Protein tyrosine phosphatase-σ regulates hematopoietic stem cell-repopulating capacity.
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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.
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred NOD
Receptor-Like Protein Tyrosine Phosphatases, Class 2
Transendothelial and Transepithelial Migration
rac1 GTP-Binding Protein
Published Version (Please cite this version)10.1172/JCI77866
Publication InfoChao, Nelson J; Chute, JP; Doan, Phuong Linh; Himburg, Heather; Nakamura, M; Quarmyne, M; ... Zhao, L (2015). Protein tyrosine phosphatase-σ regulates hematopoietic stem cell-repopulating capacity. J Clin Invest, 125(1). pp. 177-182. 10.1172/JCI77866. Retrieved from http://hdl.handle.net/10161/14160.
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Donald D. and Elizabeth G. Cooke Cancer Research Professor
My research interests are in two broad areas, clinical hematopoietic stem cell and cord blood transplantation and in the laboratory studies related to graft vs. host disease and immune reconstitution. On the clinical side we are currently conducting approximately 50 different clinical protocols ranging from preparatory regimens, supportive care studies and disease specific protocols. Most of these clinical studies are centered around studies of the sources of stem cells and the methods to
Assistant Professor of Medicine
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