Chandrakanthan, V.Rorimpandey, P.Zanini, F.Chacon, D.Olivier, J.Joshi, S.Kang, Y.C.Knezevic, K.Huang, Y.Qiao, Q.Oliver, R.A.Unnikrishnan, A.Carter, D.R.Lee, B.Brownlee, C.Power, C.Brink, R.Mendez-Ferrer, S.Enikolopov, G.Walsh, W.et al.2023-01-232023-01-232022Nature Cell Biology, 2022; 24(8):1211-12251465-73921476-4679https://hdl.handle.net/2440/137278Mouse 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 (Mesp1der 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 (Wnt1der PSCs). Co-aggregating non-haemogenic endothelial cells with Mesp1der PSCs but not Wnt1der 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 Mesp1der PSCs could potentially be harnessed to manufacture LT-HSCs from endothelium.en© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.AortaHematopoietic Stem CellsMesodermMesonephrosAnimalsMiceHematopoiesisHemangioblastsAortaHematopoietic Stem CellsMesodermMesonephrosAnimalsMiceHematopoiesisHemangioblastsJournal article10.1038/s41556-022-00955-32023-01-23631046Chandrakanthan, V. [0000-0002-4314-5029]