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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Item Type:	Article
Title:	Transient stabilization of human cardiovascular progenitor cells from human pluripotent stem cells in vitro reflects stage-specific heart development in vivo
Creators Name:	Bolesani, E., Bornhorst, D., Iyer, L.I., Zawada, D., Friese, N., Morgan, M., Lange, L., Gonzalez, D., Schrode, N., Leffler, A., Wunder, J., Franke, A., Drakhlis, L., Sebra, R., Schambach, A., Goedel, A., Dubois, N., Dobreva, G., Moretti, A., Zelarayán, L.C., Abdelilah-Seyfried, S. and Zweigerdt, R.
Abstract:	AIM: 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. METHODS AND RESULTS: Here we show that chemical modulation of Histone Acetyl Transferases (HATs; by IQ-1) and WNT (by CHIR99021), synergistically enable 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 upregulation 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 RNAseq-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 (pSHF) of mouse hearts, hallmarked by NR2F2 expression. Investigating molecular mechanisms of SCP stabilization, we found that the cell-autonomously regulated Retinoic Acid (RA) and BMP signaling is governing SCPs transition from quiescence towards proliferation and cell-autonomous differentiation, reminiscent of a niche-like behavior. CONCLUSION: The chemically defined and reversible nature our stabilization approach provides an unprecedented opportunity to dissect mechanisms of cardiovascular progenitors' specification and reveal their cellular and molecular properties.
Keywords:	hPSC-Derived Cardiovascular Progenitors, Second Heart Field, Small Molecules, WNT Pathway, Histone Acetyl, Transferases, Animals, Mice
Source:	Cardiovascular Research
ISSN:	0008-6363
Publisher:	Oxford University Press
Volume:	120
Number:	11
Page Range:	1295-1311
Date:	July 2024
Official Publication:	https://doi.org/10.1093/cvr/cvae118
PubMed:	View item in PubMed

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