TET1 regulates self-renewal of porcine skin-derived stem cells through TGF-β signaling pathway

Skin-derived stem cells (SDSCs) are a subtype of adult stem cells (ASCs). How to improve the self-renewal ability of stem cells has been a focus of recent research. However, the underlying self-renewal mechanism of SDSCs remains to be fully understood. Here, this study investigates the mechanism by which TET1 functions in the self-renewal of porcine SDSCs (pSDSCs). The results showed that the self-renewal capacity of pSDSCs gradually enhanced and the expression level of TET1 significantly increased during in vitro culture. Additionally, the self-renewal capacity of pSDSCs was inhibited after silencing TET1 by small interfering RNA (siRNA). RNA-seq analysis revealed that TET1 knockdown significantly inhibited the transforming growth factor-β (TGF-β) signaling pathway. Detailed analysis of key molecules in the TGF-β signaling pathway indicated that TET1 knockdown reduced the protein levels of TGF-β1, phosphorylated SMAD2 (p-SMAD2), and phosphorylated SMAD3 (p-SMAD3). SRI-011381, activated the TGF-β/SMAD pathway, saving the self-renewal defect caused by TET1 knockdown. Treating pSDSCs with LY2109761, a TGF-β signaling inhibitor, produced a phenotype similar to TET1 knockdown. This work identified that TET1 was a critical regulatory factor that plays a key role in maintaining pSDSCs self-renewal through the TGF-β signaling pathway. Unlike previous studies that primarily emphasized the epigenetic role of TET1, this study reveals its functional link to a signaling pathway. These findings provide a deeper understanding of SDSCs and suggest that targeting the TET1-TGF-β axis may represent a promising approach to enhance the self-renewal capacity of SDSCs.