Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Nature. 2018 Jan 11;553(7687):212-216. doi: 10.1038/nature25168. Epub 2018 Jan 3.
Haematopoiesis, the process of mature blood and immune cell production, is functionally organized as a hierarchy, with self-renewing haematopoietic stem cells and multipotent progenitor cells sitting at the very top. Multiple models have been proposed as to what the earliest lineage choices are in these primitive haematopoietic compartments, the cellular intermediates, and the resulting lineage trees that emerge from them. Given that the bulk of studies addressing lineage outcomes have been performed in the context of haematopoietic transplantation, current models of lineage branching are more likely to represent roadmaps of lineage potential than native fate. Here we use transposon tagging to clonally trace the fates of progenitors and stem cells in unperturbed haematopoiesis. Our results describe a distinct clonal roadmap in which the megakaryocyte lineage arises largely independently of other haematopoietic fates. Our data, combined with single-cell RNA sequencing, identify a functional hierarchy of unilineage- and oligolineage-producing clones within the multipotent progenitor population. Finally, our results demonstrate that traditionally defined long-term haematopoietic stem cells are a significant source of megakaryocyte-restricted progenitors, suggesting that the megakaryocyte lineage is the predominant native fate of long-term haematopoietic stem cells. Our study provides evidence for a substantially revised roadmap for unperturbed haematopoiesis, and highlights unique properties of multipotent progenitors and haematopoietic stem cells in situ.
造血是成熟血液和免疫细胞产生的过程，在功能上组织成一个层次结构，具有自我更新的造血干细胞和多能祖细胞位于最顶层。人们提出了多种模型，用以解释在这些原始造血区室、细胞中间产物以及由此产生的谱系树中，最早的谱系选择是什么。鉴于大量研究涉及造血移植背景下的谱系结果，当前的谱系分支模型更有可能代表谱系潜能的路线图，而不是固有命运。在这里，我们使用转座子标记来追踪未受干扰造血中祖细胞和干细胞的命运。我们的结果描述了一个独特的克隆路线图，其中巨核细胞谱系主要独立于其他造血命运出现。我们的数据，结合单细胞 RNA 测序，确定了多能祖细胞群体中具有单系和寡系产生克隆的功能层次结构。最后，我们的结果表明，传统定义的长期造血干细胞是巨核细胞受限祖细胞的重要来源，这表明巨核细胞谱系是长期造血干细胞的主要固有命运。我们的研究为未受干扰的造血提供了一个经过实质性修订的路线图证据，并突出了多能祖细胞和造血干细胞在原位的独特性质。
