Progesterone Receptor Membrane Component 1 suppresses the p53 and Wnt/β-catenin pathways to promote human pluripotent stem cell self-renewal.

Progesterone receptor membrane component 1 (PGRMC1) is a multifunctional heme-binding protein involved in various diseases, including cancers and Alzheimer's disease. Previously, we generated two monoclonal antibodies (MAbs) 108-B6 and 4A68 against surface molecules on human pluripotent stem cells (hPSCs). Here we show that PGRMC1 is the target antigen of both MAbs, and is predominantly expressed on hPSCs and some cancer cells. PGRMC1 is rapidly downregulated during early differentiation of hPSCs. Although PGRMC1 knockdown leads to a spread-out morphology and impaired self-renewal in hPSCs, PGRMC1 knockdown hPSCs do not show apoptosis and autophagy. Instead, PGRMC1 knockdown leads to differentiation of hPSCs into multiple lineage cells without affecting the expression of pluripotency markers. PGRMC1 knockdown increases cyclin D1 expression and decreases Plk1 expression in hPSCs. PGRMC1 knockdown also induces p53 expression and stability, suggesting that PGRMC1 maintains hPSC self-renewal through suppression of p53-dependent pathway. Analysis of signaling molecules further reveals that PGRMC1 knockdown promotes inhibitory phosphorylation of GSK-3β and increased expression of Wnt3a and β-catenin, which leads to activation of Wnt/β-catenin signaling. The results suggest that PGRMC1 suppresses the p53 and Wnt/β-catenin pathways to promote self-renewal and inhibit early differentiation in hPSCs.