Contractile forces sustain and polarize hematopoiesis from stem and progenitor cells.
Contractile forces sustain and polarize hematopoiesis from stem and progenitor cells.
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DOI：
10.1016/j.stem.2013.10.009
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发表时间：
2014-01-02
期刊：
影响因子：
23.9
通讯作者：
Discher, Dennis E.
中科院分区：
文献类型：
--
作者：
Shin, Jae-Won;Buxboim, Amnon;Spinler, Kyle R.;Swift, Joe;Christian, David A.;Hunter, Christopher A.;Leon, Catherine;Gachet, Christian;Dingal, P. C. Dave P.;Ivanovska, Irena L.;Rehfeldt, Florian;Chasis, Joel Anne;Discher, Dennis E.
干细胞的自我更新和分化依赖于不对称分裂和极化的运动过程，而在其他类型的细胞中，这一过程受非肌肉肌球蛋白II(MII)力和基质力学的调节。在这里，质谱学校准的人类造血的细胞内流式细胞术显示MIIB是一种主要的亚型，在造血干细胞和祖细胞(HSC/Ps)中被强烈极化，从而通过不对称分裂在分化的细胞中下调。MIIA是结构性的，在细胞因子触发细胞分化的过程中被去磷酸化激活，这些细胞生长在僵硬的骨内膜样基质上，而不是软的骨髓样基质上。在体内，MIIB是生成血液所必需的，而MIIA是持续植入HSC/P所必需的。根据体内评估，在用博莱比星培养中可逆地抑制这两种异构体，可以使长期的多系造血重建细胞丰富5倍或更多。巨核细胞也变得更加多倍体，产生4倍以上的血小板。因此，MII是两极分化和生态位感知的多功能节点。
Self-renewal and differentiation of stem cells depend on asymmetric division and polarized motility processes that in other cell types are modulated by nonmuscle myosin-II (MII) forces and matrix mechanics. Here, mass spectrometry-calibrated intracellular flow cytometry of human hematopoiesis reveals MIIB to be a major isoform that is strongly polarized in hematopoietic stem cells and progenitors (HSC/Ps) and thereby downregulated in differentiated cells via asymmetric division. MIIA is constitutive and activated by de-phosphorylation during cytokine-triggered differentiation of cells grown on stiff, endosteum-like matrix but not soft, marrow-like matrix. In vivo, MIIB is required for generation of blood, while MIIA is required for sustained HSC/P engraftment. Reversible inhibition of both isoforms in culture with blebbistatin enriches for long-term hematopoietic multi-lineage reconstituting cells by 5-fold or more as assessed in vivo. Megakaryocytes also become more polyploid, producing 4-fold more platelets. MII is thus a multifunctional node in polarized division and niche sensing.
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