M1 and M2 macrophages differentially regulate hematopoietic stem cell self-renewal and ex vivo expansion
M1 and M2 macrophages differentially regulate hematopoietic stem cell self-renewal and ex vivo expansion
复制标题
DOI：
10.1182/bloodadvances.2018015685
复制
发表时间：
2018-04-24
期刊：
影响因子：
7.5
通讯作者：
Zhou, Daohong
中科院分区：
文献类型：
--
作者：
Luo, Yi;Shao, Lijian;Zhou, Daohong
揭示调控造血干细胞（HSC）自我更新的细胞和分子机制，可以促进HSC体外扩增的新策略的发展。在这里，我们报告的发现，替代（M2）极化的巨噬细胞（M2-M Phi s）促进，但经典（M1）极化的巨噬细胞（M1-M Phi s）抑制，自我更新和扩增的HSC从小鼠骨髓（BM）在体外。M1-M Phi s和M2-M Phi s对小鼠BM HSC的相反作用归因于它们的一氧化氮合酶2（N 0 S2）和精氨酸酶1（Argi）的差异表达，因为N 0 S2和Argl的基因敲除或用特异性抑制剂抑制这些酶消除了M1-M Phi s和M2-M Phi s的差异作用。将人脐血CD 34（+）细胞与人脐血CD 34（-）细胞共培养，观察到M1-M Phi s和M2-M Phi s对人脐血造血干细胞的相反作用。重要的是，与未培养的hUCB CD 34（+）细胞相比，hUCB CD 34（+）细胞与人M2-M Phi s共培养8天导致CD 34（+）细胞和长期SCID小鼠再增殖细胞的数量分别增加28.7倍和6.6倍。我们的研究结果可能导致新的策略的发展，以促进离体hUCB HSC扩增，以改善hUCB HSC移植的临床实用性和结果，并可能提供新的见解与感染和炎症相关的血液功能障碍的发病机制，可导致不同的巨噬细胞极化。
Uncovering the cellular and molecular mechanisms by which hematopoietic stem cell (HSC) self-renewal is regulated can lead to the development of new strategies for promoting ex vivo HSC expansion. Here, we report the discovery that alternative (M2)-polarized macrophages (M2-M Phi s) promote, but classical (M1)-polarized macrophages (M1-M Phi s) inhibit, the self-renewal and expansion of HSCs from mouse bone marrow (BM) in vitro. The opposite effects of M1-M Phi s and M2-M Phi s on mouse BM HSCs were attributed to their differential expression of nitric oxide synthase 2 (NOS2) and arginase 1 (Argi), because genetic knockout of Nos2 and Argl or inhibition of these enzymes with a specific inhibitor abrogated the differential effects of M1-M Phi s and M2-M Phi s. The opposite effects of M1-M Phi s and M2-M Phi s on HSCs from human umbilical cord blood (hUCB) were also observed when hUCB CD34(+) cells were cocultured with M1-M Phi s and M2-M Phi s generated from hUCB CD34(-) cells. Importantly, coculture of hUCB CD34(+) cells with human M2-M Phi s for 8 days resulted in 28.7- and 6.6-fold increases in the number of CD34(+) cells and long-term SCID mice-repopulating cells, respectively, compared with uncultured hUCB CD34(+) cells. Our findings could lead to the development of new strategies to promote ex vivo hUCB HSC expansion to improve the clinical utility and outcome of hUCB HSC transplantation and may provide new insights into the pathogenesis of hematological dysfunctions associated with infection and inflammation that can lead to differential macrophage polarization.