Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion.
Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion.
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作者：
在骨髓（BM）中，造血干细胞（HSC）驻留在专门的微环境中，这些微环境严格控制其增殖状态，以适应对血细胞补充的不同需求，同时还防止衰竭。迄今为止，所有假定的小生境细胞都具有非造血起源。因此，尚不清楚来自成熟细胞的反馈如何传递到HSC以调节增殖。在这里，我们表明，巨核细胞（Mk）可以直接调节HSC池的大小。三维整装成像显示，内源性HSC经常以非随机方式位于Mk附近。Mk的选择性体内耗竭导致HSC静止期的特异性丧失，并导致功能性HSC的显著扩增。基因表达分析显示，Mk是BM中趋化因子C-X-C基序配体4（Cxcl 4，也称为血小板因子4，Pf 4）的来源，并且Cxcl 4注射通过增加静止减少HSC数量。相比之下，Cxcl 4 −/−小鼠表现出增加的HSC数量和增殖。整体成像和计算模型的结合使用高度暗示了巨核细胞小生境能够通过调节静止独立影响HSC的维持。因此，这些结果表明，终末分化的HSC后代通过直接调节HSC行为而有助于生态位活性。
In the bone marrow (BM), hematopoietic stem cells (HSCs) lodge in specialized microenvironments that tightly control their proliferative state to adapt to the varying needs for replenishment of blood cells while also preventing exhaustion. All putative niche cells suggested thus far have a non-hematopoietic origin. Thus, it remains unclear how feedback from mature cells is conveyed to HSCs to adjust proliferation. Here we show that megakaryocytes (Mk) can directly regulate HSC pool size. Three-dimensional whole-mount imaging revealed that endogenous HSCs are frequently located adjacent to Mk in a non-random fashion. Selective in vivo depletion of Mk resulted in specific loss of HSC quiescence and led to a marked expansion of functional HSCs. Gene expression analyses revealed that Mk were the source of chemokine C-X-C motif ligand 4 (Cxcl4, also named platelet factor 4, Pf4) in the BM and Cxcl4 injection reduced HSC numbers via increased quiescence. By contrast, Cxcl4−/− mice exhibited increased HSC numbers and proliferation. Combined use of whole-mount imaging and computational modelling was highly suggestive of a megakaryocytic niche capable of influencing independently HSC maintenance by regulating quiescence. Thus, these results indicate that a terminally differentiated HSC progeny contributes to niche activity by directly regulating HSC behavior.
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DOI：
10.1038/nri3132
发表时间：
2011-12-23
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
20.3
作者：
Eslin, DE;Zhang, CY;Kowalska, MA
通讯作者：
Kowalska, MA
影响因子：
1.2
作者：
Heazlewood, Shen Y.;Neaves, Rebecca J.;Nilsson, Susan K.
通讯作者：
Nilsson, Susan K.
影响因子：
2.6
作者：
Broxmeyer, Hal E.;Pelus, Louis M.;Hromas, Robert
通讯作者：
Hromas, Robert
影响因子：
64.5
作者：
Hsu YC;Pasolli HA;Fuchs E
通讯作者：
Fuchs E