Shp-2 heterozygous hematopoietic stem cells have deficient repopulating ability due to diminished self-renewal

Rebecca J. Chan, Yanjun Li, Meredith N. Hass, Amanda Walter, Cara S. Voorhorst, W. Chris Shelley, Zhenyun Yang, Christie M. Orschell, Mervin C. Yoder

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19 Scopus citations

Abstract

Objective: Improved understanding of hematopoietic stem cell (HSC) differentiation, proliferation, and self-renewal is sought to develop improved stem cell-based therapies as well as to define novel therapies for stem cell-based diseases such as leukemia. Shp-2 is a widely expressed nonreceptor protein tyrosine phosphatase that participates early in hematopoietic development. The following study was performed to examine the role of Shp-2 in HSC function. Methods: Bone marrow low-density mononuclear cells were isolated from WT and Shp-2+/- littermate controls and utilized in competitive repopulation studies, homing analysis, cell-cycle analysis, and serial transplantation studies. Results: Haploinsufficiency of Shp-2 causes a threefold reduction in HSC repopulating units following transplantation into lethally irradiated recipients. Homing of Shp-2+/- and WT cells to the bone marrow and spleen compartments was equal. Cell-cycle analysis studies revealed that the Shp-2+/- lin-Sca-1+c-kit+ cells are less quiescent than WT cells, providing a potential etiology for the observed reduced engraftment of the Shp-2+/- cells. Consistently, in serial transplantation studies, we observed a significant reduction of Shp-2+/- self-renewal compared to that of WT cells. Conclusion: These data demonstrate that Shp-2 is required for the physiologic homeostasis of the HSC compartment and potentially provide insight into how oncogenic Shp-2 may contribute to the pathogenesis of myeloproliferative disorders and leukemias.

Original languageEnglish (US)
Pages (from-to)1229-1238
Number of pages10
JournalExperimental Hematology
Volume34
Issue number9
DOIs
StatePublished - Sep 2006

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ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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