Retinoic acid signaling modulation guides in vitro specification of human heart field-specific progenitor pools

Dorota Zawada, Jessica Kornherr, Anna B. Meier, Gianluca Santamaria, Tatjana Dorn, Monika Nowak-Imialek, Daniel Ortmann, Fangfang Zhang, Mark Lachmann, Martina Dreßen, Mariaestela Ortiz, Victoria L. Mascetti, Stephen C. Harmer, Muriel Nobles, Andrew Tinker, Maria Teresa Angelis, Roger A. Pedersen, Phillip Grote, Karl-Ludwig Laugwitz (), Alessandra Moretti () and Alexander Goedel ()
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Dorota Zawada: Technical University of Munich, School of Medicine and Health
Jessica Kornherr: Technical University of Munich, School of Medicine and Health
Anna B. Meier: Technical University of Munich, School of Medicine and Health
Gianluca Santamaria: Technical University of Munich, School of Medicine and Health
Tatjana Dorn: Technical University of Munich, School of Medicine and Health
Monika Nowak-Imialek: Technical University of Munich, School of Medicine and Health
Daniel Ortmann: University of Cambridge
Fangfang Zhang: Technical University of Munich, School of Medicine and Health
Mark Lachmann: Technical University of Munich, School of Medicine and Health
Martina Dreßen: Institute Insure - Technical University of Munich, School of Medicine and Health
Mariaestela Ortiz: University of Cambridge
Victoria L. Mascetti: Bristol Heart Institute, Bristol Medical School, Translational Health Sciences
Stephen C. Harmer: University of Bristol
Muriel Nobles: Queen Mary University of London
Andrew Tinker: Queen Mary University of London
Maria Teresa Angelis: Technical University of Munich, School of Medicine and Health
Roger A. Pedersen: Stanford University
Phillip Grote: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy
Karl-Ludwig Laugwitz: Technical University of Munich, School of Medicine and Health
Alessandra Moretti: Technical University of Munich, School of Medicine and Health
Alexander Goedel: Technical University of Munich, School of Medicine and Health

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Cardiogenesis relies on the precise spatiotemporal coordination of multiple progenitor populations. Understanding the specification and differentiation of these distinct progenitor pools during human embryonic development is crucial for advancing our knowledge of congenital cardiac malformations and designing new regenerative therapies. By combining genetic labelling, single-cell transcriptomics, and ex vivo human-mouse embryonic chimeras we uncovered that modulation of retinoic acid signaling instructs human pluripotent stem cells to form heart field-specific progenitors with distinct fate potentials. In addition to the classical first and second heart fields, we observed the appearance of juxta-cardiac field progenitors giving rise to both myocardial and epicardial cells. Applying these findings to stem-cell based disease modelling we identified specific transcriptional dysregulation in first and second heart field progenitors derived from stem cells of patients with hypoplastic left heart syndrome. This highlights the suitability of our in vitro differentiation platform for studying human cardiac development and disease.

Date: 2023
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DOI: 10.1038/s41467-023-36764-x

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