TY - JOUR
T1 - Reciprocity of Action of Increasing Oct4 and Repressing p53 in Transdifferentiation of Mouse Embryonic Fibroblasts into Cardiac Myocytes
AU - Wang, Hongran
AU - Zhao, Shuying
AU - Barton, Michelle
AU - Rosengart, Todd
AU - Cooney, Austin J.
N1 - Publisher Copyright:
© Copyright 2018, Mary Ann Liebert, Inc. 2018.
PY - 2018/2
Y1 - 2018/2
N2 - p53 is a barrier to somatic cell reprogramming. Deletion or transient suppression of p53 increases the efficiency of reprogramming of somatic cells into induced pluripotent stem cells. Whether p53 represents an obstacle to a similar process transdifferentiation of somatic cells is unknown. However, it is predicted that inhibition of p53 would promote transdifferentiation of fibroblasts into cardiomyocytes. In this study, the effect of p53 on the capacity of cardiogenic transdifferentiation is evaluated using p53 wild-type (p53), p53 heterozygous mutant (p53), and p53 homozygous mutant (p53 -/- ) mouse embryonic fibroblasts (MEFs). Repression of p53 in MEFs increases the expression level of mesoderm transcription factors Brachyury (T) and MESP1. The cardiac-specific markers, Myh6 (Myosin, Heavy Chain 6), Myh7 (Myosin, Heavy Chain 7), and cTnI (cardiac muscle troponin I), show elevated expression in p53 and p53 -/- MEFs compared with wild-type MEFs, but cardiac muscle troponin T (cTnT) showed a lower expression level when p53 was inhibited. After induction to cardiac differentiation, cTnT expression increased and markers of endoderm and ectoderm decreased in p53 and p53 -/- MEFs. The effect of an important reprogramming factor Oct4 on cardiac transdifferentiation was also evaluated in the allelic series of p53 MEFs. We found that overexpression of Oct4 significantly enhanced Mesp1, Tbx5, and Isl1 expression in p53 and p53 MEFs. Oct4 also enhanced cTnT expression in all three cell lines, especially in p53 MEFs. Thus, inhibition of p53 expression and viral expression of Oct4 both promote transdifferentiation of MEFs into cardiomyocytes, establishing reciprocity of action in the process.
AB - p53 is a barrier to somatic cell reprogramming. Deletion or transient suppression of p53 increases the efficiency of reprogramming of somatic cells into induced pluripotent stem cells. Whether p53 represents an obstacle to a similar process transdifferentiation of somatic cells is unknown. However, it is predicted that inhibition of p53 would promote transdifferentiation of fibroblasts into cardiomyocytes. In this study, the effect of p53 on the capacity of cardiogenic transdifferentiation is evaluated using p53 wild-type (p53), p53 heterozygous mutant (p53), and p53 homozygous mutant (p53 -/- ) mouse embryonic fibroblasts (MEFs). Repression of p53 in MEFs increases the expression level of mesoderm transcription factors Brachyury (T) and MESP1. The cardiac-specific markers, Myh6 (Myosin, Heavy Chain 6), Myh7 (Myosin, Heavy Chain 7), and cTnI (cardiac muscle troponin I), show elevated expression in p53 and p53 -/- MEFs compared with wild-type MEFs, but cardiac muscle troponin T (cTnT) showed a lower expression level when p53 was inhibited. After induction to cardiac differentiation, cTnT expression increased and markers of endoderm and ectoderm decreased in p53 and p53 -/- MEFs. The effect of an important reprogramming factor Oct4 on cardiac transdifferentiation was also evaluated in the allelic series of p53 MEFs. We found that overexpression of Oct4 significantly enhanced Mesp1, Tbx5, and Isl1 expression in p53 and p53 MEFs. Oct4 also enhanced cTnT expression in all three cell lines, especially in p53 MEFs. Thus, inhibition of p53 expression and viral expression of Oct4 both promote transdifferentiation of MEFs into cardiomyocytes, establishing reciprocity of action in the process.
KW - Oct4
KW - cardiomyocyte differentiation
KW - fibroblast
KW - p53
KW - reprogramming
KW - transdifferentiation
UR - http://www.scopus.com/inward/record.url?scp=85041954851&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041954851&partnerID=8YFLogxK
U2 - 10.1089/cell.2017.0031
DO - 10.1089/cell.2017.0031
M3 - Article
C2 - 29412738
AN - SCOPUS:85041954851
SN - 2152-4971
VL - 20
SP - 27
EP - 37
JO - Cellular Reprogramming
JF - Cellular Reprogramming
IS - 1
ER -