Frame Jenna M, Fegan Katherine H, Conway Simon J, McGrath Kathleen E, Palis James
Department of Pediatrics, Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, New York, USA.
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA.
Stem Cells. 2016 Feb;34(2):431-44. doi: 10.1002/stem.2213. Epub 2015 Oct 23.
Adult-repopulating hematopoietic stem cells (HSCs) emerge in low numbers in the midgestation mouse embryo from a subset of arterial endothelium, through an endothelial-to-hematopoietic transition. HSC-producing arterial hemogenic endothelium relies on the establishment of embryonic blood flow and arterial identity, and requires β-catenin signaling. Specified prior to and during the formation of these initial HSCs are thousands of yolk sac-derived erythro-myeloid progenitors (EMPs). EMPs ensure embryonic survival prior to the establishment of a permanent hematopoietic system, and provide subsets of long-lived tissue macrophages. While an endothelial origin for these HSC-independent definitive progenitors is also accepted, the spatial location and temporal output of yolk sac hemogenic endothelium over developmental time remain undefined. We performed a spatiotemporal analysis of EMP emergence, and document the morphological steps of the endothelial-to-hematopoietic transition. Emergence of rounded EMPs from polygonal clusters of Kit(+) cells initiates prior to the establishment of arborized arterial and venous vasculature in the yolk sac. Interestingly, Kit(+) polygonal clusters are detected in both arterial and venous vessels after remodeling. To determine whether there are similar mechanisms regulating the specification of EMPs with other angiogenic signals regulating adult-repopulating HSCs, we investigated the role of embryonic blood flow and Wnt/β-catenin signaling during EMP emergence. In embryos lacking a functional circulation, rounded Kit(+) EMPs still fully emerge from unremodeled yolk sac vasculature. In contrast, canonical Wnt signaling appears to be a common mechanism regulating hematopoietic emergence from hemogenic endothelium. These data illustrate the heterogeneity in hematopoietic output and spatiotemporal regulation of primary embryonic hemogenic endothelium.
成年再填充造血干细胞（HSC）在妊娠中期的小鼠胚胎中少量出现，源自动脉内皮细胞的一个亚群，通过内皮向造血的转变过程产生。产生HSC的动脉造血内皮细胞依赖于胚胎血流的建立和动脉特性的形成，并且需要β-连环蛋白信号传导。在这些初始HSC形成之前和期间就已特化的是数千个卵黄囊来源的红系-髓系祖细胞（EMP）。EMP在永久性造血系统建立之前确保胚胎存活，并提供长寿组织巨噬细胞的亚群。虽然这些不依赖HSC的确定性祖细胞的内皮起源也得到认可，但卵黄囊造血内皮细胞在发育过程中的空间位置和时间输出仍不明确。我们对EMP的出现进行了时空分析，并记录了内皮向造血转变的形态学步骤。圆形EMP从Kit(+)细胞的多边形簇中出现，这一过程在卵黄囊中树状动脉和静脉血管系统建立之前就已开始。有趣的是，在重塑后，在动脉和静脉血管中都检测到了Kit(+)多边形簇。为了确定是否存在与调节成年再填充HSC的其他血管生成信号类似的调节EMP特化的机制，我们研究了胚胎血流和Wnt/β-连环蛋白信号传导在EMP出现过程中的作用。在缺乏功能性循环的胚胎中，圆形的Kit(+) EMP仍能从未重塑的卵黄囊血管系统中完全出现。相比之下，经典Wnt信号似乎是调节造血内皮细胞造血出现的一种常见机制。这些数据说明了初级胚胎造血内皮细胞造血输出的异质性以及时空调节。
