5 month-old mice resulted in the tracing of central nervous system and peripheral cells that include: cerebellar granule neurons, ependymal cells, skeletal myocytes, pancreatic beta cells, pancreatic acinar cells, tubular cells in the renal cortex, duodenal crypt cells, ileal crypt cells, and hair follicle stem cells. As Nestin expression has been reported in a subset of endothelial cells, Nes-CreERT2 mice were also utilized in these conditions. The tracing of cells in adult Nes-CreERT2 mice revealed the labeling of canonical progeny cell types such as hippocampal and olfactory granule neurons as well as ependymal cells. Interestingly, Nestin tracing also labeled skeletal myocytes, ileal crypt cells, and sparsely marked cerebellar granule neurons. Our findings provide support for endothelial cells as active contributors to adult tissue progenitor pools. This information could be of particular significance for the intravenous delivery of therapeutics to downstream endothelial-derived cellular targets. The animal experiments were approved by the Boise State University Institute Animal Care and Use Committee (approval No. 006-AC15-018) on October 31, 2018.
Collapse
Affiliation(s)
| | - Brad E Morrison
- Biomolecular Ph.D. Program, Boise State University; Department of Biological Sciences, Boise State University, Boise, ID, USA
| |
Collapse
|
|
31
|
Kapoor S, Shenoy SP, Bose B. CD34 cells in somatic, regenerative and cancer stem cells: Developmental biology, cell therapy, and omics big data perspective. J Cell Biochem 2019; 121:3058-3069. [PMID: 31886574 DOI: 10.1002/jcb.29571] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 12/11/2019] [Indexed: 12/11/2022]
Abstract
The transmembrane phosphoglycoprotein protein CD34 has conventionally been regarded as a marker for hematopoietic progenitors. Its expression on these cells has been leveraged for cell therapy applications in various hematological disorders. More recently, the expression of CD34 has also been reported on cells of nonhematopoietic origin. The list includes somatic cells such as endothelial cells, fibrocytes and interstitial cells and regenerative stem cells such as corneal keratocytes, muscle satellite cells, and muscle-derived stem cells. Furthermore, its expression on some cancer stem cells (CSCs) has also been reported. Till date, the functional roles of this molecule have been implicated in a multitude of cellular processes including cell adhesion, signal transduction, and maintenance of progenitor phenotype. However, the complete understanding about this molecule including its developmental origins, its embryonic connection, and associated functions is far from complete. Here, we review our present understanding of the structure and putative functions of the CD34 molecule based upon our literature survey. We also probed various biological databases to retrieve data related to the expression and associated molecular functions of CD34. Such information, upon synthesis, is hence likely to provide the suitability of such cells for cell therapy. Moreover, we have also covered the existing cell therapy and speculated cell therapy applications of CD34+ cells isolated from various lineages. We have also attempted here to speculate the role(s) of CD34 on CSCs. Finally, we discuss number of large-scale proteomics and transcriptomics studies that have been performed using CD34+ cells.
Collapse
Affiliation(s)
- Saketh Kapoor
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Sudheer P Shenoy
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Bipasha Bose
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| |
Collapse
|
|
32
|
Tey SR, Robertson S, Lynch E, Suzuki M. Coding Cell Identity of Human Skeletal Muscle Progenitor Cells Using Cell Surface Markers: Current Status and Remaining Challenges for Characterization and Isolation. Front Cell Dev Biol 2019; 7:284. [PMID: 31828070 PMCID: PMC6890603 DOI: 10.3389/fcell.2019.00284] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 11/01/2019] [Indexed: 12/12/2022] Open
Abstract
Skeletal muscle progenitor cells (SMPCs), also called myogenic progenitors, have been studied extensively in recent years because of their promising therapeutic potential to preserve and recover skeletal muscle mass and function in patients with cachexia, sarcopenia, and neuromuscular diseases. SMPCs can be utilized to investigate the mechanisms of natural and pathological myogenesis via in vitro modeling and in vivo experimentation. While various types of SMPCs are currently available from several sources, human pluripotent stem cells (PSCs) offer an efficient and cost-effective method to derive SMPCs. As human PSC-derived cells often display varying heterogeneity in cell types, cell enrichment using cell surface markers remains a critical step in current procedures to establish a pure population of SMPCs. Here we summarize the cell surface markers currently being used to detect human SMPCs, describing their potential application for characterizing, identifying and isolating human PSC-derived SMPCs. To date, several positive and negative markers have been used to enrich human SMPCs from differentiated PSCs by cell sorting. A careful analysis of current findings can broaden our understanding and reveal potential uses for these surface markers with SMPCs.
Collapse
Affiliation(s)
- Sin-Ruow Tey
- Department of Comparative Biosciences, University of Wisconsin, Madison, WI, United States
| | - Samantha Robertson
- Department of Comparative Biosciences, University of Wisconsin, Madison, WI, United States
| | - Eileen Lynch
- Department of Comparative Biosciences, University of Wisconsin, Madison, WI, United States
| | - Masatoshi Suzuki
- Department of Comparative Biosciences, University of Wisconsin, Madison, WI, United States.,The Stem Cell and Regenerative Medicine Center, University of Wisconsin, Madison, WI, United States
| |
Collapse
|
|
33
|
Abstract
There are a number of bone regeneration therapeutics available to aid spinal fusion; however, many are associated with pseudarthrosis, inflammation, and other complications. Mesenchymal stem cells for fusion has been promoted to mitigate these risks and achieve successful bony fusion. This article reviews the clinical studies available with use in spinal fusion. Preliminary results demonstrate that stem cells can provide high rates of fusion, comparable to autograft, without associated morbidity. Autologous and allogeneic stem cell sources showed similar rates of fusion in this review. Further research is required to evaluate which clinical situations are the optimum for stem cell use.
Collapse
Affiliation(s)
- Vivek P Shah
- Department of Orthopedic Surgery - Hsu Lab, Northwestern University, Chicago, IL 60611, USA.
| | - Wellington K Hsu
- Northwestern Department of Orthopedic Surgery, 259 East Erie Street 13th Floor Lavin Family Pavilion, Chicago, IL 60611, USA
| |
Collapse
|
|
34
|
Goldberg EJ, Schmidt CA, Green TD, Karnekar R, Yamaguchi DJ, Spangenberg EE, McClung JM. Temporal Association Between Ischemic Muscle Perfusion Recovery and the Restoration of Muscle Contractile Function After Hindlimb Ischemia. Front Physiol 2019; 10:804. [PMID: 31316393 PMCID: PMC6611152 DOI: 10.3389/fphys.2019.00804] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 06/06/2019] [Indexed: 12/15/2022] Open
Abstract
During incomplete skeletal muscle recovery from ischemia, such as that occurs with critical limb ischemia, the temporal relationship between recovery of muscle capillary perfusion and contractile function is poorly defined. We examined this relationship in BALB/cJ mice (N = 24) following unilateral hindlimb ischemia (HLI), which pre-clinically mimics the myopathy observed in critical limb ischemia patients. Specifically, we examined this relationship in two phenotypically distinct muscles (i.e., "oxidative" soleus - Sol and "glycolytic" extensor digitorum longus - EDL) 14- or 56-days after HLI. Although overall limb blood flow (LDPI) reached its' recovery peak (48% of control) by HLI d14, the capillary networks in both the Sol and EDL (whole mount confocal imaging) were disrupted and competent muscle capillary perfusion (perfused lectin+μm2/muscle μm2) remained reduced. Interestingly, both Sol and EDL muscles recovered their distinct capillary structures and perfusion (Con Sol; 0.056 ± 0.02 lectin+μm2/muscle μm2, and Con EDL; 0.039 ± 0.005 lectin+μm2/muscle μm2) by HLI d56 (Sol; 0.062 ± 0.011 lectin+μm2/muscle μm2 and EDL; 0.0035 ± 0.005 lectin+μm2/muscle μm2), despite no further improvement in limb blood flow (LDPI). Both muscles suffered severe myopathy, indicated by loss of dystrophin positive immunostaining and the absence of stimulation induced isometric force production at HLI d14. Dystrophin immunofluorescence returned at HLI d56, although neither myofiber CSA (μm2) nor isometric force production (58 and 28% sustained deficits, Sol and EDL, respectively) recovered completely in either muscle. In summary, we reveal that the temporal relationship between the restoration of muscle capillary perfusion and functional ischemic skeletal muscle regeneration favors competent muscle capillary perfusion recovery in BALB/c mice in a phenotypically non-distinct manner.
Collapse
Affiliation(s)
- Emma J Goldberg
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States.,East Carolina Diabetes and Obesity Institute, East Carolina Heart Institute, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - Cameron A Schmidt
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States.,East Carolina Diabetes and Obesity Institute, East Carolina Heart Institute, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - T D Green
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States.,East Carolina Diabetes and Obesity Institute, East Carolina Heart Institute, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - R Karnekar
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States.,East Carolina Diabetes and Obesity Institute, East Carolina Heart Institute, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - D J Yamaguchi
- Department of Cardiovascular Sciences, Brody School of Medicine, East Carolina University, Greenville, NC, United States.,Division of Surgery, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - E E Spangenberg
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States.,East Carolina Diabetes and Obesity Institute, East Carolina Heart Institute, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| | - Joseph M McClung
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States.,East Carolina Diabetes and Obesity Institute, East Carolina Heart Institute, Brody School of Medicine, East Carolina University, Greenville, NC, United States.,Department of Cardiovascular Sciences, Brody School of Medicine, East Carolina University, Greenville, NC, United States
| |
Collapse
|
|
35
|
Dissecting cell diversity and connectivity in skeletal muscle for myogenesis. Cell Death Dis 2019; 10:427. [PMID: 31160550 PMCID: PMC6546706 DOI: 10.1038/s41419-019-1647-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 03/25/2019] [Accepted: 05/06/2019] [Indexed: 12/28/2022]
Abstract
Characterized by their slow adhering property, skeletal muscle myogenic progenitor cells (MPCs) have been widely utilized in skeletal muscle tissue engineering for muscle regeneration, but with limited efficacy. Skeletal muscle regeneration is regulated by various cell types, including a large number of rapidly adhering cells (RACs) where their functions and mechanisms are still unclear. In this study, we explored the function of RACs by co-culturing them with MPCs in a biomimetic skeletal muscle organoid system. Results showed that RACs promoted the myogenic potential of MPCs in the organoid. Single-cell RNA-Seq was also performed, classifying RACs into 7 cell subtypes, including one newly described cell subtype: teno-muscular cells (TMCs). Connectivity map of RACs and MPCs subpopulations revealed potential growth factors (VEGFA and HBEGF) and extracellular matrix (ECM) proteins involvement in the promotion of myogenesis of MPCs during muscle organoid formation. Finally, trans-well experiments and small molecular inhibitors blocking experiments confirmed the role of RACs in the promotion of myogenic differentiation of MPCs. The RACs reported here revealed complex cell diversity and connectivity with MPCs in the biomimetic skeletal muscle organoid system, which not only offers an attractive alternative for disease modeling and in vitro drug screening but also provides clues for in vivo muscle regeneration.
Collapse
|
|
36
|
Huard J. Stem cells, blood vessels, and angiogenesis as major determinants for musculoskeletal tissue repair. J Orthop Res 2019; 37:1212-1220. [PMID: 29786150 DOI: 10.1002/jor.24058] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 05/21/2018] [Indexed: 02/04/2023]
Abstract
This manuscript summarizes 20 years of research from my laboratories at the University of Pittsburgh and more recently, at the University of Texas Health Science Center at Houston and the Steadman Philippon Research Institute in Vail, Colorado. The discovery of muscle-derived stem cells (MDSCs) did not arise from a deliberate search to find a novel population of muscle cells with high regenerative potential, but instead was conceived in response to setbacks encountered while working in muscle cell transplantation for Duchenne muscular dystrophy (DMD). DMD is a devastating inherited X-linked muscle disease characterized by progressive muscle weakness due to lack of dystrophin expression in muscle fiber sarcolemma.1 Although the transplantation of normal myoblasts into dystrophin-deficient muscle can restore dystrophin, this approach has been hindered by limited survival (less than 1%) of the injected cells.1 The fact that 99% of the cells were not surviving implantation was seen as a major weakness with this technology by most. My research team decided to investigate which cells represent the 1% of the cells surviving post-implantation. We have subsequently confirmed that the few cells which exhibit high survival post-implantation also display stem cell characteristics, and were termed "muscle-derived stem cells" or MDSCs. Herein, I will describe the origin of these MDSCs, the mechanisms of MDSC action during tissue repair, and finally the development of therapeutic strategies to improve regeneration and repair of musculoskeletal tissues. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1212-1220, 2019.
Collapse
Affiliation(s)
- Johnny Huard
- Department of Orthopaedic Surgery, and The Brown Foundation Institute of Molecular Medicine Center for Tissue Engineering and Aging Research, McGovern Medical School, The University of Texas Health Science Center, 1881 East Road, 3SCR6.3618, Houston, Texas, 77054.,Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, 181 W. Meadow Drive, Suite 1000, Vail, Colorado, 81657
| |
Collapse
|
|
37
|
Delle Monache S, Martellucci S, Clementi L, Pulcini F, Santilli F, Mei C, Piccoli L, Angelucci A, Mattei V. In Vitro Conditioning Determines the Capacity of Dental Pulp Stem Cells to Function as Pericyte-Like Cells. Stem Cells Dev 2019; 28:695-706. [PMID: 30887879 DOI: 10.1089/scd.2018.0192] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Dental pulp has been revealed as an accessible and a rich source of mesenchymal stem cells (MSCs) and its biological potential is currently under intense investigation. MSCs from dental pulp stem cells (DPSCs) have been indicated as a heterogeneous population oriented not only in repairing dentine but also in maintaining vascular and nervous homeostasis of the teeth. We sought to verify the phenotype of cells isolated from dental pulp of young donors and to investigate in vitro their role as pericyte-like cells. Specifically, we evaluated how culture conditions can modulate expression of pericyte markers in DPSCs and their capacity to stabilize endothelial tubes in vitro. DPSCs cultured in standard conditions expressed MSC markers and demonstrated to contain a population expressing the pericyte marker NG2. These DPSCs were associated with low sprouting capacity in extra-cellular (EC) Matrix and limited ability in retaining tubes formed by endothelial cells in a coculture angiogenesis model. When cultured in endothelial growth medium (EGM)-2, DPSCs significantly upregulated NG2, and partially alpha-smooth muscle actin. The resulting population conserved the stem marker CD73, but was negative for calponin and endothelial markers. EGM-2-conditioned DPSCs showed a higher sprouting ability in EC Matrix and efficient association with human umbilical vein endothelial cells allowing the partial retention of endothelial tubes for several days. Among growth factors contained in EGM-2 we identified basic fibroblast growth factor (bFGF) as mainly responsible for NG2 upregulation and long-term stabilization of endothelial tubes. According to the in vitro analysis, DPSCs represent an effective source of pericytes and the appropriate culture conditions could result in a population with a promising ability to stabilize vessels and promote vascular maturation.
Collapse
Affiliation(s)
- Simona Delle Monache
- 1 Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Stefano Martellucci
- 1 Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.,2 Laboratory of Experimental Medicine and Environmental Pathology, Rieti University Hub "Sabina Universitas," Rieti, Italy.,3 Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Letizia Clementi
- 1 Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Fanny Pulcini
- 1 Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Francesca Santilli
- 2 Laboratory of Experimental Medicine and Environmental Pathology, Rieti University Hub "Sabina Universitas," Rieti, Italy
| | - Cecilia Mei
- 2 Laboratory of Experimental Medicine and Environmental Pathology, Rieti University Hub "Sabina Universitas," Rieti, Italy
| | - Luca Piccoli
- 4 Department of Science Dentistry and Maxillofacial, "Sapienza" University of Rome, Rome, Italy
| | - Adriano Angelucci
- 1 Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Vincenzo Mattei
- 2 Laboratory of Experimental Medicine and Environmental Pathology, Rieti University Hub "Sabina Universitas," Rieti, Italy.,3 Department of Experimental Medicine, "Sapienza" University of Rome, Rome, Italy
| |
Collapse
|
|
38
|
Sinha KM, Tseng C, Guo P, Lu A, Pan H, Gao X, Andrews R, Eltzschig H, Huard J. Hypoxia-inducible factor 1α (HIF-1α) is a major determinant in the enhanced function of muscle-derived progenitors from MRL/MpJ mice. FASEB J 2019; 33:8321-8334. [PMID: 30970214 DOI: 10.1096/fj.201801794r] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Although the mouse strain Murphy Roths Large (MRL/MpJ) possesses high regenerative potential, the mechanism of tissue regeneration, including skeletal muscle, in MRL/MpJ mice after injury is still unclear. Our previous studies have shown that muscle-derived stem/progenitor cell (MDSPC) function is significantly enhanced in MRL/MpJ mice when compared with MDSPCs isolated from age-matched wild-type (WT) mice. Using mass spectrometry-based proteomic analysis, we identified increased expression of hypoxia-inducible factor (HIF) 1α target genes (expression of glycolytic factors and antioxidants) in sera from MRL/MpJ mice compared with WT mice. Therefore, we hypothesized that HIF-1α promotes the high muscle healing capacity of MRL/MpJ mice by increasing the potency of MDSPCs. We demonstrated that treating MRL/MpJ MDSPCs with dimethyloxalylglycine and CoCl2 increased the expression of HIF-1α and target genes, including angiogenic and cell survival genes. We also observed that HIF-1α activated the expression of paired box (Pax)7 through direct interaction with the Pax7 promoter. Furthermore, we also observed a higher myogenic potential of MDSPCs derived from prolyl hydroxylase (Phd) 3-knockout (Phd3-/-) mice, which displayed higher stability of HIF-1α. Taken together, our findings suggest that HIF-1α is a major determinant in the increased MDSPC function of MRL/MpJ mice through enhancement of cell survival, proliferation, and myogenic differentiation.-Sinha, K. M., Tseng, C., Guo, P., Lu, A., Pan, H., Gao, X., Andrews, R., Eltzschig, H., Huard, J. Hypoxia-inducible factor 1α (HIF-1α) is a major determinant in the enhanced function of muscle-derived progenitors from MRL/MpJ mice.
Collapse
Affiliation(s)
- Krishna M Sinha
- Department of Orthopedic Surgery, McGovern Medical School, University of Texas Health Science Center-Houston, Houston, Texas, USA
| | - Chieh Tseng
- Department of Orthopedic Surgery, McGovern Medical School, University of Texas Health Science Center-Houston, Houston, Texas, USA
| | - Ping Guo
- Department of Orthopedic Surgery, McGovern Medical School, University of Texas Health Science Center-Houston, Houston, Texas, USA
| | - Aiping Lu
- Department of Orthopedic Surgery, McGovern Medical School, University of Texas Health Science Center-Houston, Houston, Texas, USA
| | - Haiying Pan
- Department of Orthopedic Surgery, McGovern Medical School, University of Texas Health Science Center-Houston, Houston, Texas, USA
| | - Xueqin Gao
- Department of Orthopedic Surgery, McGovern Medical School, University of Texas Health Science Center-Houston, Houston, Texas, USA
| | - Reid Andrews
- Department of Orthopedic Surgery, McGovern Medical School, University of Texas Health Science Center-Houston, Houston, Texas, USA
| | - Holger Eltzschig
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center-Houston, Houston, Texas, USA
| | - Johnny Huard
- Department of Orthopedic Surgery, McGovern Medical School, University of Texas Health Science Center-Houston, Houston, Texas, USA.,Steadman Philippon Research Institute, Vail, Colorado, USA
| |
Collapse
|
|
39
|
Muscle-Derived Stem Cell-Enriched Scaffolds Are Capable of Enhanced Healing of a Murine Volumetric Muscle Loss Defect. Plast Reconstr Surg 2019; 143:329e-339e. [PMID: 30531618 DOI: 10.1097/prs.0000000000005273] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Volumetric muscle loss secondary to traumatic or surgical causes can lead to functional and aesthetic impairments. The authors hypothesize that an implantable muscle-derived stem cell-enriched collagen scaffold could significantly augment muscle regeneration in a murine model of volumetric muscle loss. METHODS Murine muscle-derived stem cells were isolated using a modified preplating technique and seeded onto type 1 collagen scaffolds to create the muscle-derived stem cell-enriched collagen scaffolds. Murine rectus femoris defects of 5 mm were created and randomized to one of three conditions (n = 6 per group): untreated controls, collagen scaffold only, and muscle-derived stem cell-enriched collagen scaffolds. In vivo muscle healing was quantified using micro-computed tomography. Muscle explants were analyzed using standard histology and whole-mount immunofluorescence at 8 weeks. RESULTS In vivo experiments demonstrated significantly greater quadriceps cross-sectional area in the muscle-derived stem cell-enriched collagen scaffold group compared with controls on micro-computed tomography (0.74 ± 0.21 versus 0.55 ± 0.06 versus 0.49 ± 0.04 ratio of experimental to naive quadriceps cross-sectional area; p < 0.05). Muscle explants of the muscle-derived stem cell-enriched collagen scaffold group demonstrated significantly higher cellular density compared with controls (1185 ± 360 versus 359 ± 62 versus 197 ± 68 nuclei/high-power field; p < 0.01). Immunofluorescence for laminin and myosin heavy chain confirmed formation of organized muscle fibers within the defect of the muscle-derived stem cell-enriched collagen scaffold group only. However, appreciable confocal colocalization of myosin heavy chain with green fluorescent protein expression was low. CONCLUSIONS The results of this study indicate that muscle-derived stem cell-enriched scaffolds significantly improved skeletal muscle regeneration in a murine muscle defect model. Based on the low fluorescent colocalization, host progenitor cells appear to contribute significantly to intradefect myogenesis, suggesting that deployment of a viable muscle-derived stem cell-enriched scaffold stimulates a regenerative mitogen response in native tissues.
Collapse
|
|
40
|
Teng S, Huang P. The effect of type 2 diabetes mellitus and obesity on muscle progenitor cell function. Stem Cell Res Ther 2019; 10:103. [PMID: 30898146 PMCID: PMC6427880 DOI: 10.1186/s13287-019-1186-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
In addition to its primary function to provide movement and maintain posture, the skeletal muscle plays important roles in energy and glucose metabolism. In healthy humans, skeletal muscle is the major site for postprandial glucose uptake and impairment of this process contributes to the pathogenesis of type 2 diabetes mellitus (T2DM). A key component to the maintenance of skeletal muscle integrity and plasticity is the presence of muscle progenitor cells, including satellite cells, fibroadipogenic progenitors, and some interstitial progenitor cells associated with vessels (myo-endothelial cells, pericytes, and mesoangioblasts). In this review, we aim to discuss the emerging concepts related to these progenitor cells, focusing on the identification and characterization of distinct progenitor cell populations, and the impact of obesity and T2DM on these cells. The recent advances in stem cell therapies by targeting diabetic and obese muscle are also discussed.
Collapse
Affiliation(s)
- Shuzhi Teng
- The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130021, People's Republic of China.
| | - Ping Huang
- The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130021, People's Republic of China.
| |
Collapse
|
|
41
|
Isolation and characterization of myogenic precursor cells from human cremaster muscle. Sci Rep 2019; 9:3454. [PMID: 30837559 PMCID: PMC6401155 DOI: 10.1038/s41598-019-40042-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 01/30/2019] [Indexed: 12/19/2022] Open
Abstract
Human myogenic precursor cells have been isolated and expanded from a number of skeletal muscles, but alternative donor biopsy sites must be sought after in diseases where muscle damage is widespread. Biopsy sites must be relatively accessible, and the biopsied muscle dispensable. Here, we aimed to histologically characterize the cremaster muscle with regard number of satellite cells and regenerative fibres, and to isolate and characterize human cremaster muscle-derived stem/precursor cells in adult male donors with the objective of characterizing this muscle as a novel source of myogenic precursor cells. Cremaster muscle biopsies (or adjacent non-muscle tissue for negative controls; N = 19) were taken from male patients undergoing routine surgery for urogenital pathology. Myosphere cultures were derived and tested for their in vitro and in vivo myogenic differentiation and muscle regeneration capacities. Cremaster-derived myogenic precursor cells were maintained by myosphere culture and efficiently differentiated to myotubes in adhesion culture. Upon transplantation to an immunocompromised mouse model of cardiotoxin-induced acute muscle damage, human cremaster-derived myogenic precursor cells survived to the transplants and contributed to muscle regeneration. These precursors are a good candidate for cell therapy approaches of skeletal muscle. Due to their location and developmental origin, we propose that they might be best suited for regeneration of the rhabdosphincter in patients undergoing stress urinary incontinence after radical prostatectomy.
Collapse
|
|
42
|
Summerhill V, Orekhov A. Pericytes in Atherosclerosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1147:279-297. [DOI: 10.1007/978-3-030-16908-4_13] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
43
|
Vezzani B, Shaw I, Lesme H, Yong L, Khan N, Tremolada C, Péault B. Higher Pericyte Content and Secretory Activity of Microfragmented Human Adipose Tissue Compared to Enzymatically Derived Stromal Vascular Fraction. Stem Cells Transl Med 2018; 7:876-886. [PMID: 30255987 PMCID: PMC6265639 DOI: 10.1002/sctm.18-0051] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/19/2018] [Indexed: 12/14/2022] Open
Abstract
Autologous adipose tissue is used for tissue repletion and/or regeneration as an intact lipoaspirate or as enzymatically derived stromal vascular fraction (SVF), which may be first cultured into mesenchymal stem cells (MSCs). Alternatively, transplant of autologous adipose tissue mechanically fragmented into submillimeter clusters has recently showed remarkable efficacy in diverse therapeutic indications. To document the biologic basis of the regenerative potential of microfragmented adipose tissue, we first analyzed the distribution of perivascular presumptive MSCs in adipose tissue processed with the Lipogems technology, observing a significant enrichment in pericytes, at the expense of adventitial cells, as compared to isogenic enzymatically processed lipoaspirates. The importance of MSCs as trophic and immunomodulatory cells, due to the secretion of specific factors, has been described. Therefore, we investigated protein secretion by cultured adipose tissue clusters or enzymatically derived SVF using secretome arrays. In culture, microfragmented adipose tissue releases many more growth factors and cytokines involved in tissue repair and regeneration, noticeably via angiogenesis, compared to isogenic SVF. Therefore, we suggest that the efficient tissue repair/regeneration observed after transplantation of microfragmented adipose tissue is due to the secretory ability of the intact perivascular niche. Stem Cells Translational Medicine 2018;7:876-886.
Collapse
Affiliation(s)
- Bianca Vezzani
- MRC Center for Regenerative MedicineUniversity of EdinburghEdinburghUnited Kingdom
| | - Isaac Shaw
- MRC Center for Regenerative MedicineUniversity of EdinburghEdinburghUnited Kingdom
| | - Hanna Lesme
- MRC Center for Regenerative MedicineUniversity of EdinburghEdinburghUnited Kingdom
| | - Li Yong
- MRC Center for Regenerative MedicineUniversity of EdinburghEdinburghUnited Kingdom
| | - Nusrat Khan
- MRC Center for Regenerative MedicineUniversity of EdinburghEdinburghUnited Kingdom
| | | | - Bruno Péault
- MRC Center for Regenerative MedicineUniversity of EdinburghEdinburghUnited Kingdom
- Orthopaedic Hospital Research Center and Broad Stem Cell Research CenterDavid Geffen School of Medicine, University of CaliforniaLos AngelesCaliforniaUSA
| |
Collapse
|
|
44
|
Xu Z, Yu L, Lu H, Feng W, Chen L, Zhou J, Yang X, Qi Z. A modified preplate technique for efficient isolation and proliferation of mice muscle-derived stem cells. Cytotechnology 2018; 70:1671-1683. [PMID: 30417280 DOI: 10.1007/s10616-018-0262-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 09/24/2018] [Indexed: 12/24/2022] Open
Abstract
We modified an existing protocol to develop a more efficient method to acquire and culture muscle-derived stem cells (MDSCs) and compared the characteristics of cells obtained from the two methods. This method is based on currently used multistep enzymatic digestion and preplate technique. During the replating process, we replaced the traditional medium with isolation medium to promote fibroblast-like cell adherence at initial replating step, which shortened the purifying duration by up to 4 days. Moreover, we modified the culture container to provide a stable microenvironment that promotes MDSC adherence. We compared the cell morphology, growth curve and the expression of specific markers (Sca-1, CD34, PAX7 and Desmin) between the two cell groups separately obtained from the two methods. Afterwards, we compared the neural differentiation capacity of MDSCs with other muscle-derived cell lineages. The protocol developed here is a fast and effective method to harvest and purify MDSCs from mice limb skeletal muscle.
Collapse
Affiliation(s)
- Zhuqiu Xu
- Chinese Academy of Medical Science, Peking Union Medical College, Plastic Surgery Hospital, Beijing, 100041, China
| | - Lu Yu
- Chinese Academy of Medical Science, Peking Union Medical College, Plastic Surgery Hospital, Beijing, 100041, China
| | - Haibin Lu
- Chinese Academy of Medical Science, Peking Union Medical College, Plastic Surgery Hospital, Beijing, 100041, China
| | - Weifeng Feng
- Chinese Academy of Medical Science, Peking Union Medical College, Plastic Surgery Hospital, Beijing, 100041, China
| | - Lulu Chen
- Chinese Academy of Medical Science, Peking Union Medical College, Plastic Surgery Hospital, Beijing, 100041, China
| | - Jing Zhou
- Chinese Academy of Medical Science, Peking Union Medical College, Plastic Surgery Hospital, Beijing, 100041, China
| | - Xiaonan Yang
- Chinese Academy of Medical Science, Peking Union Medical College, Plastic Surgery Hospital, Beijing, 100041, China.
| | - Zuoliang Qi
- Chinese Academy of Medical Science, Peking Union Medical College, Plastic Surgery Hospital, Beijing, 100041, China.
| |
Collapse
|
|
45
|
Wosczyna MN, Rando TA. A Muscle Stem Cell Support Group: Coordinated Cellular Responses in Muscle Regeneration. Dev Cell 2018; 46:135-143. [PMID: 30016618 PMCID: PMC6075730 DOI: 10.1016/j.devcel.2018.06.018] [Citation(s) in RCA: 202] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 06/12/2018] [Accepted: 06/20/2018] [Indexed: 01/11/2023]
Abstract
Skeletal muscle has an extraordinary regenerative capacity due to the activity of tissue-specific muscle stem cells. Consequently, these cells have received the most attention in studies investigating the cellular processes of skeletal muscle regeneration. However, efficient capacity to rebuild this tissue also depends on additional cells in the local milieu, as disrupting their normal contributions often leads to incomplete regeneration. Here, we review these additional cells that contribute to the regenerative process. Understanding the complex interactions between and among these cell populations has the potential to lead to therapies that will help promote normal skeletal muscle regeneration under conditions in which this process is suboptimal.
Collapse
Affiliation(s)
- Michael N Wosczyna
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Thomas A Rando
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Tissue Regeneration, Repair and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
| |
Collapse
|
|
46
|
Valencia AP, Lai JK, Iyer SR, Mistretta KL, Spangenburg EE, Davis DL, Lovering RM, Gilotra MN. Fatty Infiltration Is a Prognostic Marker of Muscle Function After Rotator Cuff Tear. Am J Sports Med 2018; 46:2161-2169. [PMID: 29750541 PMCID: PMC6397750 DOI: 10.1177/0363546518769267] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Massive rotator cuff tears (RCTs) begin as primary tendon injuries and cause a myriad of changes in the muscle, including atrophy, fatty infiltration (FI), and fibrosis. However, it is unclear which changes are most closely associated with muscle function. PURPOSE To determine if FI of the supraspinatus muscle after acute RCT relates to short-term changes in muscle function. STUDY DESIGN Controlled laboratory study. METHODS Unilateral RCTs were induced in female rabbits via tenotomy of the supraspinatus and infraspinatus. Maximal isometric force and rate of fatigue were measured in the supraspinatus in vivo at 6 and 12 weeks after tenotomy. Computed tomography scanning was performed, followed by histologic analysis of myofiber size, FI, and fibrosis. RESULTS Tenotomy resulted in supraspinatus weakness, reduced myofiber size, FI, and fibrosis, but no differences were evident between 6 and 12 weeks after tenotomy except for increased collagen content at 12 weeks. FI was a predictor of supraspinatus weakness and was strongly correlated to force, even after accounting for muscle cross-sectional area. While muscle atrophy accounted for the loss in force in tenotomized muscles with minimal FI, it did not account for the greater loss in force in tenotomized muscles with the most FI. Collagen content was not strongly correlated with maximal isometric force, even when normalized to muscle size. CONCLUSION After RCT, muscle atrophy results in the loss of contractile force from the supraspinatus, but exacerbated weakness is observed with increased FI. Therefore, the level of FI can help predict contractile function of torn rotator cuff muscles. CLINICAL RELEVANCE Markers to predict contractile function of RCTs will help determine the appropriate treatment to improve functional recovery after RCTs.
Collapse
Affiliation(s)
- Ana P. Valencia
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, Maryland, USA
- Department of Kinesiology, School of Public Health, University of Maryland, Baltimore, Maryland, USA
| | - Jim K. Lai
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Shama R. Iyer
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Katherine L. Mistretta
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Espen E. Spangenburg
- Department of Physiology, East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA
| | - Derik L. Davis
- Department of Diagnostic Radiology and Nuclear Medicine, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Richard M. Lovering
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, Maryland, USA
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Mohit N. Gilotra
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, Maryland, USA
- Department of Orthopaedics, Baltimore Veteran Affairs Medical Center, Baltimore, Maryland, USA
- Address correspondence to Mohit N. Gilotra, MD, Department of Orthopaedics, School of Medicine and VA Maryland Health Care System, University of Maryland, AHB, Rm 540, 100 Penn St, Baltimore, MD 21201, USA ()
| | | |
Collapse
|
|
47
|
Meng J, Muntoni F, Morgan J. CD133+ cells derived from skeletal muscles of Duchenne muscular dystrophy patients have a compromised myogenic and muscle regenerative capability. Stem Cell Res 2018; 30:43-52. [PMID: 29783100 PMCID: PMC6048760 DOI: 10.1016/j.scr.2018.05.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 05/03/2018] [Accepted: 05/10/2018] [Indexed: 01/01/2023] Open
Abstract
Cell-mediated gene therapy is a possible means to treat muscular dystrophies like Duchenne muscular dystrophy. Autologous patient stem cells can be genetically-corrected and transplanted back into the patient, without causing immunorejection problems. Regenerated muscle fibres derived from these cells will express the missing dystrophin protein, thus improving muscle function. CD133+ cells derived from normal human skeletal muscle contribute to regenerated muscle fibres and form muscle stem cells after their intra-muscular transplantation into an immunodeficient mouse model. But it is not known whether CD133+ cells derived from DMD patient muscles have compromised muscle regenerative function. To test this, we compared CD133+ cells derived from DMD and normal human muscles. DMD CD133+ cells had a reduced capacity to undergo myogenic differentiation in vitro compared with CD133+ cells derived from normal muscle. In contrast to CD133+ cells derived from normal human muscle, those derived from DMD muscle formed no satellite cells and gave rise to significantly fewer muscle fibres of donor origin, after their intra-muscular transplantation into an immunodeficient, non-dystrophic, mouse muscle. DMD CD133+ cells gave rise to more clones of smaller size and more clones that were less myogenic than did CD133+ cells derived from normal muscle. The heterogeneity of the progeny of CD133+ cells, combined with the reduced proliferation and myogenicity of DMD compared to normal CD133+ cells, may explain the reduced regenerative capacity of DMD CD133+ cells.
The myogenicity of CD133+ cells from Duchenne muscular dystrophy skeletal muscle is compromised. Duchenne muscular dystrophy CD133+ cells regenerate skeletal muscle less than normal CD133+ cells. Skeletal muscle-derived CD133+ cells consist of myoblasts, pericytes and fibroblasts.
Collapse
Affiliation(s)
- Jinhong Meng
- Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neuroscience Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, 30 Guilford Street, London WC1N 1EH, UK
| | - Francesco Muntoni
- Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neuroscience Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, 30 Guilford Street, London WC1N 1EH, UK
| | - Jennifer Morgan
- Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neuroscience Programme, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, 30 Guilford Street, London WC1N 1EH, UK.
| |
Collapse
|
|
48
|
Tang Z, Li X, Tan Y, Fan H, Zhang X. The material and biological characteristics of osteoinductive calcium phosphate ceramics. Regen Biomater 2018; 5:43-59. [PMID: 29423267 PMCID: PMC5798025 DOI: 10.1093/rb/rbx024] [Citation(s) in RCA: 157] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 07/16/2017] [Accepted: 07/20/2017] [Indexed: 12/14/2022] Open
Abstract
The discovery of osteoinductivity of calcium phosphate (Ca-P) ceramics has set an enduring paradigm of conferring biological regenerative activity to materials with carefully designed structural characteristics. The unique phase composition and porous structural features of osteoinductive Ca-P ceramics allow it to interact with signaling molecules and extracellular matrices in the host system, creating a local environment conducive to new bone formation. Mounting evidence now indicate that the osteoinductive activity of Ca-P ceramics is linked to their physicochemical and three-dimensional structural properties. Inspired by this conceptual breakthrough, many laboratories have shown that other materials can be also enticed to join the rank of tissue-inducing biomaterials, and besides the bones, other tissues such as cartilage, nerves and blood vessels were also regenerated with the assistance of biomaterials. Here, we give a brief historical recount about the discovery of the osteoinductivity of Ca-P ceramics, summarize the underlying material factors and biological characteristics, and discuss the mechanism of osteoinduction concerning protein adsorption, and the interaction with different types of cells, and the involvement of the vascular and immune systems.
Collapse
Affiliation(s)
- Zhurong Tang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, P.R. China
| | - Xiangfeng Li
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, P.R. China
| | - Yanfei Tan
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, P.R. China
| | - Hongsong Fan
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, P.R. China
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, P.R. China
| |
Collapse
|
|
49
|
Persichini T, Funari A, Colasanti M, Sacchetti B. Clonogenic, myogenic progenitors expressing MCAM/CD146 are incorporated as adventitial reticular cells in the microvascular compartment of human post-natal skeletal muscle. PLoS One 2017; 12:e0188844. [PMID: 29186180 PMCID: PMC5706678 DOI: 10.1371/journal.pone.0188844] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 11/14/2017] [Indexed: 12/13/2022] Open
Abstract
Recent observation identifies subendothelial (mural) cells expressing MCAM, a specific system of clonogenic, self-renewing, osteoprogenitors (a.k.a, "mesenchymal stem cells") in the microvascular compartment of post-natal human bone marrow (BM). In this study, we used MCAM/CD146, as a marker to localize, isolate and assay subendothelial clonogenic cells from the microvasculature of postnatal human skeletal muscle. We show here that these cells share with their BM counterpart, anatomic position (subendothelial/adventitial) and ex vivo clonogenicity (CFU-Fs). When assayed under the stringent conditions, these cells display a high spontaneous myogenic potential (independent of co-culture with myoblasts or of in vivo fusion with local myoblasts), which is otherwise only attained in cultures of satellite cells. These muscle-derived mural cells activated a myogenic program in culture. Cultured CD146+ cells expressed the myogenic factors (Pax7, Pax3 and Myf5), NCAM/CD56, desmin as well as proteins characteristic of more advanced myogenic differentiation, such as myosin heavy chain. In vivo, these cells spontaneously generate myotubes and myofibrils. These data identify the anatomy and phenotype of a novel class of committed myogenic progenitor in human post-natal skeletal muscle of subendothelial cells associated with the abluminal surface of microvascular compartment distinct from satellite cells.
Collapse
Affiliation(s)
| | - Alessia Funari
- Department of Molecular Medicine, University “Sapienza”, Rome, Italy
| | | | - Benedetto Sacchetti
- Department of Science, University ROMA TRE, Rome, Italy
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| |
Collapse
|
|
50
|
Lorant J, Saury C, Schleder C, Robriquet F, Lieubeau B, Négroni E, Leroux I, Chabrand L, Viau S, Babarit C, Ledevin M, Dubreil L, Hamel A, Magot A, Thorin C, Guevel L, Delorme B, Péréon Y, Butler-Browne G, Mouly V, Rouger K. Skeletal Muscle Regenerative Potential of Human MuStem Cells following Transplantation into Injured Mice Muscle. Mol Ther 2017; 26:618-633. [PMID: 29221805 DOI: 10.1016/j.ymthe.2017.10.013] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 10/15/2017] [Accepted: 10/18/2017] [Indexed: 01/18/2023] Open
Abstract
After intra-arterial delivery in the dystrophic dog, allogeneic muscle-derived stem cells, termed MuStem cells, contribute to long-term stabilization of the clinical status and preservation of the muscle regenerative process. However, it remains unknown whether the human counterpart could be identified, considering recent demonstrations of divergent features between species for several somatic stem cells. Here, we report that MuStem cells reside in human skeletal muscle and display a long-term ability to proliferate, allowing generation of a clinically relevant amount of cells. Cultured human MuStem (hMuStem) cells do not express hematopoietic, endothelial, or myo-endothelial cell markers and reproducibly correspond to a population of early myogenic-committed progenitors with a perivascular/mesenchymal phenotypic signature, revealing a blood vessel wall origin. Importantly, they exhibit both myogenesis in vitro and skeletal muscle regeneration after intramuscular delivery into immunodeficient host mice. Together, our findings provide new insights supporting the notion that hMuStem cells could represent an interesting therapeutic candidate for dystrophic patients.
Collapse
Affiliation(s)
- Judith Lorant
- PAnTher, INRA, École Nationale Vétérinaire, Agro-alimentaire et de l'alimentation Nantes-Atlantique (Oniris), Université Bretagne Loire (UBL), Nantes 44307, France
| | - Charlotte Saury
- PAnTher, INRA, École Nationale Vétérinaire, Agro-alimentaire et de l'alimentation Nantes-Atlantique (Oniris), Université Bretagne Loire (UBL), Nantes 44307, France; Macopharma, Biotherapy Division, Mouvaux, 59420, France
| | - Cindy Schleder
- PAnTher, INRA, École Nationale Vétérinaire, Agro-alimentaire et de l'alimentation Nantes-Atlantique (Oniris), Université Bretagne Loire (UBL), Nantes 44307, France
| | - Florence Robriquet
- PAnTher, INRA, École Nationale Vétérinaire, Agro-alimentaire et de l'alimentation Nantes-Atlantique (Oniris), Université Bretagne Loire (UBL), Nantes 44307, France; Université de Nantes, UBL, Nantes, France
| | | | - Elisa Négroni
- Institut de Myologie, Sorbonne Universités, UPMC Université Paris 06, INSERM, CNRS, Paris 75013, France
| | - Isabelle Leroux
- PAnTher, INRA, École Nationale Vétérinaire, Agro-alimentaire et de l'alimentation Nantes-Atlantique (Oniris), Université Bretagne Loire (UBL), Nantes 44307, France
| | | | - Sabrina Viau
- Macopharma, Biotherapy Division, Mouvaux, 59420, France
| | - Candice Babarit
- PAnTher, INRA, École Nationale Vétérinaire, Agro-alimentaire et de l'alimentation Nantes-Atlantique (Oniris), Université Bretagne Loire (UBL), Nantes 44307, France
| | - Mireille Ledevin
- PAnTher, INRA, École Nationale Vétérinaire, Agro-alimentaire et de l'alimentation Nantes-Atlantique (Oniris), Université Bretagne Loire (UBL), Nantes 44307, France
| | - Laurence Dubreil
- PAnTher, INRA, École Nationale Vétérinaire, Agro-alimentaire et de l'alimentation Nantes-Atlantique (Oniris), Université Bretagne Loire (UBL), Nantes 44307, France
| | - Antoine Hamel
- Service de Chirurgie Infantile, Centre Hospitalier Universitaire (CHU), Nantes 44093, France
| | - Armelle Magot
- Centre de Référence des maladies neuromusculaires Nantes-Angers, Service des Explorations Fonctionnelles, CHU, Nantes 44093, France
| | - Chantal Thorin
- Laboratoire de Physiopathologie Animale et Pharmacologie fonctionnelle, Oniris, Nantes 44307, France
| | - Laëtitia Guevel
- PAnTher, INRA, École Nationale Vétérinaire, Agro-alimentaire et de l'alimentation Nantes-Atlantique (Oniris), Université Bretagne Loire (UBL), Nantes 44307, France; Université de Nantes, UBL, Nantes, France
| | - Bruno Delorme
- Macopharma, Biotherapy Division, Mouvaux, 59420, France
| | - Yann Péréon
- Centre de Référence des maladies neuromusculaires Nantes-Angers, Service des Explorations Fonctionnelles, CHU, Nantes 44093, France
| | - Gillian Butler-Browne
- Institut de Myologie, Sorbonne Universités, UPMC Université Paris 06, INSERM, CNRS, Paris 75013, France
| | - Vincent Mouly
- Institut de Myologie, Sorbonne Universités, UPMC Université Paris 06, INSERM, CNRS, Paris 75013, France
| | - Karl Rouger
- PAnTher, INRA, École Nationale Vétérinaire, Agro-alimentaire et de l'alimentation Nantes-Atlantique (Oniris), Université Bretagne Loire (UBL), Nantes 44307, France.
| |
Collapse
|