Single-cell profiling reveals three endothelial-to-hematopoietic transitions with divergent isoform expression landscapes
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.
Authors
- Natalia Moncaut
- Robert Sellers
- Harshangda Bhatnagar
- Georges Lacaud (ORCID: https://orcid.org/0000-0002-5630-2417)
- Emanuele Azzoni (ORCID: https://orcid.org/0000-0002-4572-5692)
- Syed Murtuza Baker (ORCID: https://orcid.org/0000-0002-6633-333X)
- Giulia Quattrini (ORCID: https://orcid.org/0000-0002-3750-710X)
- Wolfgang Breitwieser
- Gianluca Sala (ORCID: https://orcid.org/0000-0002-4494-915X)
- Roshana Thambyrajah (ORCID: https://orcid.org/0000-0002-3941-760X)
- Wen Hao Neo (ORCID: https://orcid.org/0000-0002-6827-3027)
- Cristiana Barone (ORCID: https://orcid.org/0000-0001-5517-3214)
- John Weightman (ORCID: https://orcid.org/0000-0002-3569-3914)
- Muhammad Zaki Hidayatullah Fadlullah (ORCID: https://orcid.org/0000-0002-3111-8090)
- Michael Lie‐A‐Ling (ORCID: https://orcid.org/0000-0003-0194-4313)
- Filipa Timóteo-Ferreira (ORCID: https://orcid.org/0000-0002-9454-162X)
- Sten Eirik W. Jacobsen (ORCID: https://orcid.org/0000-0002-1362-3659)
- Joana Carrelha (ORCID: https://orcid.org/0000-0002-0324-2617)
- Mudassar Iqbal (ORCID: https://orcid.org/0000-0002-5006-4331)
Institutions
- Universidad de Cantabria (ES)
- Karolinska University Hospital (SE)
- University of Utah (US)
- Huntsman Cancer Institute (US)
- Karolinska Institutet (SE)
- University of Manchester (GB)
- University of Oxford (GB)
- MRC Weatherall Institute of Molecular Medicine (GB)
- Azienda Ospedaliera San Gerardo (IT)
- Cancer Research UK Manchester Institute (GB)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Imperial College London (GB)
- University of Milano-Bicocca (IT)
Publication Details
- Journal
- Nature Cardiovascular Research
- Published
- 2025-11-11
- DOI
- https://doi.org/10.1038/s44161-025-00740-z
- Primary Topic
- Zebrafish Biomedical Research Applications
- Type
- article
- Field-Weighted Citation Impact
- 0.00