BMP signaling regulation by GREMLIN 2 promotes proliferation and differentiation of human iPS cell-derived cardiac progenitors to cardiomyocytes

Abstract

Heart development depends on coordinated proliferation and differentiation of cardiac progenitor cells, but how the two processes are synchronized is not well understood. The data herein show that the secreted BMP antagonist GREMLIN 2 (GREM2) is induced in cardiac progenitor cells 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 pro-cardiogenic differentiation methods. These data show that inhibition of canonical BMP signaling by GREM2 is necessary to promote proliferation of cardiac progenitor cells. 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.