Protein tyrosine phosphatase-σ regulates hematopoietic stem cell-repopulating capacity

Hematopoietic stem cell (HSC) function is regulated by activation of receptor tyrosine kinases (RTI(s). Receptor protein tyrosine phosphatases (PTPs) counterbalance RTK signaling; however, the functions of receptor PTPs in HSCs remain incompletely understood. We found that a receptor PTP, PTP sigma, was substantially overexpressed in mouse and human HSCs compared with more mature hematopoietic cells. Competitive transplantation of bone marrow cells from PTP sigma-deficient mice revealed that the loss of PTP sigma substantially increased long-term HSC-repopulating capacity compared with BM cells from control mice. While HSCs from PTP sigma-deficient mice had no apparent alterations in cell-cycle status, apoptosis, or homing capacity, these HSCs exhibited increased levels of activated RAC1, a RhoGTPase that regulates HSC engraftment capacity. shRNA-mediated silencing of PTP sigma also increased activated RAC1 levels in wild-type HSCs. Functionally, PTP sigma-deficient BM cells displayed increased cobblestone area-forming cell (CAFE) capacity and augmented transendothelial migration capacity, which was abrogated by RAC inhibition. Specific selection of human cord blood CD34(+)CD38(-)CD45RA(-)lin(-) PTP sigma(-) cells substantially increased the repopulating capacity of human HSCs compared with CD34+CD38-CD45RA-lin- cells and CD34(+)CD38(-)CD45RA(-)lin(-)PTP sigma(+) cells. Our results demonstrate that PTP sigma regulates HSC functional capacity via RAC1 inhibition and suggest that selecting for PTP sigma-negative human HSCs may be an effective strategy for enriching human HSCs for transplantation.