日本熊本大学Toshio Suda、Tomomasa Yokomizo等研究人员合作发现胎儿肝脏造血干细胞和祖细胞的独立起源。该项研究成果于2022年9月14日在线发表在《自然》杂志上。

研究人员利用小鼠体内的遗传追踪来分析了造血干细胞（HSC）和来自动脉内造血集群祖细胞的形成，这些集群含有HSC并表达转录因子肝脏白血病因子（HLF）。通过动力学研究，研究人员观察到HSC和明确的祖细胞（以前被认为是HSC的后代），从HLF⁺前体群体中同时形成，随后在胎儿肝脏中以HSC非依赖的方式迅速形成分层造血群体结构。转录因子EVI1在前体群体中异质表达，EVI1^hi细胞主要定位在胚胎内的动脉，并优先产生HSC。通过遗传操纵EVI1的表达，研究人员能够改变体内前体的HSC和祖细胞输出。

利用命运追踪，研究人员还证明了胎儿HSC在妊娠晚期慢慢被用来产生短期HSC。这些数据表明，胎儿HSC在出生前对祖细胞和功能性血细胞的产生贡献很小。因此，发育过程中不依赖干细胞的途径为组织和干细胞库的快速和同步增长提供了合理的策略。

据了解，自我更新和分化受到严格控制，以维持成人骨髓中HSC的平衡。在胎儿发育过程中，HSC的扩增（自我更新）和分化的造血细胞的产生（分化）都是维持身体生长的造血系统所必需的。然而，目前仍不清楚这两项看似对立的任务是如何在短暂的胚胎期内完成的。

附：英文原文

Title: Independent origins of fetal liver haematopoietic stem and progenitor cells

Author: Yokomizo, Tomomasa, Ideue, Takako, Morino-Koga, Saori, Tham, Cheng Yong, Sato, Tomohiko, Takeda, Naoki, Kubota, Yoshiaki, Kurokawa, Mineo, Komatsu, Norio, Ogawa, Minetaro, Araki, Kimi, Osato, Motomi, Suda, Toshio

Issue&Volume: 2022-09-14

Abstract: Self-renewal and differentiation are tightly controlled to maintain haematopoietic stem cell (HSC) homeostasis in the adult bone marrow1,2. 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 growth3,4. 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 EVI1hi 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.

DOI: 10.1038/s41586-022-05203-0

Source: https://www.nature.com/articles/s41586-022-05203-0