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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]

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

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  • Media type: E-Article
  • Title: Transient stabilization of human cardiovascular progenitor cells from human pluripotent stem cells in vitro reflects stage-specific heart development in vivo
  • Contributor: 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]
  • Published: July 2024
  • Published in: Cardiovascular research ; 120(2024), 11 vom: Juli, Seite 1295-1311
  • Language: English
  • DOI: 10.1093/cvr/cvae118
  • Identifier:
  • Origination:
  • Footnote: Veröffentlicht: 05. Juni 2024
  • Description: 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.
  • Access State: Open Access