Shp-2 heterozygous hematopoietic stem cells have deficient repopulating ability due to diminished self-renewal
Shp-2 heterozygous hematopoietic stem cells have deficient repopulating ability due to diminished self-renewal
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DOI：
10.1016/j.exphem.2006.04.017
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发表时间：
2006-09-01
影响因子：
2.6
通讯作者：
Yoder, Mervin C.
中科院分区：
文献类型：
--
作者：
Chan, Rebecca J.;Li, Yanjun;Yoder, Mervin C.
Objective.寻求对造血干细胞（HSC）分化、增殖和自我更新的更好理解，以开发改进的基于干细胞的疗法以及定义用于基于干细胞的疾病如白血病的新疗法。Shp-2是一种广泛表达的非受体蛋白酪氨酸磷酸酶，参与造血发育的早期。本研究旨在检测Shp-2在HSC功能中的作用。从WT和Shp-2（+/-）同窝对照中分离骨髓低密度单核细胞，并用于竞争性再增殖研究、归巢分析、细胞周期分析和系列移植研究。Shp-2的单倍不足导致移植到致死性照射受者后HSC再增殖单位减少三倍。Shp-2（+/-）和WT细胞向骨髓和脾隔室的归巢相同。细胞周期分析研究显示，Shp-2（+/-）lin（-）Sca-1（+）c-kit（+）细胞比WT细胞更不静止，这为观察到的Shp-2（+/-）细胞植入减少提供了潜在病因。与此一致，在系列移植研究中，我们观察到与WT细胞相比，Shp-2（+/-）自我更新显著减少。这些数据表明，Shp-2是所需的HSC隔室的生理稳态，并可能提供洞察致癌的Shp-2如何可能有助于骨髓增生性疾病和白血病的发病机制。(c)2006年国际实验血液学学会。爱思唯尔公司出版
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-l(+)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. (c) 2006 International Society for Experimental Hematology. Published by Elsevier Inc.