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

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

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^der 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^der PSCs). Co-aggregating non-haemogenic endothelial cells with Mesp1^der PSCs but not Wnt1^der 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^der PSCs could potentially be harnessed to manufacture LT-HSCs from endothelium.

PMID:35902769 | PMC:PMC9359911 | DOI:10.1038/s41556-022-00955-3