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中胚层衍生的 PDGFRA 细胞调节背主动脉中造血干细胞的出现。

Mesoderm-derived PDGFRA cells regulate the emergence of hematopoietic stem cells in the dorsal aorta.

机构信息

Adult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.

Department of Pathology, School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia.

出版信息

Nat Cell Biol. 2022 Aug;24(8):1211-1225. doi: 10.1038/s41556-022-00955-3. Epub 2022 Jul 28.

DOI:10.1038/s41556-022-00955-3
PMID:35902769
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9359911/
Abstract

Mouse haematopoietic stem cells (HSCs) first emerge at embryonic day 10.5 (E10.5), on the ventral surface of the dorsal aorta, by endothelial-to-haematopoietic transition. We investigated whether mesenchymal stem cells, which provide an essential niche for long-term HSCs (LT-HSCs) in the bone marrow, reside in the aorta-gonad-mesonephros and contribute to the development of the dorsal aorta and endothelial-to-haematopoietic transition. Here we show that mesoderm-derived PDGFRA stromal cells (Mesp1 PSCs) contribute to the haemogenic endothelium of the dorsal aorta and populate the E10.5-E11.5 aorta-gonad-mesonephros but by E13.5 were replaced by neural-crest-derived PSCs (Wnt1 PSCs). Co-aggregating non-haemogenic endothelial cells with Mesp1 PSCs but not Wnt1 PSCs resulted in activation of a haematopoietic transcriptional programme in endothelial cells and generation of LT-HSCs. Dose-dependent inhibition of PDGFRA or BMP, WNT and NOTCH signalling interrupted this reprogramming event. Together, aorta-gonad-mesonephros Mesp1 PSCs could potentially be harnessed to manufacture LT-HSCs from endothelium.

摘要

小鼠造血干细胞（HSCs）最早于胚胎第 10.5 天（E10.5）在背主动脉的腹侧表面通过内皮细胞向造血细胞的转变而出现。我们研究了骨髓中长时程造血干细胞（LT-HSCs）的重要龛位是否存在于中胚层衍生的血小板衍生生长因子受体α基质细胞（Mesp1 PSCs）中，以及它们是否参与背主动脉的发育和内皮细胞向造血细胞的转变。在这里，我们显示中胚层衍生的血小板衍生生长因子受体α基质细胞（Mesp1 PSCs）有助于背主动脉的造血内皮细胞的形成，并在 E10.5-E11.5 时期占据主动脉-性腺-中肾，但到 E13.5 时被神经嵴衍生的 PSCs（Wnt1 PSCs）所取代。将非造血内皮细胞与 Mesp1 PSCs 而非 Wnt1 PSCs 共同聚集，可导致内皮细胞中造血转录程序的激活，并产生 LT-HSCs。PDGFRA 或 BMP、WNT 和 NOTCH 信号的剂量依赖性抑制中断了这种重编程事件。总之，来自中肾-性腺-中肾的 Mesp1 PSCs 可能被用来从内皮细胞制造 LT-HSCs。

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