MEIS1 通过靶向 TAL1 和 FLI1 调控人多能干细胞中的造血内皮生成、巨核细胞生成和血小板生成。
MEIS1 Regulates Hemogenic Endothelial Generation, Megakaryopoiesis, and Thrombopoiesis in Human Pluripotent Stem Cells by Targeting TAL1 and FLI1.
机构信息
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin 300020, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, Tianjin 300020, China.
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
出版信息
Stem Cell Reports. 2018 Feb 13;10(2):447-460. doi: 10.1016/j.stemcr.2017.12.017. Epub 2018 Jan 18.
Human pluripotent stem cells (hPSCs) provide an unlimited source for generating various kinds of functional blood cells. However, efficient strategies for generating large-scale functional blood cells from hPSCs are still lacking, and the mechanism underlying human hematopoiesis remains largely unknown. In this study, we identified myeloid ectopic viral integration site 1 homolog (MEIS1) as a crucial regulator of hPSC early hematopoietic differentiation. MEIS1 is vital for specification of APLNR mesoderm progenitors to functional hemogenic endothelial progenitors (HEPs), thereby controlling formation of hematopoietic progenitor cells (HPCs). TAL1 mediates the function of MEIS1 in HEP specification. In addition, MEIS1 is vital for megakaryopoiesis and thrombopoiesis from hPSCs. Mechanistically, FLI1 acts as a downstream gene necessary for the function of MEIS1 during megakaryopoiesis. Thus, MEIS1 controls human hematopoiesis in a stage-specific manner and can be potentially manipulated for large-scale generation of HPCs or platelets from hPSCs for therapeutic applications in regenerative medicine.
人类多能干细胞（hPSCs）为生成各种功能性血细胞提供了无限的来源。然而，从 hPSCs 高效生成大规模功能性血细胞的策略仍然缺乏，人类造血的机制在很大程度上仍然未知。在这项研究中，我们鉴定出髓系异位病毒整合位点 1 同源物（MEIS1）是 hPSC 早期造血分化的关键调节因子。MEIS1 对于 APLNR 中胚层祖细胞向功能性造血内皮祖细胞（HEPs）的特化至关重要，从而控制造血祖细胞（HPCs）的形成。TAL1 介导 MEIS1 在 HEP 特化中的功能。此外，MEIS1 对于 hPSCs 中的巨核细胞生成和血小板生成也是必不可少的。在机制上，FLI1 作为 MEIS1 在巨核细胞生成过程中发挥功能所必需的下游基因。因此，MEIS1 以特定于阶段的方式控制人类造血，可以潜在地操纵 hPSCs 大规模生成 HPCs 或血小板，用于再生医学中的治疗应用。
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