Gene Regulation, Stem Cells and Development Group, Department of Genomic Oncology, GENYO: Centre for Genomics and Oncological Research Pfizer-University of Granada-Junta de Andalucía, PTS Granada, Granada, Spain.
Department of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, Granada, Spain.
Stem Cells. 2017 Nov;35(11):2253-2266. doi: 10.1002/stem.2700. Epub 2017 Sep 23.
Runt-related transcription factor 1 (Runx1) is a master hematopoietic transcription factor essential for hematopoietic stem cell (HSC) emergence. Runx1-deficient mice die during early embryogenesis due to the inability to establish definitive hematopoiesis. Here, we have used human pluripotent stem cells (hPSCs) as model to study the role of RUNX1 in human embryonic hematopoiesis. Although the three RUNX1 isoforms a, b, and c were induced in CD45+ hematopoietic cells, RUNX1c was the only isoform induced in hematoendothelial progenitors (HEPs)/hemogenic endothelium. Constitutive expression of RUNX1c in human embryonic stem cells enhanced the appearance of HEPs, including hemogenic (CD43+) HEPs and promoted subsequent differentiation into blood cells. Conversely, specific deletion of RUNX1c dramatically reduced the generation of hematopoietic cells from HEPs, indicating that RUNX1c is a master regulator of human hematopoietic development. Gene expression profiling of HEPs revealed a RUNX1c-induced proinflammatory molecular signature, supporting previous studies demonstrating proinflammatory signaling as a regulator of HSC emergence. Collectively, RUNX1c orchestrates hematopoietic specification of hPSCs, possibly in cooperation with proinflammatory signaling. Stem Cells 2017;35:2253-2266.
runt 相关转录因子 1（Runx1）是一种主要的造血转录因子，对于造血干细胞（HSC）的出现至关重要。Runx1 缺陷小鼠由于无法建立明确的造血而在胚胎早期死亡。在这里，我们使用人类多能干细胞（hPSCs）作为模型来研究 RUNX1 在人类胚胎造血中的作用。尽管在 CD45+造血细胞中诱导了三种 RUNX1 异构体 a、b 和 c，但仅在造血内皮祖细胞（HEPs）/造血内皮中诱导了 RUNX1c。RUNX1c 在人胚胎干细胞中的组成型表达增强了 HEPs 的出现，包括造血（CD43+）HEPs，并促进了随后向血细胞的分化。相反，RUNX1c 的特异性缺失大大减少了 HEPs 生成造血细胞的能力，表明 RUNX1c 是人类造血发育的主要调节剂。HEPs 的基因表达谱揭示了 RUNX1c 诱导的促炎分子特征，支持了先前的研究，表明促炎信号作为 HSC 出现的调节剂。总之，RUNX1c 协调 hPSCs 的造血特化，可能与促炎信号协同作用。干细胞 2017；35:2253-2266.
