Lillehei Heart Institute and Department of Pediatrics, University of Minnesota, 312 Church St. SE, Minneapolis, MN 55455, USA.
Nat Cell Biol. 2011 Jan;13(1):72-8. doi: 10.1038/ncb2137. Epub 2010 Dec 19.
During development, haemogenesis occurs invariably at sites of vasculogenesis. Between embryonic day (E) 9.5 and E10.5 in mice, endothelial cells in the caudal part of the dorsal aorta generate haematopoietic stem cells and are referred to as haemogenic endothelium. The mechanisms by which haematopoiesis is restricted to this domain, and how the morphological transformation from endothelial to haematopoietic is controlled are unknown. We show here that HoxA3, a gene uniquely expressed in the embryonic but not yolk sac vasculature, restrains haematopoietic differentiation of the earliest endothelial progenitors, and induces reversion of the earliest haematopoietic progenitors into CD41-negative endothelial cells. This reversible modulation of endothelial-haematopoietic state is accomplished by targeting key haematopoietic transcription factors for downregulation, including Runx1, Gata1, Gfi1B, Ikaros, and PU.1. Through loss-of-function, and gain-of-function epistasis experiments, and the identification of antipodally regulated targets, we show that among these factors, Runx1 is uniquely able to erase the endothelial program set up by HoxA3. These results suggest both why a frank endothelium does not precede haematopoiesis in the yolk sac, and why haematopoietic stem cell generation requires Runx1 expression only in endothelial cells.
在发育过程中，造血总是发生在血管发生的部位。在小鼠胚胎第 9.5 天到第 10.5 天，背主动脉尾部的内皮细胞产生造血干细胞，被称为造血内皮细胞。造血仅限于该区域的机制，以及从内皮细胞向造血细胞的形态转化如何受到控制，目前尚不清楚。我们在这里表明，仅在胚胎而不在卵黄囊脉管系统中表达的 HoxA3 基因限制了最早内皮祖细胞的造血分化，并诱导最早造血祖细胞逆转回 CD41 阴性内皮细胞。通过下调关键的造血转录因子，包括 Runx1、Gata1、Gfi1B、Ikaros 和 PU.1，实现了这种内皮-造血状态的可逆调节。通过功能丧失和功能获得的上位性实验，以及对反义调节靶点的鉴定，我们表明，在这些因子中，Runx1 是唯一能够消除 HoxA3 建立的内皮程序的因子。这些结果表明，为什么在卵黄囊中，真正的内皮细胞不会先于造血发生，以及为什么造血干细胞的产生仅需要 Runx1 在内皮细胞中表达。
