Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.
Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
Nature. 2022 Jun;606(7915):747-753. doi: 10.1038/s41586-022-04804-z. Epub 2022 Jun 15.
Haematopoietic stem cells (HSCs) arise in the embryo from the arterial endothelium through a process known as the endothelial-to-haematopoietic transition (EHT). This process generates hundreds of blood progenitors, of which a fraction go on to become definitive HSCs. It is generally thought that most adult blood is derived from those HSCs, but to what extent other progenitors contribute to adult haematopoiesis is not known. Here we use in situ barcoding and classical fate mapping to assess the developmental and clonal origins of adult blood in mice. Our analysis uncovers an early wave of progenitor specification-independent of traditional HSCs-that begins soon after EHT. These embryonic multipotent progenitors (eMPPs) predominantly drive haematopoiesis in the young adult, have a decreasing yet lifelong contribution over time and are the predominant source of lymphoid output. Putative eMPPs are specified within intra-arterial haematopoietic clusters and represent one fate of the earliest haematopoietic progenitors. Altogether, our results reveal functional heterogeneity during the definitive wave that leads to distinct sources of adult blood.
造血干细胞（HSCs）来源于胚胎中的动脉内皮细胞，通过一个称为内皮细胞向造血细胞过渡（EHT）的过程。这个过程产生了数百个血液祖细胞，其中一部分继续成为确定性 HSCs。一般认为，大多数成人血液来源于这些 HSCs，但其他祖细胞在多大程度上参与成人造血尚不清楚。在这里，我们使用原位条形码和经典的命运图谱来评估小鼠成人体内血液的发育和克隆起源。我们的分析揭示了 EHT 后不久开始的、与传统 HSCs 无关的祖细胞特化的早期波。这些胚胎多能祖细胞（eMPP）主要驱动年轻成人体内的造血作用，随着时间的推移，其贡献逐渐减少但终生存在，是淋巴细胞输出的主要来源。推定的 eMPP 在动脉内造血簇内被指定，并代表最早的造血祖细胞的一种命运。总之，我们的结果揭示了在导致不同的成人血液来源的决定性波期间的功能异质性。
