HAND1 level controls the specification of multipotent cardiac and extraembryonic progenitors from human pluripotent stem cells
Lynch, Adam T Phillips, Naomi Douglas, Megan Dorgnach, Marta Lin, I-Hsuan Adamson, Antony D Darieva, Zoulfia Whittle, Jessica Hanley, Neil A Bobola, Nicoletta
Lynch, Adam T
Phillips, Naomi
Douglas, Megan
Dorgnach, Marta
Lin, I-Hsuan
Adamson, Antony D
Darieva, Zoulfia
Whittle, Jessica
Hanley, Neil A
Bobola, Nicoletta
Affiliation
University of Manchester; University of Birmingham; University Hospitals Birmingham NHS Foundation Trust
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Publication date
2025-03-31
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Abstract
Diverse sets of progenitors contribute to the development of the embryonic heart, but the mechanisms of their specification have remained elusive. Here, using a human pluripotent stem cell (hPSC) model, we deciphered cardiac and non-cardiac lineage trajectories in differentiation and identified transcription factors underpinning cell specification, identity and function. We discovered a concentration-dependent, fate determining function for the basic helix-loop-helix transcription factor HAND1 in mesodermal progenitors and uncovered its gene regulatory network. At low expression level, HAND1 directs differentiation towards multipotent juxta-cardiac field progenitors able to make cardiomyocytes and epicardial cells, whereas at high level it promotes the development of extraembryonic mesoderm. Importantly, HAND1-low progenitors can be propagated in their multipotent state. This detailed mechanistic insight into human development has the potential to accelerate the delivery of effective disease modelling, including for congenital heart disease, and cell therapy-based regenerative medicine.
Citation
Lynch AT, Phillips N, Douglas M, Dorgnach M, Lin IH, Adamson AD, Darieva Z, Whittle J, Hanley NA, Bobola N, Birket MJ. HAND1 level controls the specification of multipotent cardiac and extraembryonic progenitors from human pluripotent stem cells. EMBO J. 2025 May;44(9):2541-2565. doi: 10.1038/s44318-025-00409-0. Epub 2025 Mar 31.
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Article