title: Insulin-like growth factor binding protein 4 enhances cardiomyocytes induction in murine-induced pluripotent stem cells.
abstract: Insulin-like growth factor binding protein 4 (IGFBP4) has been reported to play critical role in cardiomyocytes differentiation of embryonic stem cells (ESCs). But whether it promotes cardiomyocytes induction of iPSCs is unclear. In the present study, we aim to explore the role of IGFBP4 in the cardiogenesis of mouse iPSCs. We observed that IGFBP4 treatment at late stage during differentiation process of mouse iPSCs greatly enhanced the beating frequency of embryoid bodies (EBs). The expressions of Nkx2.5 (cardiac-specific transcription factor), α-MHC, α-actinin, and Troponin I (cardiac-specific protein) were significantly enhanced by IGFBP4 treatment. Immunostaining analysis showed that α-MHC, TNNT2 and connexin 43, typical cardiac markers, were obviously expressed in isolated cardiomyocytes from iPSCs with or without IGFBP4 treatment. Further study revealed that IGFBP4 had little effect on the apoptosis of EBs, but it significantly promoted the proliferation of cardiomyocytes from iPSCs characterized by higher ratio EdU positive cells in differentiated cardiomyocytes. We next observed that IGFBP4 inhibited β-catenin expression in cytosol of EBs at late stage during differentiation of iPSCs. Knockdown of β-catenin using a siRNA technique promoted the proliferation of differentiated cardiomyocytes and enhanced cardiomyocytes induction of iPSCs, suggesting that the effect of IGFBP4 on cardiomyocytes differentiation of iPSCs has relationship with β-catenin signaling pathway. In conclusion, IGFBP4 promotes cardiogenesis of iPSCs by enhancing the proliferation of differentiated cardiomyocytes through inhibiting β-catenin signaling.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xue
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yan
authors.forename: Hui
authors.initials: H
authors.lastname: Gong
authors.forename: Bo
authors.initials: B
authors.lastname: Fang
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhou
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Ding
authors.forename: Peipei
authors.initials: P
authors.lastname: Yin
authors.forename: Guoping
authors.initials: G
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Ye
authors.forename: Chunjie
authors.initials: C
authors.lastname: Yang
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058732:Embryoid Bodies / Q000378:metabolism*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects*; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018974:Insulin-Like Growth Factor Binding Protein 4; D051176:beta Catenin
keywords: CARDIOMYOCYTES; DIFFERENTIATION; IGFBP4; MOUSE IPSCS; PROLIFERATION