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Stem Cells Dev. 2017 May 1;26(9):678-693. doi: 10.1089/scd.2016.0226. Epub 2017 Mar 20.

Coordinated Proliferation and Differentiation of Human-Induced Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Depend on Bone Morphogenetic Protein Signaling Regulation by GREMLIN 2.

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1 Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee.
2 Department of Pharmacology, Vanderbilt University School of Medicine , Nashville, Tennessee.
3 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine , Nashville, Tennessee.
4 Department of Pediatrics, Emory University School of Medicine , Atlanta, Georgia .
5 Stem Cell and Regenerative Medicine Center, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin.
6 Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati , Cincinnati, Ohio.


Heart development depends on coordinated proliferation and differentiation of cardiac progenitor cells (CPCs), but how the two processes are synchronized is not well understood. Here, we show that the secreted Bone Morphogenetic Protein (BMP) antagonist GREMLIN 2 (GREM2) is induced in CPCs shortly after cardiac mesoderm specification during differentiation of human pluripotent stem cells. GREM2 expression follows cardiac lineage differentiation independently of the differentiation method used, or the origin of the pluripotent stem cells, suggesting that GREM2 is linked to cardiogenesis. Addition of GREM2 protein strongly increases cardiomyocyte output compared to established procardiogenic differentiation methods. Our data show that inhibition of canonical BMP signaling by GREM2 is necessary to promote proliferation of CPCs. However, canonical BMP signaling inhibition alone is not sufficient to induce cardiac differentiation, which depends on subsequent JNK pathway activation specifically by GREM2. These findings may have broader implications in the design of approaches to orchestrate growth and differentiation of pluripotent stem cell-derived lineages that depend on precise regulation of BMP signaling.


BMP signaling; GREMLIN 2; cardiomyocyte differentiation; human pluripotent stem cells

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