Dataset Information

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

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.

SUBMITTER: Chandrakanthan V

PROVIDER: S-EPMC9359911 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Mesoderm-derived PDGFRA<sup>+</sup> cells regulate the emergence of hematopoietic stem cells in the dorsal aorta.

Chandrakanthan Vashe V Rorimpandey Prunella P Zanini Fabio F Chacon Diego D Olivier Jake J Joshi Swapna S Kang Young Chan YC Knezevic Kathy K Huang Yizhou Y Qiao Qiao Q Oliver Rema A RA Unnikrishnan Ashwin A Carter Daniel R DR Lee Brendan B Brownlee Chris C Power Carl C Brink Robert R Mendez-Ferrer Simon S Enikolopov Grigori G Walsh William W Göttgens Berthold B Taoudi Samir S Beck Dominik D Pimanda John E JE

Nature cell biology 20220728 8

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<sup>+</sup> stroma ...[more]

PMID: 35902769

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Project description:During embryonic development, the first hematopoietic stem cells (HSCs) arise from a transient population of endothelial cells lining the ventral surface of the dorsal aorta, via a process of endothelial to hematopoietic transition (EHT) at embryonic day (E) 10.5. This region contains resident PDGFRA+ stromal cells (PSCs), but their identity and role in HSC generation in the AGM are not well understood. Using a library of compound transgenic mice, we identified a population of PDGFRA+/Nestin-GFP (N-GFP)-/PDGFRB-/CD31- cells with PSC activity in the E10.5 and E11.5 mouse AGM. Freshly isolated PSCs were adept at forming blood vessels with CD31+ luminal endothelium enveloped by PDGFRB+ pericytes, when transplanted subcutaneously into mice. Conditional ablation of PDGFRA+ or Nestin+ cells led to either complete or partial loss of PSCs respectively, with severe loss of endothelial and pericyte-like cells, and concomitant loss of blood formation in the AGM. Lineage tracing studies using tamoxifen induction in PDGFRACreERT2/R26eYFP embryos showed that stromal, sub-endothelial, endothelial and long-term repopulating hematopoietic stem cells (LT-HSCs) cells in the E11.5 AGM were progeny of PDGFRA cells. Using transgenic reporter mice, we showed that MesP1 (mesoderm) derived PDGFRA+ cells dominated the sub-endothelial and deeper ventral stroma in the AGM at E10.5 and E11.5 but were replaced by Wnt1 (neural crest) derived cells at E13.5. Re-aggregation of E11.5 Mesp1 derived PSC cells with E13.5 aortic or adult cardiac non-hemogenic endothelial cells resulted in the generation of endothelial cell derived LT-HSCs. RNA-sequencing analysis of non-hemogenic E13.5 endothelial cells showed up-regulation of EHT genes, WNT, BMP and Notch cell signalling pathways when re-aggregated with E11.5 Mesp1 derived PSCs. LT-HSC generation from these re-aggregates was suppressed by dose-dependent inhibition of PDGF-AA/PDGFRA signalling. Taken together, we report that PSC populations in the AGM are temporally dynamic, and that MesP1-derived PSCs regulate hemogenic potential of the endothelium and that this cooperativity is dependent on PDGF-AA/PDGFRA signalling. This submission represents the RNAseq component of the study.

Dataset Information

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

Publications

Mesoderm-derived PDGFRA<sup>+</sup> cells regulate the emergence of hematopoietic stem cells in the dorsal aorta.

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Dataset Information

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

Publications

Mesoderm-derived PDGFRA<sup>+</sup> cells regulate the emergence of hematopoietic stem cells in the dorsal aorta.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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