Muscle stem cell activation in a mouse model of rotator cuff injury

Davies, M.R.Q.; Garcia, Steven; Tamaki, Stanley; Liu, Xuhui; Lee, Solomon; Jose, Anthony; Pomerantz, Jason H.

doi:10.1002/jor.23679

Cited by 14 publications

(17 citation statements)

References 23 publications

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“…46,48 In animal models of RC injury, these cells have been found to be present as well, as identified by the marker PDGFRα/β, and were shown to expand after RC injury and co-localize to fat deposits within the muscle. 6,9,50 Inhibition of TGF-β resulted in a decrease in FI because of FAP cell apoptosis, confirming the importance of these FAP cells in FI. 7 Conditional cellular depletion of FAPs has been shown to decrease FI in animal models, further supporting the role of these cells in the development of FI.…”

Section: Discussionmentioning

confidence: 71%

“…32 It has recently been determined that this cell line expands after RC injury, that it co-localizes to fat deposits within the muscle, and that outcomes of RC injury and repair are dependent on FAP presence in a small-animal model. 6,50 Despite the correlation of FAPs with the development of FI, it does not suggest that the presence of FAPs is entirely deleterious. Recently, FAPs have been demonstrated to possess the capacity to transition to a beige fat phenotype both within RC tissue and in other muscle injury models.…”

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confidence: 97%

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confidence: 99%

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Human Rotator Cuff Tears Have an Endogenous, Inducible Stem Cell Source Capable of Improving Muscle Quality and Function After Rotator Cuff Repair

et al. 2020

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Background: The muscle quality of the rotator cuff (RC), measured by atrophy and fatty infiltration (FI), is a key determinant of outcomes in RC injury and repair. The ability to regenerate muscle after repair has been shown to be limited. Purpose: To determine if there is a source of resident endogenous stem cells, fibroadipogenic progenitor cells (FAPs), within RC injury patients, and if these cells are capable of adipogenic, fibrogenic, and pro-myogenic differentiation. Study Design: Controlled laboratory study. Methods: A total of 20 patients between the ages of 40 and 75 years with partial- or full-thickness RC tears of the supraspinatus and evidence of atrophy and FI Goutallier grade 1, 2, or 3 were selected from 2 surgeons at an orthopaedic center. During the surgical repair procedure, supraspinatus muscle biopsy specimens were obtained for analysis as were deltoid muscle biopsy specimens to serve as the control. FAPs and satellite cells were quantified using fluorescence-activated cell sorting. Muscle FI and fibrosis was quantified using Oil Red O and Masson trichrome staining. FAP differentiation and gene expression profiles were compared across tear sizes after culture in adipogenic, fibrogenic, and beta-3 agonist (amibegron) conditions. Analysis of variance was used for statistical comparisons between groups, with P < .05 as statistically significant. Results: Histologic analysis confirmed the presence of fat in biopsy specimens from patients with full-thickness tears. There were more FAPs in the full-thickness tear group compared with the partial-thickness tear group (9.43% ± 4.25% vs 3.84% ± 2.54%; P < .01). Full-thickness tears were divided by tear size, with patients with larger tears having significantly more FAPs than those with smaller tears. FAPs from muscles with full-thickness tendon tears had more adipogenic and fibrogenic potential than those with partial tears. Induction of a beige adipose tissue (BAT) phenotype in FAPs was possible, as demonstrated by increased expression of BAT markers and pro-myogenic genes including insulin-like growth factor 1 and follistatin. Conclusion: Endogenous FAPs are present within the RC and likely are the source of FI. These FAPs were increased in muscles with in larger tears but are capable of adopting a pro-myogenic BAT phenotype that could be utilized to improve muscle quality and patient function after RC repair.

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Section: Discussionmentioning

confidence: 71%

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Human Rotator Cuff Tears Have an Endogenous, Inducible Stem Cell Source Capable of Improving Muscle Quality and Function After Rotator Cuff Repair

et al. 2020

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“…S atellite cells are activated after a rotator cuff tear in mice, and their biological activity is thought to play an important role in pathological changes in rotator cuff disease 28 . Meyer and colleagues found that cells from patients with partial-thickness tears had reduced proliferative capacity in vitro, but no difference in fusion, when compared with cells from untorn rotator cuff muscles and full-thickness tears 29 .…”

Section: Discussionmentioning

confidence: 99%

Reduced Myogenic and Increased Adipogenic Differentiation Capacity of Rotator Cuff Muscle Stem Cells

Schubert

Noah

Bedi

et al. 2019

The Journal of Bone and Joint Surgery

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Background: Fat accumulation commonly occurs in chronically torn rotator cuff muscles, and increased fat within the rotator cuff is correlated with poor clinical outcomes. The extent of lipid deposition is particularly pronounced in injured rotator cuff muscles compared with other commonly injured muscles such as the gastrocnemius. Satellite cells, which are a tissue-resident muscle stem-cell population, can differentiate into fat cells. We hypothesized that satellite cells from the rotator cuff have greater intrinsic adipogenic differentiation potential than do gastrocnemius satellite cells, and this difference is due to variations in epigenetic imprinting between the cells. Methods: Satellite cells from gastrocnemius and rotator cuff muscles of mice were cultured in adipogenic media, and the capacity to differentiate into mature muscle cells and adipogenic cells was assessed (n ‡ 9 plates per muscle group). We also performed DNA methylation analysis of gastrocnemius and rotator cuff satellite cells to determine whether epigenetic differences were present between the 2 groups (n = 5 mice per group). Results: Compared with the gastrocnemius, satellite cells from the rotator cuff had a 23% reduction in myogenic differentiation and an 87% decrease in the expression of the differentiated muscle cell marker MRF4 (myogenic regulatory factor 4). With respect to adipogenesis, rotator cuff satellite cells had a 4.3-fold increase in adipogenesis, a 12-fold increase in the adipogenic transcription factor PPARg (peroxisome proliferator-activated receptor gamma), and a 65-fold increase in the adipogenic marker FABP4 (fatty-acid binding protein 4). Epigenetic analysis identified 355 differentially methylated regions of DNA between rotator cuff and gastrocnemius satellite cells, and pathway enrichment analysis suggested that these regions were involved with lipid metabolism and adipogenesis. Conclusions: Satellite cells from rotator cuff muscles have reduced myogenic and increased adipogenic differentiation potential compared with gastrocnemius muscles. There appears to be a cellular and genetic basis behind the generally poor rates of rotator cuff muscle healing. Clinical Relevance: The reduced myogenic and increased adipogenic capacity of rotator cuff satellite cells is consistent with the increased fat content and poor muscle healing rates often observed for chronically torn rotator cuff muscles. For patients undergoing rotator cuff repair, transplantation of autologous satellite cells from other muscles less prone to fatty infiltration may improve clinical outcomes. R otator cuff tears are a common upper-extremity disorder, with >250,000 surgical repairs performed annually in the U.S. 1. Achieving positive clinical outcomes following repair can be limited by fatty infiltration or myosteatosis, which is the combined atrophy, fibrosis, and fat accumulation within and around myofibers 2-4. The relative amount of fat in torn rotator cuff muscles is often greater than in other injured muscle groups 5-7 , and many patients devel...

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“…A study using electron microscope exhibited that satellite cells are uniformly distributed throughout the whole muscle. 34 Davies et al 35 reported transient activation of muscle stem cell in the murine rotator cuff muscles after tendon transection. They, however, did not examine the distribution of stem cells in the muscle.…”

Section: Discussionmentioning

confidence: 99%

Fatty degeneration and wnt10b expression in the supraspinatus muscle after surgical repair of torn rotator cuff tendon

Kuwahara

Kishimoto

Itoigawa

et al. 2019

J Orthop Surg (Hong Kong)

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Purpose: In the torn rotator cuff muscles, decreased expression of wnt10b prior to elevation of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα) has previously been reported. The purpose of this study is to elucidate the expression profiles of these adipogenesis-related genes after rotator cuff detachment and reattachment in a rabbit model. Methods: We investigated gene expression profiles of PPARγ, C/EBPα, and wnt10b in different parts of rabbit supraspinatus (SSP) muscle after tendon detachment ( n = 6 for each time point). In addition, we assessed expression of the same genes after SSP reattachment with different intervals from initial detachment ( n = 6). Fatty degeneration of the SSP muscle was examined by Oil red-O staining. Gene expression profiles were examined by quantitative real-time polymerase chain reaction. Results: After SSP detachment, Oil red-O-positive oil deposits increased after 3 weeks. In the SSP reattachment model, numerous Oil red-O-positive cells were present at 5-week reattachment, following 2- and 3-week detachment. PPARγ and C/EBPα messenger ribonucleic acid expression exhibited a significant increase at 2 and 3 weeks after SSP detachment and remained increased at 5-week reattachment after 2- and 3-week detachment. A decreased expression of wnt10b was observed from 1 week after SSP detachment. Expression of wnt10b was recovered not in the central area of the SSP muscle but in the periphery after reattachment. Adipogenic change was not observed when SSP tendon was reattached after 1-week detachment. Conclusions: These results may suggest that once the adipogenic transcription factors, PPARγ and C/EBPα, were elevated, repair surgery after rotator cuff tear could not prevent the emergence of fat in the SSP muscle.

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Muscle stem cell activation in a mouse model of rotator cuff injury

Cited by 14 publications

References 23 publications

Human Rotator Cuff Tears Have an Endogenous, Inducible Stem Cell Source Capable of Improving Muscle Quality and Function After Rotator Cuff Repair

Human Rotator Cuff Tears Have an Endogenous, Inducible Stem Cell Source Capable of Improving Muscle Quality and Function After Rotator Cuff Repair

Reduced Myogenic and Increased Adipogenic Differentiation Capacity of Rotator Cuff Muscle Stem Cells

Fatty degeneration and wnt10b expression in the supraspinatus muscle after surgical repair of torn rotator cuff tendon

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