中国科学院动物研究所Feng Liu和中国医学科学院和北京协和医学院Lu Wang共同合作，近期取得重要工作进展。他们研究发现造血内皮细胞谱系能力的激活先于造血干细胞异质性的形成。相关研究成果2023年4月4日在线发表于《细胞研究》杂志上。

据介绍，造血干细胞和祖细胞（HSPC）被认为是一个异质性群体，但HSPC异质性的确切产生时间、地点和方式在很大程度上尚不清楚。

使用单细胞多组学、谱系追踪和功能测定的组合，研究人员表明胚胎HSPC起源于斑马鱼胚胎发生过程中的异质性造血内皮细胞（HEC）。综合单细胞转录组和染色质可及性分析表明，在HEC水平上启动淋巴/骨髓命运的转录异质性和调控程序。spi2+HEC会产生淋巴/骨髓启动的HSPC（L/M-HSPC），并在急性炎症下表现出应激反应功能。

此外，研究人员发现Spi2是通过严格控制内皮细胞向造血细胞的过渡程序来形成L/M-HSPC所必需的。最后，斑马鱼和人类HEC的单细胞转录比较以及人类诱导的基于多能干细胞的造血分化结果支持L/M-HEC的演化保守性和SPI1（哺乳动物中的spi2同源物）在人类中的保守性作用。

总之，这些结果揭示了HSPC异质性的谱系起源、生物学功能和分子决定簇，并为体外诱导可移植谱系引发的HSPC新策略奠定了基础。

附：英文原文

Title: Activation of lineage competence in hemogenic endothelium precedes the formation of hematopoietic stem cell heterogeneity

Author: Xia, Jun, Liu, Mengyao, Zhu, Caiying, Liu, Shicheng, Ai, Lanlan, Ma, Dongyuan, Zhu, Ping, Wang, Lu, Liu, Feng

Issue&Volume: 2023-04-04

Abstract: Hematopoietic stem and progenitor cells (HSPCs) are considered as a heterogeneous population, but precisely when, where and how HSPC heterogeneity arises remain largely unclear. Here, using a combination of single-cell multi-omics, lineage tracing and functional assays, we show that embryonic HSPCs originate from heterogeneous hemogenic endothelial cells (HECs) during zebrafish embryogenesis. Integrated single-cell transcriptome and chromatin accessibility analysis demonstrates transcriptional heterogeneity and regulatory programs that prime lymphoid/myeloid fates at the HEC level. Importantly, spi2+ HECs give rise to lymphoid/myeloid-primed HSPCs (L/M-HSPCs) and display a stress-responsive function under acute inflammation. Moreover, we uncover that Spi2 is required for the formation of L/M-HSPCs through tightly controlling the endothelial-to-hematopoietic transition program. Finally, single-cell transcriptional comparison of zebrafish and human HECs and human induced pluripotent stem cell-based hematopoietic differentiation results support the evolutionary conservation of L/M-HECs and a conserved role of SPI1 (spi2 homolog in mammals) in humans. These results unveil the lineage origin, biological function and molecular determinant of HSPC heterogeneity and lay the foundation for new strategies for induction of transplantable lineage-primed HSPCs in vitro.

DOI: 10.1038/s41422-023-00797-0

Source: https://www.nature.com/articles/s41422-023-00797-0