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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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Hauptverfasser: Bolesani, Emiliano (VerfasserIn) , Bornhorst, Dorothee (VerfasserIn) , Iyer, Lavanya M (VerfasserIn) , Zawada, Dorota (VerfasserIn) , Friese, Nina (VerfasserIn) , Morgan, Michael (VerfasserIn) , Lange, Lucas (VerfasserIn) , Gonzalez, David M (VerfasserIn) , Schrode, Nadine (VerfasserIn) , Leffler, Andreas (VerfasserIn) , Wunder, Julian (VerfasserIn) , Franke, Annika (VerfasserIn) , Drakhlis, Lika (VerfasserIn) , Sebra, Robert (VerfasserIn) , Schambach, Axel (VerfasserIn) , Goedel, Alexander (VerfasserIn) , Dubois, Nicole C (VerfasserIn) , Dobreva, Gergana (VerfasserIn) , Moretti, Alessandra (VerfasserIn) , Zelaráyan, Laura C (VerfasserIn) , Abdelilah-Seyfried, Salim (VerfasserIn) , Zweigerdt, Robert (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: July 2024
In: Cardiovascular research
Year: 2024, Jahrgang: 120, Heft: 11, Pages: 1295-1311
ISSN:1755-3245
DOI:10.1093/cvr/cvae118
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1093/cvr/cvae118
Volltext
Verfasserangaben: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
Beschreibung
Zusammenfassung: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.
Beschreibung:Veröffentlicht: 05. Juni 2024
Gesehen am 26.11.2024
Beschreibung:Online Resource
ISSN:1755-3245
DOI:10.1093/cvr/cvae118

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