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Stem Cells. 2014 Jun;32(6):1493-502. doi: 10.1002/stem.1660.

Insulin-like growth factor promotes cardiac lineage induction in vitro by selective expansion of early mesoderm.

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Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Laboratory of Experimental Cardiology, Department of Cardiology, Heart Center Leiden, Leiden University Medical Center, Leiden, The Netherlands.


A thorough understanding of the developmental signals that direct pluripotent stem cells (PSCs) toward a cardiac fate is essential for translational applications in disease modeling and therapy. We screened a panel of 44 cytokines/signaling molecules for their ability to enhance Nkx2.5(+) cardiac progenitor cell (CPC) formation during in vitro embryonic stem cell (ESC) differentiation. Treatment of murine ESCs with insulin or insulin-like growth factors (IGF1/2) during early differentiation increased mesodermal cell proliferation and, consequently, CPC formation. Furthermore, we show that downstream mediators of IGF signaling (e.g., phospho-Akt and mTOR) are required for this effect. These data support a novel role for IGF family ligands to expand the developing mesoderm and promote cardiac differentiation. Insulin or IGF treatment could provide an effective strategy to increase the PSC-based generation of CPCs and cardiomyocytes for applications in regenerative medicine.


Akt; Cardiac differentiation; Cardiac progenitor cell; Cardiomyocyte; Development; Embryonic stem cell; In vitro screening; Insulin; Insulin-like growth factor; Mesoderm

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