PMID- 32946788 OWN - NLM STAT- MEDLINE VI - 27 IP - 5 TI - Multi-layered Spatial Transcriptomics Identify Secretory Factors Promoting Human Hematopoietic Stem Cell Development. PG - 822-839.e8 CI - Copyright © 2020 Elsevier Inc. All rights reserved. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell Stem Cell JT - Cell stem cell JID - 101311472 IS - 1875-9777 (Electronic) LID - S1934-5909(20)30400-8 [pii] LID - 10.1016/j.stem.2020.08.004 [doi] FAU - Crosse, Edie I AU - Crosse EI AD - MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK. FAU - Gordon-Keylock, Sabrina AU - Gordon-Keylock S AD - MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK. FAU - Rybtsov, Stanislav AU - Rybtsov S AD - MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK. FAU - Binagui-Casas, Anahi AU - Binagui-Casas A AD - MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK. FAU - Felchle, Hannah AU - Felchle H AD - MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK. FAU - Nnadi, Nneka C AU - Nnadi NC AD - MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK. FAU - Kirschner, Kristina AU - Kirschner K AD - Institute of Cancer Sciences, University of Glasgow, Bearsden G61 1QH, UK. FAU - Chandra, Tamir AU - Chandra T AD - MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH4 2XU, UK. FAU - Tamagno, Sara AU - Tamagno S AD - MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK. FAU - Webb, David J AU - Webb DJ AD - BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK. FAU - Rossi, Fiona AU - Rossi F AD - MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK. FAU - Anderson, Richard A AU - Anderson RA AD - MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh EH16 4TJ UK. FAU - Medvinsky, Alexander AU - Medvinsky A AD - MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK. Electronic address: a.medvinsky@ed.ac.uk. IS - 1875-9777 (Linking) SB - IM MH - *Endothelial Cells MH - Gonads MH - Hematopoiesis MH - Hematopoietic Stem Cells MH - Humans MH - Mesonephros MH - *Transcriptome/genetics OTO - NOTNLM OT - *AGM region OT - *HSC OT - *embryo OT - *endothelin OT - *hematopoiesis OT - *single cell transcriptome OT - *spatial transcriptome PMC - PMC7671940 DCOM- 20210512 LR - 20210512 DP - 20201105 DEP - 20200917 AB - Hematopoietic stem cells (HSCs) first emerge in the embryonic aorta-gonad-mesonephros (AGM) region. Studies of model organisms defined intersecting signaling pathways that converge to promote HSC emergence predominantly in the ventral domain of the dorsal aorta. Much less is known about mechanisms driving HSC development in humans. Here, to identify secreted signals underlying human HSC development, we combined spatial transcriptomics analysis of dorsoventral polarized signaling in the aorta with gene expression profiling of sorted cell populations and single cells. Our analysis revealed a subset of aortic endothelial cells with a downregulated arterial signature and a predicted lineage relationship with the emerging HSC/progenitor population. Analysis of the ventrally polarized molecular landscape identified endothelin 1 as an important secreted regulator of human HSC development. The obtained gene expression datasets will inform future studies on mechanisms of HSC development in vivo and on generation of clinically relevant HSCs in vitro.