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Xu Y, Zhang WX, Wang LN, Ming YQ, Li YL, Ni GX. Stem cell therapies in tendon-bone healing. World J Stem Cells 2021; 13:753-775. [PMID: 34367476 PMCID: PMC8316867 DOI: 10.4252/wjsc.v13.i7.753] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/08/2021] [Accepted: 06/23/2021] [Indexed: 02/06/2023] Open
Abstract
Tendon-bone insertion injuries such as rotator cuff and anterior cruciate ligament injuries are currently highly common and severe. The key method of treating this kind of injury is the reconstruction operation. The success of this reconstructive process depends on the ability of the graft to incorporate into the bone. Recently, there has been substantial discussion about how to enhance the integration of tendon and bone through biological methods. Stem cells like bone marrow mesenchymal stem cells (MSCs), tendon stem/progenitor cells, synovium-derived MSCs, adipose-derived stem cells, or periosteum-derived periosteal stem cells can self-regenerate and potentially differentiate into different cell types, which have been widely used in tissue repair and regeneration. Thus, we concentrate in this review on the current circumstances of tendon-bone healing using stem cell therapy.
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Affiliation(s)
- Yue Xu
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Wan-Xia Zhang
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Li-Na Wang
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Yue-Qing Ming
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Yu-Lin Li
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Guo-Xin Ni
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China.
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3D Bioprinting of Human Adipose-Derived Stem Cells and Their Tenogenic Differentiation in Clinical-Grade Medium. Int J Mol Sci 2020; 21:ijms21228694. [PMID: 33218011 PMCID: PMC7698777 DOI: 10.3390/ijms21228694] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 11/11/2020] [Accepted: 11/13/2020] [Indexed: 12/20/2022] Open
Abstract
Defining the best combination of cells and biomaterials is a key challenge for the development of tendon tissue engineering (TE) strategies. Adipose-derived stem cells (ASCs) are ideal candidates for this purpose. In addition, controlled cell-based products adherent to good manufacturing practice (GMP) are required for their clinical scale-up. With this aim, in this study, ASC 3D bioprinting and GMP-compliant tenogenic differentiation were investigated. In detail, primary human ASCs were embedded within a nanofibrillar-cellulose/alginate bioink and 3D-bioprinted into multi-layered square-grid matrices. Bioink viscoelastic properties and scaffold ultrastructural morphology were analyzed by rheology and scanning electron microscopy (SEM). The optimal cell concentration for printing among 3, 6 and 9 × 106 ASC/mL was evaluated in terms of cell viability. ASC morphology was characterized by SEM and F-actin immunostaining. Tenogenic differentiation ability was then evaluated in terms of cell viability, morphology and expression of scleraxis and collagen type III by biochemical induction using BMP-12, TGF-β3, CTGF and ascorbic acid supplementation (TENO). Pro-inflammatory cytokine release was also assessed. Bioprinted ASCs showed high viability and survival and exhibited a tenocyte-like phenotype after biochemical induction, with no inflammatory response to the bioink. In conclusion, we report a first proof of concept for the clinical scale-up of ASC 3D bioprinting for tendon TE.
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Jankowski M, Dompe C, Sibiak R, Wąsiatycz G, Mozdziak P, Jaśkowski JM, Antosik P, Kempisty B, Dyszkiewicz-Konwińska M. In Vitro Cultures of Adipose-Derived Stem Cells: An Overview of Methods, Molecular Analyses, and Clinical Applications. Cells 2020; 9:cells9081783. [PMID: 32726947 PMCID: PMC7463427 DOI: 10.3390/cells9081783] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 07/23/2020] [Accepted: 07/24/2020] [Indexed: 02/06/2023] Open
Abstract
Adipose-derived stem cells (ASCs) exhibiting mesenchymal stem cell (MSC) characteristics, have been extensively studied in recent years. Because they have been shown to differentiate into lineages such as osteogenic, chondrogenic, neurogenic or myogenic, the focus of most of the current research concerns either their potential to replace bone marrow as a readily available and abundant source of MSCs, or to employ them in regenerative and reconstructive medicine. There is close to consensus regarding the methodology used for ASC isolation and culture, whereas a number of molecular analyses implicates them in potential therapies of a number of pathologies. When it comes to clinical application, there is a range of examples of animal trials and clinical studies employing ASCs, further emphasizing the advancement of studies leading to their more widespread use. Nevertheless, in vitro studies will most likely continue to play a significant role in ASC studies, both providing the molecular knowledge of their ex vivo properties and possibly serving as an important step in purification and application of those cells in a clinical setting. Therefore, it is important to consider current methods of ASC isolation, culture, and processing. Furthermore, molecular analyses and cell surface properties of ASCs are essential for animal studies, clinical studies, and therapeutic applications of the MSC properties.
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Affiliation(s)
- Maurycy Jankowski
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (R.S.); (M.D.-K.)
| | - Claudia Dompe
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
- The School of Medicine, Medical Sciences and Nutrition, Aberdeen University, Aberdeen AB25 2ZD, UK
| | - Rafał Sibiak
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (R.S.); (M.D.-K.)
| | - Grzegorz Wąsiatycz
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Toruń, Poland; (G.W.); (P.A.)
| | - Paul Mozdziak
- Physiology Graduate Program, North Carolina State University, Raleigh, NC 27695, USA;
| | - Jędrzej M. Jaśkowski
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Toruń, Poland;
| | - Paweł Antosik
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Toruń, Poland; (G.W.); (P.A.)
| | - Bartosz Kempisty
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (R.S.); (M.D.-K.)
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Toruń, Poland; (G.W.); (P.A.)
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 20 Jihlavská St., 601 77 Brno, Czech Republic
- Correspondence:
| | - Marta Dyszkiewicz-Konwińska
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (M.J.); (R.S.); (M.D.-K.)
- Department of Biomaterials and Experimental Dentistry, Poznan University of Medical Sciences, 60-812 Poznan, Poland
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Rak Kwon D, Jung S, Jang J, Park GY, Suk Moon Y, Lee SC. A 3-Dimensional Bioprinted Scaffold With Human Umbilical Cord Blood-Mesenchymal Stem Cells Improves Regeneration of Chronic Full-Thickness Rotator Cuff Tear in a Rabbit Model. Am J Sports Med 2020; 48:947-958. [PMID: 32167836 DOI: 10.1177/0363546520904022] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Chronic full-thickness rotator cuff tears (FTRCTs) represent a major clinical concern because they show highly compromised healing capacity. PURPOSE To evaluate the efficacy of using a 3-dimensional (3D) bioprinted scaffold with human umbilical cord blood (hUCB)-mesenchymal stem cells (MSCs) for regeneration of chronic FTRCTs in a rabbit model. STUDY DESIGN Controlled laboratory study. METHODS A total of 32 rabbits were randomly assigned to 4 treatment groups (n = 8 per group) at 6 weeks after a 5-mm FTRCT was created on the supraspinatus tendon. Group 1 (G1-SAL) was transplanted with normal saline. Group 2 (G2-MSC) was transplanted with hUCB-MSCs (0.2 mL, 1 × 106) into FTRCTs. Group 3 (G3-3D) was transplanted with a 3D bioprinted construct without MSCs, and group 4 (G4-3D+MSC) was transplanted with a 3D bioprinted construct containing hUCB-MSCs (0.2 mL, 1 × 106 cells) into FTRCTs. All 32 rabbits were euthanized at 4 weeks after treatment. Examination of gross morphologic changes and histologic results was performed on all rabbits after sacrifice. Motion analysis was also performed before and after treatment. RESULTS In G4-3D+MSC, newly regenerated collagen type 1 fibers, walking distance, fast walking time, and mean walking speed were greater than those in G2-MSC based on histochemical and motion analyses. In addition, when compared with G3-3D, G4-3D+MSC showed more prominent regenerated tendon fibers and better parameters of motion analysis. However, there was no significant difference in gross tear size among G2-MSC, G3-3D, and G4-3D+MSC, although these groups showed significant decreases in tear size as compared with the control group (G1-SAL). CONCLUSION Findings of this study show that a tissue engineering strategy based on a 3D bioprinted scaffold filled with hUCB-MSCs can improve the microenvironment for regenerative processes of FTRCT without any surgical repair. CLINICAL RELEVANCE In the case of rotator cuff tear, the cell loss of the external MSCs can be increased by exposure to synovial fluid. Therefore, a 3D bioprinted scaffold in combination with MSCs without surgical repair may be effective in increasing cell retention in FTRCT.
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Affiliation(s)
- Dong Rak Kwon
- Department of Rehabilitation Medicine, School of Medicine, Catholic University of Daegu, Daegu, Republic of Korea
| | - Seungman Jung
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Republic of Korea
| | - Jinah Jang
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Republic of Korea.,Department of Creative IT Engineering, Pohang University of Science and Technology, Pohang, Republic of Korea.,Department of Mechanical Engineering, Pohang University of Science and Technology, Pohang, Republic of Korea
| | - Gi-Young Park
- Department of Rehabilitation Medicine, School of Medicine, Catholic University of Daegu, Daegu, Republic of Korea
| | - Yong Suk Moon
- Department of Anatomy, School of Medicine, Catholic University of Daegu, Daegu, Republic of Korea
| | - Sang Chul Lee
- Department and Research Institute of Rehabilitation Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea
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Kaizawa Y, Franklin A, Leyden J, Behn AW, Tulu US, Sotelo Leon D, Wang Z, Abrams GD, Chang J, Fox PM. Augmentation of chronic rotator cuff healing using adipose-derived stem cell-seeded human tendon-derived hydrogel. J Orthop Res 2019; 37:877-886. [PMID: 30747435 DOI: 10.1002/jor.24250] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 01/24/2019] [Indexed: 02/04/2023]
Abstract
Rotator cuff (RTC) repair outcomes are unsatisfactory due to the poor healing capacity of the tendon bone interface (TBI). In our preceding study, tendon hydrogel (tHG), which is a type I collagen rich gel derived from human tendons, improved biomechanical properties of the TBI in a rat chronic RTC injury model. Here we investigated whether adipose-derived stem cell (ASC)-seeded tHG injection at the repair site would further improve RTC healing. Rats underwent bilateral supraspinatus tendon detachment. Eight weeks later injured supraspinatus tendons were repaired with one of four treatments. In the control group, standard transosseous suture repair was performed. In the ASC, tHG, tHGASC groups, ASC in media, tHG, and ASC-seeded tHG were injected at repair site after transosseous suture repair, respectively. Eight weeks after repair, the TBI was evaluated biomechanically, histologically, and via micro CT. Implanted ASCs were detected in ASC and tHGASC groups 7 weeks after implantation. ACS implantation improved bone morphometry at the supraspinatus insertion on the humerus. Injection of tHG improved biomechanical properties of the repaired TBI. RTC healing in tHGASC group was significantly better than control but statistically equivalent to the tHG group based on biomechanical properties, fibrocartilage area at the TBI, and bone morphometry at the supraspinatus insertion. In a rat RTC chronic injury model, no biomechanical advantage was gained with ASC augmentation of tHG. Clinical Significance: Tendon hydrogel augmentation with adipose derived stem cells does not significantly improve TBI healing over tHG alone in a chronic rotator cuff injury model. © 2019 Orthopaedic Research Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
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Affiliation(s)
- Yukitoshi Kaizawa
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, 770 Welch Rd., Suite 400, Palo Alto, California, 94304.,Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, California, 94304
| | - Austin Franklin
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, 770 Welch Rd., Suite 400, Palo Alto, California, 94304.,Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, California, 94304
| | - Jacinta Leyden
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, 770 Welch Rd., Suite 400, Palo Alto, California, 94304.,Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, California, 94304
| | - Anthony W Behn
- Department of Orthopaedic Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Palo Alto, California, 94305
| | - Ustun S Tulu
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, 770 Welch Rd., Suite 400, Palo Alto, California, 94304
| | - Daniel Sotelo Leon
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, 770 Welch Rd., Suite 400, Palo Alto, California, 94304.,Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, California, 94304
| | - Zhen Wang
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, 770 Welch Rd., Suite 400, Palo Alto, California, 94304.,Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, California, 94304
| | - Geoffrey D Abrams
- Department of Orthopaedic Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Palo Alto, California, 94305
| | - James Chang
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, 770 Welch Rd., Suite 400, Palo Alto, California, 94304.,Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, California, 94304
| | - Paige M Fox
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, 770 Welch Rd., Suite 400, Palo Alto, California, 94304.,Division of Plastic and Reconstructive Surgery, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, California, 94304
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Stanco D, Caprara C, Ciardelli G, Mariotta L, Gola M, Minonzio G, Soldati G. Tenogenic differentiation protocol in xenogenic-free media enhances tendon-related marker expression in ASCs. PLoS One 2019; 14:e0212192. [PMID: 30753235 PMCID: PMC6372228 DOI: 10.1371/journal.pone.0212192] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 01/29/2019] [Indexed: 12/03/2022] Open
Abstract
Adipose-derived stem cells (ASCs) are multipotent and immune-privileged mesenchymal cells, making them ideal candidates for therapeutic purposes to manage tendon disorders. Providing safe and regulated cell therapy products to patients requires adherence to good manufacturing practices. To this aim we investigated the in vitro tenogenic differentiation potential of ASCs using a chemically defined serum-free medium (SF) or a xenogenic-free human pooled platelet lysate medium (hPL) suitable for cell therapy and both supplemented with CTGF, TGFβ-3, BMP-12 and ascorbic acid (AA) soluble factors. Human ASCs were isolated from 4 healthy donors and they were inducted to differentiate until 14 days in both hPL and SF tenogenic media (hPL-TENO and SF-TENO). Cell viability and immunophenotype profile were analysed to evaluate mesenchymal stem cell (MSC) characteristics in both xenogenic-free media. Moreover, the expression of stemness and tendon-related markers upon cell differentiation by RT-PCR, protein staining and cytofluorimetric analysis were also performed. Our results showed the two xenogenic-free media well support cell viability of ASCs and maintain their MSC nature as demonstrated by their typical immunophenototype profile and by the expression of NANOG, OCT4 and Ki67 genes. Moreover, both hPL-TENO and SF-TENO expressed significant high levels of the tendon-related genes SCX, COL1A1, COL3A1, COMP, MMP3 and MMP13 already at early time points in comparison to the respective controls. Significant up-regulations in scleraxis, collagen and tenomodulin proteins were also demonstrated at in both differentiated SF and hPL ASCs. In conclusion, we demonstrated firstly the feasibility of both serum and xenogenic-free media tested to culture ASCs moving forward the GMP-compliant approaches for clinical scale expansion of human MSCs needed for therapeutical application of stem cells. Moreover, a combination of CTGF, BMP-12, TGFβ3 and AA factors strongly and rapidly induce human ASCs to differentiate into tenocyte-like cells.
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Affiliation(s)
- Deborah Stanco
- Swiss Stem Cell Foundation, Gentilino, Switzerland
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
| | | | - Gianluca Ciardelli
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
| | | | - Mauro Gola
- Swiss Stem Cell Foundation, Gentilino, Switzerland
| | | | - Gianni Soldati
- Swiss Stem Cell Foundation, Gentilino, Switzerland
- * E-mail:
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Lui PPY. Stem cell technology for tendon regeneration: current status, challenges, and future research directions. STEM CELLS AND CLONING-ADVANCES AND APPLICATIONS 2015; 8:163-74. [PMID: 26715856 PMCID: PMC4685888 DOI: 10.2147/sccaa.s60832] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Tendon injuries are a common cause of physical disability. They present a clinical challenge to orthopedic surgeons because injured tendons respond poorly to current treatments without tissue regeneration and the time required for rehabilitation is long. New treatment options are required. Stem cell-based therapies offer great potential to promote tendon regeneration due to their high proliferative, synthetic, and immunomodulatory activities as well as their potential to differentiate to the target cell types and undergo genetic modification. In this review, I first recapped the challenges of tendon repair by reviewing the anatomy of tendon. Next, I discussed the advantages and limitations of using different types of stem cells compared to terminally differentiated cells for tendon tissue engineering. The safety and efficacy of application of stem cells and their modified counterparts for tendon tissue engineering were then summarized after a systematic literature search in PubMed. The challenges and future research directions to enhance, optimize, and standardize stem cell-based therapies for augmenting tendon repair were then discussed.
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Affiliation(s)
- Pauline Po Yee Lui
- Headquarter, Hospital Authority, Hong Kong SAR, People's Republic of China
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Meyer GA, Gibbons MC, Sato E, Lane JG, Ward SR, Engler AJ. Epimuscular Fat in the Human Rotator Cuff Is a Novel Beige Depot. Stem Cells Transl Med 2015; 4:764-74. [PMID: 25999520 PMCID: PMC4479624 DOI: 10.5966/sctm.2014-0287] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 03/30/2015] [Indexed: 02/07/2023] Open
Abstract
UNLABELLED : Chronic rotator cuff (RC) tears are a common and debilitating injury, characterized by dramatic expansion of adipose tissue, muscle atrophy, and limited functional recovery. The role of adipose expansion in RC pathology is unknown; however, given the identified paracrine/endocrine regulation by other adipose depots, it likely affects tissue function outside its boundaries. Therefore, we characterized the epimuscular (EM) fat depot of the human rotator cuff, defined its response to RC tears, and evaluated its influence on myogenesis in vitro. EM fat biopsies exhibited morphological and functional features of human beige fat compared with patient-matched s.c. biopsies, which appeared whiter. The transcriptional profile of EM fat and isolated EM adipose-derived stem cells (ASCs) shifted as a function of the tear state; EM fat from intact cuffs had significantly elevated expression of the genes associated with uncoupled respiration, and the EM fat from torn cuffs had increased expression of beige-selective genes. EM ASC cocultures with human- and mouse-derived myogenic cells exhibited increased levels of myogenesis compared with s.c. cultures. Increased fusion and decreased proliferation of myogenic cells, rather than changes to the ASCs, were found to underlie this effect. Taken together, these data suggest that EM fat in the human rotator cuff is a novel beige adipose depot influenced by cuff state with therapeutic potential for promoting myogenesis in neighboring musculature. SIGNIFICANCE Rotator cuff tears affect millions of people in the U.S.; however, current interventions are hindered by persistent muscle degeneration. This study identifies the therapeutic potential for muscle recovery in the epimuscular fat in the rotator cuff, previously considered a negative feature of the pathology, and finds that this fat is beige, rather than white. This is important for two reasons. First, the stem cells that were isolated from this beige fat are more myogenic than those from white fat, which have been the focus of stem cell-based therapies to date, suggesting epimuscular fat could be a better stem cell source to augment rotator cuff repair. Second, these beige stem cells promote myogenesis in neighboring cells in culture, suggesting the potential for this fat to be manipulated therapeutically to promote muscle recovery through secreted signals.
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Affiliation(s)
- Gretchen A Meyer
- Departments of Bioengineering, Orthopedic Surgery, and Radiology, University of California, San Diego, La Jolla, California, USA; Sanford Consortium for Regenerative Medicine, La Jolla, California, USA
| | - Michael C Gibbons
- Departments of Bioengineering, Orthopedic Surgery, and Radiology, University of California, San Diego, La Jolla, California, USA; Sanford Consortium for Regenerative Medicine, La Jolla, California, USA
| | - Eugene Sato
- Departments of Bioengineering, Orthopedic Surgery, and Radiology, University of California, San Diego, La Jolla, California, USA; Sanford Consortium for Regenerative Medicine, La Jolla, California, USA
| | - John G Lane
- Departments of Bioengineering, Orthopedic Surgery, and Radiology, University of California, San Diego, La Jolla, California, USA; Sanford Consortium for Regenerative Medicine, La Jolla, California, USA
| | - Samuel R Ward
- Departments of Bioengineering, Orthopedic Surgery, and Radiology, University of California, San Diego, La Jolla, California, USA; Sanford Consortium for Regenerative Medicine, La Jolla, California, USA
| | - Adam J Engler
- Departments of Bioengineering, Orthopedic Surgery, and Radiology, University of California, San Diego, La Jolla, California, USA; Sanford Consortium for Regenerative Medicine, La Jolla, California, USA
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