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.
Type
Journal articleSubject
AnimalsCells, Cultured
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Humans
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred NOD
Neuropeptides
Receptor-Like Protein Tyrosine Phosphatases, Class 2
Transendothelial and Transepithelial Migration
rac1 GTP-Binding Protein
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https://hdl.handle.net/10161/14160Published Version (Please cite this version)
10.1172/JCI77866Publication Info
Quarmyne, Mamle; Doan, Phuong L; Himburg, Heather A; Yan, Xiao; Nakamura, Mai; Zhao,
Liman; ... Chute, John P (2015). Protein tyrosine phosphatase-σ regulates hematopoietic stem cell-repopulating capacity.
J Clin Invest, 125(1). pp. 177-182. 10.1172/JCI77866. Retrieved from https://hdl.handle.net/10161/14160.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Nelson Jen An Chao
Donald D. and Elizabeth G. Cooke Cancer Distinguished 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
Phuong Linh Doan
Associate Professor of Medicine
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