Mesoderm-Derived PDGFRA + Cells Regulate the Emergence of Hematopoietic Stem Cells in the Dorsal Aorta
Mesoderm-Derived PDGFRA + Cells Regulate the Emergence of Hematopoietic Stem Cells in the Dorsal Aorta
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.
Beck Dominik、Zanini Fabio、G?ttgens Berthold、Chandrakanthan Vashe、Chacon Diego、Kang Young Chan、Huang Yizhou、Oliver Rema A.、Unnikrishnan Ashwin、Lee Brendan、Pimanda John E.、Rorimpandey Prunella、Taoudi Samir、Knezevic Kathy、Qiao Qiao、Enikolopov Grigori、Mendez-Ferrer Simon、Brownlee Chris、Walsh William、Power Carl、Carter Daniel R.
Centre for Health Technologies and the School of Biomedical Engineering, University of Technology SydneyAdult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney||Prince of Wales Clinical School, UNSW Sydney||Garvan-Weizmann Centre for Cellular Genomics||UNSW Futures Institute for Cellular GenomicsWellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Haematology, University of CambridgeAdult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney||Department of Pathology, School of Medical Sciences, UNSW SydneyCentre for Health Technologies and the School of Biomedical Engineering, University of Technology SydneyAdult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney||Department of Pathology, School of Medical Sciences, UNSW SydneyCentre for Health Technologies and the School of Biomedical Engineering, University of Technology Sydney||Children?ˉs Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW SydneySurgical & Orthopaedic Research Laboratories, Prince of Wales Clinical School, UNSW SydneyAdult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney||Prince of Wales Clinical School, UNSW SydneyBiological Resources Imaging Laboratory, Mark Wainwright Analytical Centre, Lowy Cancer Research Centre, UNSW SydneyAdult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney||Department of Pathology, School of Medical Sciences, UNSW Sydney||Department of Haematology, The Prince of Wales HospitalAdult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney||Department of Pathology, School of Medical Sciences, UNSW SydneyDivisions of Molecular Medicine, Cancer and Haematology, Walter and Eliza Hall InstituteAdult Cancer Program, Lowy Cancer Research Centre, UNSW Sydney||Department of Pathology, School of Medical Sciences, UNSW SydneyAdult Cancer Program, Lowy Cancer Research Centre, UNSW SydneyCenter for Developmental Genetics and Department of Anesthesiology, Stony Brook UniversityWellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Haematology, University of CambridgeBiological Resources Imaging Laboratory, Mark Wainwright Analytical Centre, Lowy Cancer Research Centre, UNSW SydneySurgical & Orthopaedic Research Laboratories, Prince of Wales Clinical School, UNSW SydneyBiological Resources Imaging Laboratory, Mark Wainwright Analytical Centre, Lowy Cancer Research Centre, UNSW SydneyCentre for Health Technologies and the School of Biomedical Engineering, University of Technology Sydney||Children?ˉs Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney||School of Women?ˉs and Children?ˉs Health, UNSW Sydney
基础医学细胞生物学分子生物学
Beck Dominik,Zanini Fabio,G?ttgens Berthold,Chandrakanthan Vashe,Chacon Diego,Kang Young Chan,Huang Yizhou,Oliver Rema A.,Unnikrishnan Ashwin,Lee Brendan,Pimanda John E.,Rorimpandey Prunella,Taoudi Samir,Knezevic Kathy,Qiao Qiao,Enikolopov Grigori,Mendez-Ferrer Simon,Brownlee Chris,Walsh William,Power Carl,Carter Daniel R..Mesoderm-Derived PDGFRA + Cells Regulate the Emergence of Hematopoietic Stem Cells in the Dorsal Aorta[EB/OL].(2025-03-28)[2025-04-30].https://www.biorxiv.org/content/10.1101/2021.08.08.455592.点此复制
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