Phosphatase, Mg2+/Mn2+ Dependent 1B (Ppm1b) regulates the self-renewal of HSCs through the Wnt/ß-catenin pathway [scRNA-Seq]

Hematopoietic stem cells (HSCs) have unique abilities to renew themselves and generate differentiated progenies of all blood cell lineages; however, how HSCs maintain the balance of self-renewal and lineage differentiation remains largely unknown. Herein, we showed that in mice the hematologic system deletion of Phosphatase, Mg2+/Mn2+ Dependent 1B (Ppm1b), a protein serine or threonine phosphatase highly expressed in HSCs, induces the suppression of phenotypic HSC expansion due to the blockage of cell cycle. Loss of Ppm1b impairs HSC self-renewal and hematopoietic reconstitution which were revealed by limiting dilution and BM transplantation assays. Through transcriptomic analysis, we observed that the Wnt/ß-catenin pathway is downregulated in Ppm1b-deficient mice. Mechanistically, we provided evidence that Ppm1b interacted with ß-catenin by performing a proximity ligation assay. Moreover, using an HN252 as a small molecule probe, we further found that Ppm1b inhibition suppressed the self-renewal of HSC and led to a decrease in common lymphoid progenitor cells, resulting in a reduction of B cells in the bone marrow and peripheral blood in turn. In the study we characterized an indispensable role of Ppm1b in regulating HSC self-renewal and B cell development via Wnt/ß-catenin pathway. Overall design: Single cell- and bulk RNA-seq were performed on Ppm1bCKO and Ppm1bfl/fl mouse Lsk cells isolated from the BM.