Biology subjects

Taoudi, S.

Publications and source records attributed to Taoudi, S..

3 recordsLinked to original sources

bioRxiv2021

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

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.

developmental biology↗

bioRxiv2020

Quantitation analysis by flow cytometry shows that Wt1 is required for development of the proepicardium and epicardium

The epicardium is a cell layer found on the external surface of the heart. During development it has an epithelial identity and contains progenitor cells for coronary smooth muscle and cardiac fibroblasts. The epicardium has been suggested to have therapeutic potential in cardiac repair. Study of epicardial development has been difficult because it is dynamic and morphologically complex. We developed a flow cytometry-based method to quantify cardiac development including the epicardial lineage. This provided accurate and sensitive analysis of (1) the emergence of epicardial progenitors within the proepicardium (2) their transfer to the heart to form the epicardium, and (3) their epithelial-to-mesenchymal transition (EMT) to create the subepicardium. Platelet-derived growth factor alpha (Pdgfra) and Wilms tumor protein (Wt1) have both been reported to be pro-mesenchymal during epicardial EMT. Quantitative analysis with flow cytometry confirmed a pro-mesenchymal role for Pdgfra but not for Wt1. Analysis of Wt1 null embryos showed that they had (1) poor formation of proepicardial villi, (2) reduced transfer of proepicardial cells to the heart, (3) a discontinuous epicardium with poor epithelial identity, and (4) a proportionally excessive number of mesenchymal-like cells. This data shows that Wt1 is essential for epicardial formation and maintenance rather than being pro-mesenchymal.

developmental biology↗

bioRxiv2020

The clonal and molecular aetiology of emergency dendritic cell development

Extrinsic regulation of single haematopoietic stem and progenitor cell (HSPC) fate is crucial for immune cell development. Here, we examine the aetiology of Flt3 ligand (Flt3L)-mediated emergency development of type 1 conventional dendritic cells (cDC1s), which results in enhanced immunity against infections and cancer. Using cellular barcoding, we demonstrate a predominant role of enhanced clonal expansion and moderate contribution via recruitment of additional cDC1-generating HSPCs. The selective cDC1 expansion occurs primarily via multi-/oligo-potent clones, without compromising output to other lineages. To understand the molecular hallmarks early during a Flt3L response, we develop Divi-Seq to simultaneously profile cell division history, surface phenotype and transcriptional state of single HSPCs. We discover that Flt3L-responsive HSPCs maintain a proliferative early progenitor-like state, which leads to selective emergence of CD11c+cKit+ transitional precursors with high cellular output to cDC1s. These findings inform the mechanistic action of Flt3L in natural immunity and immunotherapy at a clonal level.

immunology↗