ESRG maintains human pluripotent stem cell self-renewal by binding NPM1 to regulate BMP4 protein and TGF-β signaling pathway

Human pluripotent stem cells (hPSCs) present considerable potential for regenerative medicine; however, their clinical application is hindered by an incomplete understanding of the molecular mechanisms governing self-renewal. The long non-coding RNA ESRG is integral to maintaining hPSC self-renewal, with its depletion leading to reduced levels of nucleophosmin 1 (NPM1) protein, thereby compromising the self-renewal capacity of hPSCs. Mechanistically, ESRG physically interacts with NPM1, and a reduction in ESRG/NPM1 expression results in elevated bone morphogenetic protein 4 (BMP4) levels and decreased polypyrimidine tract-binding protein 1 (PTBP1) levels, which subsequently suppress TGF-β signaling by destabilizing TGF-β1 mRNA. Notably, treatment with the TGF-β activator SRI-011381 partially mitigates the self-renewal defects induced by ESRG or NPM1 downregulation. Collectively, our findings elucidate that the ESRG/NPM1/BMP4/PTBP1/TGF-β axis precisely regulates hPSC self-renewal. This study enhances the understanding of the molecular regulatory network underlying hPSC self-renewal maintenance and identifies ESRG as a potential target for optimizing hPSC in vitro expansion, thereby advancing the field of regenerative medicine.