Shp-2 heterozygous hematopoietic stem cells have deficient repopulating ability due to diminished self-renewal

Improved understanding of hematopoietic stem cell (HSC) differentiation, proliferation, and self-renewal is sought to develop improved stem cell–based therapies as well as to define novel therapies for stem cell–based diseases such as leukemia. Shp-2 is a widely expressed nonreceptor protein tyrosine phosphatase that participates early in hematopoietic development. The following study was performed to examine the role of Shp-2 in HSC function. Bone marrow low-density mononuclear cells were isolated from WT and Shp-2 +/− littermate controls and utilized in competitive repopulation studies, homing analysis, cell-cycle analysis, and serial transplantation studies. Haploinsufficiency of Shp-2 causes a threefold reduction in HSC repopulating units following transplantation into lethally irradiated recipients. Homing of Shp-2 +/− and WT cells to the bone marrow and spleen compartments was equal. Cell-cycle analysis studies revealed that the Shp-2 +/− lin −Sca-1 +c-kit + cells are less quiescent than WT cells, providing a potential etiology for the observed reduced engraftment of the Shp-2 +/− cells. Consistently, in serial transplantation studies, we observed a significant reduction of Shp-2 +/− self-renewal compared to that of WT cells. These data demonstrate that Shp-2 is required for the physiologic homeostasis of the HSC compartment and potentially provide insight into how oncogenic Shp-2 may contribute to the pathogenesis of myeloproliferative disorders and leukemias.