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Adipose Stromal Cells in the Human Rotator Cuff are Resistant to Fibrotic Microenvironmental Cues

ABSTRACT: Rotator cuff tears are the most common upper extremity orthopaedic injury, causing degenerative changes within the bone, tendon, joint capsule, bursa, and muscle. These degenerative changes are linked to poor rehabilitative and surgical outcomes, which has launched investigations into co-therapeutic biologics. Specifically, Mesenchymal Stem Cells (MSCs) have shown promise in mitigating degenerative changes in animal models of RC tears, however reports of their impact on clinical outcomes remain mixed. Here we describe an alternative source of MSCs in the human shoulder, adipose stromal cells (ASCs) from the subacromial fat (SAF) pad. Compared to the gold-standard subcutaneous (SQ) fat, we show that SAF ASCs are less sensitive to chemical and mechanical fibrotic cues, 1) retaining smaller cell area with reduced actin stress fiber alignment across a range of physiological and pathological stiffnesses, 2) reduced traction forces and ECM production and 3) reduced myofibroblastic conversion in response to cytokine challenge. Furthermore, we show that SAF ASCs enhance fusion of primary human myoblasts via paracrine signaling. Despite a fibrotic signature in SAF from rotator cuffs with tendon tears, SAF ASCs sourced from torn rotator cuffs were equally effective at resisting fibroblastic conversion and promoting myogenesis as those from intact rotator cuffs, further supporting autologous clinical use of these cells. In conclusion, this study describes human SAF ASCs as an alternative, and potentially superior, cell source for rotator cuff therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293949 | GEO | 2026/04/03

REPOSITORIES: GEO

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	GSE293949_Gene_Counts_Organized.xlsx	Xlsx

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Project description:Objective To identify transcript level differences between traumatic and degenerative tears of tendon tissues in shoulder joint using RNA-seq. Methods Tendon tissues were isolated from female and male patients with traumatic or degenerative tears during arthroscopic surgery (N = 31). Differentially expressed transcript were identified and biological processes enriched in traumatic and degenerative tears were probed computationally. Expression pattern of selected transcripts was validated by real-time qPCR. Results We identified 339 and 336 transcripts differentially expressed between traumatic and degenerative tears in females and males respectively at a fold-change greater than |2| and a p-value  0.05. In females, GSTM1, MT1G, S1008A, ACSM3, DSC, FAM110C and VNN2 were the most prominent transcripts elevated in traumatic tears and CHAD, CLEC3A, IBSP, TNMD, APLNR, and CPA3 were most highly repressed in traumatic tears. Transcripts elevated in traumatic tears represented catabolic processes, immune response, and metabolic processes while those repressed in traumatic tears represented tissue morphogenesis and developmental processes, angiogenesis, and extracellular matrix organization. In males, ELOA3B, CXCL8, ADM, TNS4 and SPOCK1 were the most prominent transcripts elevated in traumatic tears and MYL2, TNNC1, MB, CPA3, APLNR, and CA3 were most highly repressed in traumatic tears. Transcripts elevated in traumatic tears represented localization of endoplasmic reticulum, chromosome organization, leukocyte/neutrophil degranulation, and protein transport whereas those repressed in traumatic tears represented muscle development, blood circulation (angiogenesis), and muscle cell differentiation. Numerous novel lncRNAs were also identified to be differentially expressed between traumatic and degenerative tears in both sexes. Conclusions and Clinical Relevance This study improves our molecular understanding of tendon tissues in patients with rotator cuff tendinopathy based on underlying etiology (trauma and degeneration). It also provides new insights into sex-based transcript differences that may help drive clinical decision making in female and male patients with traumatic and degenerative shoulder injuries.

Project description:Objective: To identify transcript level differences between traumatic and degenerative tears of subacromial bursal tissues in shoulder joint using RNA-seq. Methods: Bursal tissues were collected from female and male patients with traumatic or degenerative tears during arthroscopic surgery (N=32). Differentially expressed transcript between traumatic and degenerative tears were detected by RNA-seq and biological processes were identified computationally. RNA-seq results were selectively validated by real-time qPCR. Results: We identified 334 protein-coding transcripts differentially expressed between traumatic and degenerative tears in females and 167 in males at a fold-change greater than |2| and a P < 0.05. In females, XIRP2, MYL1, MYBPC1, TNNT1, and LMOD2, were the highly expressed in traumatic tears and TPSD1, CDSN, RCVRN, LTBP4, and PTGS1 were prominently repressed in traumatic tears. Transcripts elevated in traumatic tears represented muscle cell differentiation and development, and muscle contraction whereas those elevated in degenerative tears represented cell activation, neutrophil granulation, immune response, and protein transport. In males, AZGP1, CNTFR, COL9A1, ZNF98 and EREG were highly elevated in traumatic tears whereas MYL2, HOXD11, SLC6A7, CADM1, and MMP17 were most highly repressed in traumatic tears. Transcripts elevated in traumatic tears represented metabolic processes, catabolic processes, and transmembrane protein transport while processes related to cell cycle were mainly repressed in traumatic tears. We also identified a number of novel lncRNAs differentially expressed between traumatic and degenerative tears in both females and males. Conclusions: This study increases our molecular understanding of bursal tissues in patients with rotator cuff tendinopathy based on the nature of disease that is trauma or degeneration. These finding also provide new insights into sex-based transcript differences that could inform clinical decision making in treating patients with traumatic and degenerative shoulder injuries.

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Adipose Stromal Cells in the Human Rotator Cuff are Resistant to Fibrotic Microenvironmental Cues

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