Wen Hao Neo, Muhammad Zaki Hidayatullah Fadlullah, Harshangda Bhatnagar, Cristiana Barone, Giulia Quattrini, Filipa Timóteo-Ferreira, Joana Carrelha, Gianluca Sala, Robert Sellers, John Weightman, Wolfgang Breitwieser, Natalia Moncaut, Roshana Thambyrajah, Sten Eirik W. Jacobsen, Mudassar Iqbal, Syed Murtuza Baker, Emanuele Azzoni, Michael Lie‐A‐Ling, Georges Lacaud
Hemogenic endothelium (HE) is recognized as the origin of all definitive blood cells, including hematopoietic stem cells (HSCs); however, the mechanisms governing the hematopoietic progenitor versus HSC fate choice within the HE remain unknown. Here we combine differentiation assays with full-length single-cell transcriptome data for extra-embryonic yolk sac (YS) and intra-embryonic aorta-gonad-mesonephros (AGM) region HE populations. We identified and localized three differentiation trajectories, each containing a distinct HE subset: erythromyeloid progenitor-primed HE in the YS plexus, lymphomyeloid progenitor-primed HE in large YS arteries and hematopoietic stem and progenitor cell-primed HE in the AGM. Chromatin modifiers and spliceosome components were enriched in AGM HE. This correlated with a higher isoform complexity of the AGM HE transcriptome. Distinct AGM HE-specific isoform expression patterns were observed for a broad range of genes, including stemness-associated factors like Runx1. Our data form a unique resource for studying cell fate decisions in different HE populations.