Tbx20 Promotes Cardiomyocyte Proliferation and Persistence of Fetal Characteristics in Adult Mouse Hearts

While differentiated cardiomyocytes proliferate prior to birth, adult cardiomyocytes in mammals exhibit relatively little proliferative activity. The T-box transcription factor Tbx20 is necessary and sufficient to promote prenatal cardiomyocyte proliferation, and Tbx20 also is required for adult cardiac homeostasis. The ability of Tbx20 to promote post-natal and adult cardiomyocyte proliferation was examined in mice with cardiomyocyte-specific Tbx20 gain-of-function beginning in the fetal period. In adult hearts, increased Tbx20 expression promotes cardiomyocyte proliferation and results in increased numbers of small, cycling, mononucleated cardiomyocytes, marked by persistent expression of fetal contractile protein genes. In adult cardiomyocytes in vivo and in neonatal rat cardiomyocytes in culture, Tbx20 promotes the activation of BMP2/pSmad1/5/8 and PI3K/AKT/GSK3β/β-catenin signaling pathways concomitant with increased cell proliferation. Inhibition of PI3K/AKT/GSK3β/β-catenin signaling reduces, but does not eliminate, Tbx20-mediated increases in cell proliferation, providing evidence for parallel regulatory pathways downstream of BMP/Smad1/5/8 signaling in promoting cardiomyocyte proliferation after birth. Thus, Tbx20 overexpression beginning in the fetal period activates multiple cardiac proliferative pathways after birth and maintains adult cardiomyocytes in an immature state in vivo.