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Protein tyrosine phosphatase-I? regulates hematopoietic stem cell-repopulating capacity. J Clin Invest 2015 Jan;125(1):177-82

Date

11/22/2014

Pubmed ID

25415437

Pubmed Central ID

PMC4382260

DOI

10.1172/JCI77866

Scopus ID

2-s2.0-84920461717   18 Citations

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, PTPI?, was substantially overexpressed in mouse and human HSCs compared with more mature hematopoietic cells. Competitive transplantation of bone marrow cells from PTPI?-deficient mice revealed that the loss of PTPI? substantially increased long-term HSC-repopulating capacity compared with BM cells from control mice. While HSCs from PTPI?-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 PTPI? also increased activated RAC1 levels in wild-type HSCs. Functionally, PTPI?-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 CD34a??CD38a?>CD45RAa?>lina?> PTPI?a?> cells substantially increased the repopulating capacity of human HSCs compared with CD34a??CD38a?>CD45RAa?>lina?> cells and CD34a??CD38a?>CD45RAa?>lina?>PTPI?a?? cells. Our results demonstrate that PTPI? regulates HSC functional capacity via RAC1 inhibition and suggest that selecting for PTPI?-negative human HSCs may be an effective strategy for enriching human HSCs for transplantation.

Author List

Quarmyne M, Doan PL, Himburg HA, Yan X, Nakamura M, Zhao L, Chao NJ, Chute JP

Author

Heather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cells, 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