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Transient stabilization of human cardiovascular progenitor cells from human pluripotent stem cells in vitro reflects stage-specific heart development in vivo

Understanding the molecular identity of human pluripotent stem cell (hPSC)-derived cardiac progenitors and mechanisms controlling their proliferation and differentiation is valuable for developmental biology and regenerative medicine.Here, we show that chemical modulation of histone acetyl transfera...

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Main Authors: Bolesani, Emiliano (Author) , Bornhorst, Dorothee (Author) , Iyer, Lavanya M (Author) , Zawada, Dorota (Author) , Friese, Nina (Author) , Morgan, Michael (Author) , Lange, Lucas (Author) , Gonzalez, David M (Author) , Schrode, Nadine (Author) , Leffler, Andreas (Author) , Wunder, Julian (Author) , Franke, Annika (Author) , Drakhlis, Lika (Author) , Sebra, Robert (Author) , Schambach, Axel (Author) , Goedel, Alexander (Author) , Dubois, Nicole C (Author) , Dobreva, Gergana (Author) , Moretti, Alessandra (Author) , Zelaráyan, Laura C (Author) , Abdelilah-Seyfried, Salim (Author) , Zweigerdt, Robert (Author)
Format: Article (Journal)
Language:English
Published: July 2024
In: Cardiovascular research
Year: 2024, Volume: 120, Issue: 11, Pages: 1295-1311
ISSN:1755-3245
DOI:10.1093/cvr/cvae118
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1093/cvr/cvae118
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Author Notes:Emiliano Bolesani, Dorothee Bornhorst, Lavanya M Iyer, Dorota Zawada, Nina Friese, Michael Morgan, Lucas Lange, David M Gonzalez, Nadine Schrode, Andreas Leffler, Julian Wunder, Annika Franke, Lika Drakhlis, Robert Sebra, Axel Schambach, Alexander Goedel, Nicole C Dubois, Gergana Dobreva, Alessandra Moretti, Laura C Zelaráyan, Salim Abdelilah-Seyfried, and Robert Zweigerdt
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Summary:Understanding the molecular identity of human pluripotent stem cell (hPSC)-derived cardiac progenitors and mechanisms controlling their proliferation and differentiation is valuable for developmental biology and regenerative medicine.Here, we show that chemical modulation of histone acetyl transferases (by IQ-1) and WNT (by CHIR99021) synergistically enables the transient and reversible block of directed cardiac differentiation progression on hPSCs. The resulting stabilized cardiovascular progenitors (SCPs) are characterized by ISL1pos/KI-67pos/NKX2-5neg expression. In the presence of the chemical inhibitors, SCPs maintain a proliferation quiescent state. Upon small molecules, removal SCPs resume proliferation and concomitant NKX2-5 up-regulation triggers cell-autonomous differentiation into cardiomyocytes. Directed differentiation of SCPs into the endothelial and smooth muscle lineages confirms their full developmental potential typical of bona fide cardiovascular progenitors. Single-cell RNA-sequencing-based transcriptional profiling of our in vitro generated human SCPs notably reflects the dynamic cellular composition of E8.25-E9.25 posterior second heart field of mouse hearts, hallmarked by nuclear receptor sub-family 2 group F member 2 expression. Investigating molecular mechanisms of SCP stabilization, we found that the cell-autonomously regulated retinoic acid and BMP signalling is governing SCP transition from quiescence towards proliferation and cell-autonomous differentiation, reminiscent of a niche-like behaviour.The chemically defined and reversible nature of our stabilization approach provides an unprecedented opportunity to dissect mechanisms of cardiovascular progenitors’ specification and reveal their cellular and molecular properties.
Item Description:Veröffentlicht: 05. Juni 2024
Gesehen am 26.11.2024
Physical Description:Online Resource
ISSN:1755-3245
DOI:10.1093/cvr/cvae118

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