Identification of ALPPL2 as a Naive Pluripotent State-Specific Surface Protein Essential for Human Naive Pluripotency Regulation

Human naive pluripotent stem cells established from the epiblasts of preimplantation blastocysts provide a useful model for mechanistic studies of pluripotency regulation and lineage differentiation. Important advances have been made to optimize culture conditions and define molecular criteria for naive pluripotency. However, the identity of naive-specific surface markers and the underlying molecular mechanism of naive pluripotency regulation remain poorly understood. Here, we identify alkaline phosphatase placental-like 2 (ALPPL2) as a prominent naive-specific surface marker by systematic proteomic and transcriptomic analyses. Furthermore, we demonstrate that ALPPL2 is essential for both the establishment and maintenance of naive pluripotency. Moreover, we show that ALPPL2 can interact with the RNA-binding protein IGF2BP1 to stabilize the mRNA levels of the naive pluripotency transcription factors TFCP2L1 and STAT3 to regulate naive pluripotency. Overall, our study identifies a functional surface marker for human naive pluripotency, providing a powerful tool for human-naive-pluripotency-related mechanistic studies.