Independent origins of fetal liver haematopoietic stem and progenitor cells
Independent origins of fetal liver haematopoietic stem and progenitor cells
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DOI：
10.1038/s41586-022-05203-0
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发表时间：
2022-09-14
期刊：
影响因子：
64.8
通讯作者：
Suda, Toshio
中科院分区：
文献类型：
--
作者：
Yokomizo, Tomomasa;Ideue, Takako;Suda, Toshio
自我更新和分化受到严格控制，以维持成年骨髓中造血干细胞（HSC）的内稳态。在胎儿发育过程中，造血干细胞的扩增（自我更新）以及分化的造血细胞的产生（分化）对于维持造血系统以适应身体生长都是必需的。然而，在短暂的胚胎期内这两项看似相互对立的任务是如何完成的，仍不清楚。在此，我们利用小鼠体内遗传追踪技术，分析了动脉内造血簇中造血干细胞和祖细胞的形成，这些造血簇包含造血干细胞前体并表达转录因子肝白血病因子（HLF）。通过动力学研究，我们观察到造血干细胞和特定祖细胞（此前被认为是造血干细胞的后代）同时从HLF⁺前体群中形成，随后在胎儿肝脏中以不依赖造血干细胞的方式迅速形成分级造血群体结构。转录因子EVI1在前体群中异质表达，其中EVI1（高表达）细胞主要定位于胚胎内动脉，并优先产生造血干细胞。通过基因操作EVI1的表达，我们能够在体内改变前体产生造血干细胞和祖细胞的数量。通过命运追踪，我们还证明在妊娠晚期胎儿造血干细胞缓慢用于产生短期造血干细胞。这些数据表明，胎儿造血干细胞在出生前对祖细胞和功能性血细胞的产生贡献极小。因此，发育过程中不依赖干细胞的途径为组织和干细胞池的快速同步生长提供了一种合理策略。
Self-renewal and differentiation are tightly controlled to maintain haematopoietic stem cell (HSC) homeostasis in the adult bone marrow(1,)(2). During fetal development, expansion of HSCs (self-renewal) and production of differentiated haematopoietic cells (differentiation) are both required to sustain the haematopoietic system for body growth(3,4). However, it remains unclear how these two seemingly opposing tasks are accomplished within the short embryonic period. Here we used in vivo genetic tracing in mice to analyse the formation of HSCs and progenitors from intra-arterial haematopoietic clusters, which contain HSC precursors and express the transcription factor hepatic leukaemia factor (HLF). Through kinetic study, we observed the simultaneous formation of HSCs and defined progenitors-previously regarded as descendants of HSCs5-from the HLF+ precursor population, followed by prompt formation of the hierarchical haematopoietic population structure in the fetal liver in an HSC-independent manner. The transcription factor EVI1 is heterogeneously expressed within the precursor population, with EVI1(hi) cells being predominantly localized to intra-embryonic arteries and preferentially giving rise to HSCs. By genetically manipulating EVI1 expression, we were able to alter HSC and progenitor output from precursors in vivo. Using fate tracking, we also demonstrated that fetal HSCs are slowly used to produce short-term HSCs at late gestation. These data suggest that fetal HSCs minimally contribute to the generation of progenitors and functional blood cells before birth. Stem cell-independent pathways during development thus offer a rational strategy for the rapid and simultaneous growth of tissues and stem cell pools.