| First Author | Quarmyne M | Year | 2015 |
| Journal | J Clin Invest | Volume | 125 |
| Issue | 1 | Pages | 177-82 |
| PubMed ID | 25415437 | Mgi Jnum | J:219369 |
| Mgi Id | MGI:5620567 | Doi | 10.1172/JCI77866 |
| Citation | Quarmyne M, et al. (2015) Protein tyrosine phosphatase-sigma regulates hematopoietic stem cell-repopulating capacity. J Clin Invest 125(1):177-82 |
| abstractText | Hematopoietic stem cell (HSC) function is regulated by activation of receptor tyrosine kinases (RTKs). 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, PTPsigma, was substantially overexpressed in mouse and human HSCs compared with more mature hematopoietic cells. Competitive transplantation of bone marrow cells from PTPsigma-deficient mice revealed that the loss of PTPsigma substantially increased long-term HSC-repopulating capacity compared with BM cells from control mice. While HSCs from PTPsigma-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 PTPsigma also increased activated RAC1 levels in wild-type HSCs. Functionally, PTPsigma-deficient BM cells displayed increased cobblestone area-forming cell (CAFC) capacity and augmented transendothelial migration capacity, which was abrogated by RAC inhibition. Specific selection of human cord blood CD34(+)CD38(-)CD45RA(-)lin(-) PTPsigma(-) cells substantially increased the repopulating capacity of human HSCs compared with CD34(+)CD38(-)CD45RA(-)lin(-) cells and CD34(+)CD38(-)CD45RA(-)lin(-)PTPsigma(+) cells. Our results demonstrate that PTPsigma regulates HSC functional capacity via RAC1 inhibition and suggest that selecting for PTPsigma-negative human HSCs may be an effective strategy for enriching human HSCs for transplantation. |
