title: Protein tyrosine phosphatase-σ regulates hematopoietic stem cell-repopulating capacity.
abstract: 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, PTPσ, was substantially overexpressed in mouse and human HSCs compared with more mature hematopoietic cells. Competitive transplantation of bone marrow cells from PTPσ-deficient mice revealed that the loss of PTPσ substantially increased long-term HSC-repopulating capacity compared with BM cells from control mice. While HSCs from PTPσ-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 PTPσ also increased activated RAC1 levels in wild-type HSCs. Functionally, PTPσ-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⁻ PTPσ⁻ cells substantially increased the repopulating capacity of human HSCs compared with CD34⁺CD38⁻CD45RA⁻lin⁻ cells and CD34⁺CD38⁻CD45RA⁻lin⁻PTPσ⁺ cells. Our results demonstrate that PTPσ regulates HSC functional capacity via RAC1 inhibition and suggest that selecting for PTPσ-negative human HSCs may be an effective strategy for enriching human HSCs for transplantation.
authors.forename: Mamle
authors.initials: M
authors.lastname: Quarmyne
authors.forename: Phuong L
authors.initials: PL
authors.lastname: Doan
authors.forename: Heather A
authors.initials: HA
authors.lastname: Himburg
authors.forename: Xiao
authors.initials: X
authors.lastname: Yan
authors.forename: Mai
authors.initials: M
authors.lastname: Nakamura
authors.forename: Liman
authors.initials: L
authors.lastname: Zhao
authors.forename: Nelson J
authors.initials: NJ
authors.lastname: Chao
authors.forename: John P
authors.initials: JP
authors.lastname: Chute
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000201:enzymology*; D006801:Humans; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009479:Neuropeptides / Q000378:metabolism; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000502:physiology*; D057705:Transendothelial and Transepithelial Migration; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D009479:Neuropeptides; C484602:Rac1 protein, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D020830:rac1 GTP-Binding Protein