Abstract
Hematopoietic stem cells (HSC) are primarily dormant in a cell-cycle quiescence state to preserve their self-renewal capacity and long-term maintenance. How HSC maintain the balance between activation and quiescence remains largely unknown. Herein, we found that phosphatase, Mg2+/Mn2+ dependent 1B (Ppm1b) is required for the expansion of phenotypic HSC in vitro. By using a conditional knockout mouse model in which Ppm1b was specifically depleted in hematopoietic cells, we demonstrated that loss of Ppm1b impaired the HSC homeostasis and hematopoietic reconstitution. Ppm1b deficiency mice also exhibited B-cell leukocytopenia, which is due to the compromised commitment and proliferation of B-biased lymphoid progenitor cells from common lymphoid progenitors. With the aid of a small molecular inhibitor, we confirmed the roles of Ppm1b in adult hematopoiesis that phenocopied the effects with loss of Ppm1b. Furthermore, transcriptome profiling of Ppm1b-deficient HSC revealed the disruptive quiescence of HSC. Mechanistically, Ppm1b interacted with β-catenin and mediated its dephosphorylation. Loss of Ppm1b led to the decrease in the active β-catenin (non-phosphorylated) that interrupted the Wnt/β-catenin signaling in HSC, which consequently suppressed HSC expansion. Together, our study identified an indispensable role for Ppm1b in regulating HSC homeostasis via the Wnt/β-catenin pathway.