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Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells.

ABSTRACT: Clarifying the mechanisms via which pacemaker- like cells are generated is critical for identifying novel targets for arrhythmia-associated disorders and constructing pacemakers with the ability to adapt to physiological requirements. T-box 18 (Tbx18)+ epicardial progenitor cells (EPCs) have the potential to differentiate into pacemaker cells. Although bone morphogenetic protein 4 (Bmp4) is likely to contribute, its role and regulatory mechanisms in the differentiation of Tbx18+ EPCs into pacemaker-like cells have remained to be fully elucidated. In the present study, the association between Bmp4, GATA binding protein 4 (Gata4) and hyperpolarization- activated cyclic nucleotide gated potassium channel 4 (Hcn4) to regulate NK2 homeobox 5 (Nkx2.5), which is known to be required for the differentiation of Tbx18+ EPCs into pacemaker-like cells, was assessed. Tbx18+ EPCs were isolated from Tbx18:Cre/Rosa26Renhanced yellow fluorescence protein (EYFP) murine embryos at embryonic day 11.5 and divided into the following four treatment groups: Control, Bmp4, Bmp4+LDN193189 (a Bmp inhibitor) and LDN193189. In vitro Bmp4 promoted the expression of Hcn4 in Tbx18+ EPCs via lineage tracing of Tbx18:Cre/Rosa26REYFP mice, which was likely due to upregulation of Gata4 expression. Gata4 knockdown experiments were then performed using the following five treatment groups: Control, control small interfering RNA (siRNA), Bmp4, Bmp4+siRNA targeting Gata4 (siGata4) and siGata4 group. Knockdown of Gata4 caused a downregulation of Hcn4 and an upregulation of Nkx2.5, but had no effect on Bmp4 expression. In conclusion, it was indicated that in Tbx18+ EPCs, the expression of Nkx2.5 was regulated by Bmp4 via Gata4. Taken together, these results provide important information on regulatory networks of pacemaker cell differentiation and may serve as a basis for further studies.

SUBMITTER: Wu L

PROVIDER: S-EPMC6425233 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells.

Wu Ling L Du Jianlin J Jing Xiaodong X Yan Yuling Y Deng Songbai S Hao Zhengtao Z She Qiang Q

Experimental and therapeutic medicine 20190204 4

Clarifying the mechanisms via which pacemaker- like cells are generated is critical for identifying novel targets for arrhythmia-associated disorders and constructing pacemakers with the ability to adapt to physiological requirements. T-box 18 (Tbx18)<sup>+</sup> epicardial progenitor cells (EPCs) have the potential to differentiate into pacemaker cells. Although bone morphogenetic protein 4 (Bmp4) is likely to contribute, its role and regulatory mechanisms in the differentiation of Tbx18<sup>+< ...[more]

PMID: 30906456

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Project description:BackgroundAdipose-derived mesenchymal stem cells (ADMSCs) are a promising source of material source for medical regeneration of cartilage. Growth factors, including transforming growth factor-β (TGFβ) subfamily members and bone morphogenetic proteins (BMPs), play important roles in inducing and promoting chondrogenic differentiation of MSCs. However, these exogenous growth factors have some drawbacks related to their cost, biological half-life, and safety for clinical application. Several studies have reported that statins, the competitive inhibitors of 3-hydroxy-2-methylglutaryl coenzyme A (HMG-CoA) reductase, induce the expression of BMP2 in multiple cell types as the pleotropic effects. The objective of this study was to investigate the effects of fluvastatin during chondrogenic differentiation of human ADMSCs (hADMSCs).MethodsThe effects of fluvastatin were analyzed during chondrogenic differentiation of hADMSCs in the pellet culture without exogenous growth factors by qRT-PCR and histology. For functional studies, Noggin, an antagonist of BMPs, mevalonic acid (MVA) and geranylgeranyl pyrophosphate (GGPP), metabolites of the mevalonate pathway, ROCK inhibitor (Y27632), or RAC1 inhibitor (NSC23766) were applied to cells during chondrogenic differentiation. Furthermore, RhoA activity was measured by RhoA pulldown assay during chondrogenic differentiation with or without fluvastatin. Statistically significant differences between groups were determined by Student's t-test or the Tukey-Kramer test.ResultsFluvastatin-treated cells expressed higher levels of BMP2, SOX9, ACAN, and COL2A1 than control cells, and accumulated higher levels of glycosaminoglycans (GAGs). Noggin significantly inhibited the fluvastatin-mediated upregulation of ACAN and COL2A1. Both MVA and GGPP suppressed the effects of fluvastatin on the expressions of BMP2, SOX9, ACAN, and COL2A1. Furthermore, fluvastatin suppressed the RhoA activity, and inhibition of RhoA-ROCK signaling by Y27632 increased the expressions of BMP2, SOX9, ACAN, and COL2A1, as well as fluvastatin.ConclusionsOur results suggest that fluvastatin promotes chondrogenic differentiation of hADMSCs by inducing endogenous BMP2, and that one of the mechanisms underlying the effects is inhibition of RhoA-ROCK signaling via suppression of GGPP. Fluvastatin is a safe and low-cost compound that holds promise for use in transplantation of hADMSCs for cartilage regeneration.

Dataset Information

Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells.

Publications

Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells.

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