Adipogenic differentiation was inhibited by downregulation of PPARγ signaling pathway in aging tendon stem/progenitor cells

Abstract

Background Tendon stem/progenitor cells (TSPCs) play a vital role in tendon repair and regeneration. Previously we found more adipocytes accumulated in the patellar tendon injury sites in aging rats compared with the young ones, of which the mechanism is still unknown. Here, we want to identify whether erroneous differentiation of TSPCs by aging accounts for the adipocyte accumulation. Methods TSPCs from young and aging rats were isolated and propagated. Both young and aging TSPCs were induced to differentiate into adipocytes, and Oil red O staining, quantitative real-time polymerase chain reaction (qRT-PCR), western-blot and immunofluorescent staining were used to evaluate the capability of TSPCs. RNA sequencing was utilized to screen out different genes and signaling pathways related to adipogenesis between young and aging TSPCs. Results The Oil red O staining showed there were more adipocytes formed in young TSPCs. Besides, adipogenic markers perilipin, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding proteins alpha (C/EBPα) and Fatty acid-binding protein 4 (FABP4) were elevated both at gene and protein level. PPARγ signaling pathway was selected as our target via RNA sequencing. After adding the signaling activators, Rosiglitazone maleate (RM), inhibited adipogenesis of aging TSCs was reversed. Conclusions In conclusion, aging inhibited adipogenesis of TSPCs by down‐regulating PPARγ signaling. It is not likely that the adipocyte accumulation in aging tendon during repair was due to the aging of TSPCs. This may provide new targets for curing aging tendon injuries or tendinopathies.

Global research trends and hotspots on tendon-derived stem cell: a bibliometric visualization study

“…Long noncoding RNA MEG3 inhibits the osteogenic differentiation potential of TDSCs through the miR-129-5p/transcription factor 4 (TCF4)/β-Catenin axis, thus reducing ectopic ossification caused by trauma in tendon tissue ( Liu et al, 2023b ). Vascular endothelial growth factor (VEGF) and PPAR gamma can also suppress adipogenic differentiation of TDSCs, presenting them as promising therapeutic targets for tendon degeneration ( Lai et al, 2021 ; Lai et al, 2022 ). The recruitment and accumulation of endogenous TDSCs at the site of tendon injury initiate their participation in the repair process.…”

The Functions and Mechanisms of Tendon Stem/Progenitor Cells in Tendon Healing

“…In addition to this, A-TSPCs express higher levels of CD44 compared to Y-TSPCs, suggesting a poorer healing capacity of the injured tissue. By contrast, Lai et al [ 105 ] showed that the patellar tendon adipose accumulation in aged rats was not due to A-TSPC, but due to inhibition of PPAR γ signaling pathway by aging, thereby preventing adipogenesis in TSPCs. To verify the adipogenic capacity of senescent TSPCs, they were tested in vitro for oil red O staining, and the number of fat droplets in senescent TSPCs was found to be significantly reduced.…”

Caveolin-1 is involved in fatty infiltration and bone-tendon healing of rotator cuff tear

“…The cAMP/PKA pathway has been involved in the regulation of adipogenic differentiation of tendon stem cells (TSCs) by IGF-1 and BMP-2 (Liu et al 2014). TSCs are derived from tendon tissues and are the endogenous cell source for tenocyte turnover and tendon functional maintenance, playing a vital role in tendon repair and regeneration (Shi et al 2017;Lai et al 2021). We therefore hypothesized that GATA6 could affect the fatty infiltration and bone-tendon healing after RCT via regulation of the Caveolin-1/cAMP/ PKA axis.…”