Stem cell dysfunction and failure have been found in joints afflicted by osteoarthritis (OA). However, the exact factors in the OA microenvironment that impair stem cell functions and the role of stem cell dysfunction in OA development have not been fully clarified. In this study, we evaluated the functional status of synovial mesenchymal stem cells (SMSCs) from OA patients and explored the influence of OA-SMSCs on cartilage degradation in a rat model. We then screened 138 Wnt signaling-related genes in the synovium of OA patients, focusing on the effects of five WNT ligands on SMSC functions. The OA synovium showed mild hyperplasia, and we found a large number of CD90 + /CD105 + stem cells in synovial hyperplasia. The OA-SMSCs revealed a cellular senescence phenotype, with decreased proliferation and chondrogenic capacity, accompanied by enhanced migration, proinflammatory and matrix degradation activities. The intra-articular transplantation of these OA-SMSCs significantly aggravated the degradation and destruction of the articular cartilage. Of 138 Wnt signaling genes, the expression of 86 genes was consistently altered in the OA synovium, among which the increased expression of DVL2, WNT10A, and DKK3 was the most marked. In general, we found that canonical Wnt/b-catenin pathways were inhibited in the OA synovium, whereas noncanonical PCP and Wnt/Ca2 + pathways were activated. In vitro, WNT10A had an obvious antisenescence effect on SMSCs. WNT5B significantly inhibited the chondrogenic differentiation of SMSCs, and WNT10A and WNT5A increased the expression of inflammatory cytokines in SMSCs. In a rat model, WNT5A significantly aggravated joint degeneration, whereas WNT10A had a mild protective effect on cartilage integrity. In conclusion, stem cells in the OA synovium were functionally abnormal and promoted the development of OA, whereas dysregulation of the Wnt signaling pathway revealed a comprehensive influence on SMSC functions and cartilage degradation.

No abstract

Background: Fatty infiltration (FI) of the rotator cuff muscles is correlated with shoulder function and retear rates after rotator cuff repair. High-intensity interval training (HIIT) induces beige adipose tissue to express more uncoupling protein 1 (UCP1) to consume lipids. The beta-3 adrenergic receptor (β3AR) is located on adipocyte membrane and induces thermogenesis. Purpose: To test the role of HIIT in improving muscle quality and contractility in a delayed rotator cuff repair mouse model via β3AR. Study Design: Controlled laboratory study. Methods: Three-month-old C57BL/6J mice underwent a unilateral supraspinatus (SS) tendon transection with a 6-week delayed tendon repair. Mice ran on a treadmill with the HIIT program for 6 weeks after tendon transection or after delayed repair. To study the role of β3AR, SR59230A, a selective β3AR antagonist, was administered to mice 10 minutes before each exercise through intraperitoneal injection. The SS, interscapular brown adipose tissue (iBAT), and subcutaneous inguinal white adipose tissue (ingWAT) were harvested at the end of the 12th week after tendon transection and were analyzed by histology and Western blotting. Tests were performed to assess muscle contractility of the SS. Results: Histologic analysis of SS showed that HIIT prevented and reversed muscle atrophy and FI. The contractile tests showed higher contractility of the SS in the HIIT groups than in the no-exercise group. In the HIIT groups, SS, iBAT, and ingWAT all showed increased expression of tyrosine hydroxylase, UCP1, and upregulated β3AR thermogenesis pathway. However, SR59230A inhibited HIIT, suggesting that the effect of HIIT depends on β3AR. Conclusion: HIIT improved SS quality and function after delayed rotator cuff repair through a β3AR-dependent mechanism. Clinical Relevance: HIIT may serve as a new rehabilitation method for patients with rotator cuff muscle atrophy and FI after rotator cuff repair to improve postoperative clinical outcomes.

IntroductionPromoting muscle regeneration through stem cell therapy has potential risks. We investigated the effect of umbilical cord mesenchymal stem cells (UMSCs) Exosomes (Exo) Follistatin on muscle regeneration.Material and methodsThe Exo was derived from UMSCs cells and was utilized to affect the mice muscle injury model and C2C12 cells myotubes atrophy model. The western blot, qRT-PCR and IF were utilized to determine the effects of Exo on the levels of Follistatin, MyHC, MyoD, Myostatin, MuRF1, MAFbx, α-SMA, Collagen I, Smad2, and AKT. In addition, HE and Masson staining were used to assess muscle tissue damage in mice.ResultsThe level of Follistatin in Exo was significantly higher than that in UMSCs. UMSCs-Exo increased the levels of Follistatin, MyHC, MyoD, and p-Smad2 and decreased the levels of Myostatin, MuRF1, MAFbx, α-SMA, Collagen I, p-AKT, and p-mTOR in mice or C2C12 cells. In addition, UMSCs-Exo decreased levels of inflammation and fibrosis in mice. However, UMSCs-Exo-si-Follistatin reversed the effect of UMSCs-Exo. Transfection of oe-Smad2 up-regulated the protein levels of Collagen I, α-SMA, and changed the ratio of p-Smad2/Smad2 expression to 0.33, and 0.34, 0.73. LY294002 decreased the levels of MyHC, MyoD, and the ratio of p-AKT/ AKT and p-mTOR/mTOR expression to 0.12, 0.17, 0.33, and 0.41, increased the levels of MuRF1 and MAFbx to 0.36 and 0.34.ConclusionsThis study demonstrated that Follistatin in UMSCs-Exo inhibits fibrosis and promotes muscle regeneration in mice by regulating Smad and AKT signaling.