Activin A Modulates CRIPTO-1/HNF4α+Cells to Guide Cardiac Differentiation from Human Embryonic Stem Cells.
The use of human pluripotent stem cells in basic and translational cardiac research requires efficient differentiation protocols towards cardiomyocytes. In vitro differentiation yields heterogeneous populations of ventricular-, atrial-, and nodal-like cells hindering their potential applications in regenerative therapies. We described the effect of the growth factor Activin A during early human embryonic stem cell fate determination in cardiac differentiation. Addition of high levels of Activin A during embryoid body cardiac differentiation augmented the generation of endoderm derivatives, which in turn promoted cardiomyocyte differentiation. Moreover, a dose-dependent increase in the coreceptor expression of the TGF-βsuperfamily memberCRIPTO-1was observed in response to Activin A. We hypothesized that interactions between cells derived from meso- and endodermal lineages in embryoid bodies contributed to improved cell maturation in early stages of cardiac differentiation, improving the beating frequency and the percentage of contracting embryoid bodies. Activin A did not seem to affect the properties of cardiomyocytes at later stages of differentiation, measuring action potentials, and intracellular Ca2+dynamics. These findings are relevant for improving our understanding on human heart development, and the proposed protocol could be further explored to obtain cardiomyocytes with functional phenotypes, similar to those observed in adult cardiac myocytes.
Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
Robin
R
Duelen
Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, 3000 Leuven, Belgium.
Guillaume
G
Gilbert
Stem Cell Institute Leuven and Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
Abdulsamie
A
Patel
Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
Nathalie
N
de Schaetzen
Child Neurology, University Hospitals Leuven, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
Liesbeth
L
De Waele
Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, 3000 Leuven, Belgium.
Llewelyn
L
Roderick
Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, 3000 Leuven, Belgium.
Karin R
KR
Sipido
Stem Cell Institute Leuven and Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
Catherine M
CM
Verfaillie
Child Neurology, University Hospitals Leuven, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
Gunnar M
GM
Buyse
Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; Tissue Engineering Laboratory, Department of Development and Regeneration, KU Leuven, Campus Kulak Kortrijk, 8500 Kortrijk, Belgium.
Lieven
0000-0002-5896-6823
L
Thorrez
Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; Division of Human Anatomy, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy.
Maurilio
0000-0002-2422-3757
M
Sampaolesi