1. Coordinated Proliferation and Differentiation of Human-Induced Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Depend on Bone Morphogenetic Protein Signaling Regulation by GREMLIN 2.
- Author
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Bylund JB, Trinh LT, Awgulewitsch CP, Paik DT, Jetter C, Jha R, Zhang J, Nolan K, Xu C, Thompson TB, Kamp TJ, and Hatzopoulos AK
- Subjects
- Bone Morphogenetic Proteins metabolism, Bone Morphogenetic Proteins pharmacology, Cell Differentiation drug effects, Cell Line, Cell Proliferation drug effects, Cells, Cultured, Cytokines, Gene Expression Profiling, Gene Expression Regulation, Developmental, Humans, Induced Pluripotent Stem Cells cytology, Induced Pluripotent Stem Cells drug effects, Intercellular Signaling Peptides and Proteins metabolism, Intercellular Signaling Peptides and Proteins pharmacology, Myocardium cytology, Myocardium metabolism, Myocytes, Cardiac cytology, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism, Organogenesis genetics, Signal Transduction drug effects, Signal Transduction genetics, Stem Cells cytology, Stem Cells drug effects, Bone Morphogenetic Proteins genetics, Cell Differentiation genetics, Cell Proliferation genetics, Induced Pluripotent Stem Cells metabolism, Intercellular Signaling Peptides and Proteins genetics, Stem Cells metabolism
- Abstract
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.
- Published
- 2017
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