Mesoderm-Derived PDGFRA+ Cells Regulate the Emergence of Hematopoietic Stem Cells in the Dorsal Aorta

Vashe Chandrakanthan; Prunella Rorimpandey; Fabio Zanini; Diego Chacon Fajardo; Jake Olivier; Swapna Mahurkar Joshi; Young Chan Kang; Kathy Knezevic; Yizhou Huang; Qiao Qiao; Rema A. Oliver; Ashwin Unnikrishnan; Daniel R. Carter; Brendan Lee; Chris Brownlee; Carl Andrew Power; Robert Adrian Brink; Simón Méndez‐Ferrer; Grigori Enikolopov; William Robert Walsh; Berthold Göttgens; Samir Taoudi; Dominik Beck; John E. Pimanda

doi:10.1038/s41556-022-00955-3

Developmental BiologyNature Cell BiologyJul 28, 2022

Peer-reviewed journal article

Mesoderm-Derived PDGFRA+ Cells Regulate the Emergence of Hematopoietic Stem Cells in the Dorsal Aorta

Vashe Chandrakanthan iD, Prunella Rorimpandey, Fabio Zanini iD, Diego Chacon Fajardo iD, Jake Olivier iD, Swapna Mahurkar Joshi, Young Chan Kang iD, Kathy Knezevic iD, Yizhou Huang iD, Qiao Qiao iD, Rema A. Oliver iD, Ashwin Unnikrishnan iD, Daniel R. Carter iD, Brendan Lee iD, Chris Brownlee, Carl Andrew Power iD, Robert Adrian Brink iD, Simón Méndez‐Ferrer iD, Grigori Enikolopov iD, William Robert Walsh iD, Berthold Göttgens iD, Samir Taoudi iD, Dominik Beck iD, John E. Pimanda iD

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Abstract

Mouse hematopoietic stem cells (HSCs) first emerge at embryonic day 10.5 (E10.5) on the ventral surface of the dorsal aorta, by endothelial-to-hematopoietic transition (EHT). We investigated whether cells with mesenchymal stem cell-like activity, which provide an essential niche for long-term HSCs (LT-HSCs) in the bone marrow, reside in the aorta- gonad-mesonephros (AGM) and contribute to the structural development of the dorsal aorta and EHT. Using transgenic mice, we demonstrate a lineage hierarchy for AGM stromal cells and traced the E10.5/E11.5 aortic endothelium and HSCs to mesoderm derived (Mesp1) PDGFRA+ stromal cells (Mesp1der PSCs). Mesp1der PSCs dominate the sub-endothelial and ventral stroma in the E10.5-E11.5 AGM but by E13.5 were replaced by neural crest (Wnt1) derived PDGFRA+ stromal cells (Wnt1der PSCs). Co-aggregating non-hemogenic embryonic and adult endothelial cells with Mesp1der PSCs but not with Wnt1der PSCs resulted in activation of a hematopoietic transcriptional program in endothelial cells accompanied by EHT and generation of LT-HSCs. Dose-dependent inhibition of PDGFRA signalling or BMP, WNT, NOTCH signalling interrupted this reprogramming event. This partnership between endothelial cells and AGM Mesp1der PSCs could potentially be harnessed to manufacture LT-HSCs from endothelium.