Wnt/β-catenin-mediated signaling re-activates proliferation of matured cardiomyocytes

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Wnt/β-catenin-mediated signaling re-activates proliferation of matured cardiomyocytes
Title:
Wnt/β-catenin-mediated signaling re-activates proliferation of matured cardiomyocytes
Journal Title:
Stem Cell Research & Therapy
Keywords:
Publication Date:
07 December 2018
Citation:
Fan, Y., Ho, B.X., Pang, J.K.S. et al. Wnt/β-catenin-mediated signaling re-activates proliferation of matured cardiomyocytes. Stem Cell Res Ther 9, 338 (2018). https://doi.org/10.1186/s13287-018-1086-8
Abstract:
Background: The Wnt/β-catenin signaling pathway plays an important role in the development of second heart field (SHF Isl1+) that gives rise to the anterior heart field (AHF) cardiac progenitor cells (CPCs) for the formation of the right ventricle, outflow tract (OFT), and a portion of the inflow tract (IFT). During early cardiogenesis, these AHF CPCs reside within the pharyngeal mesoderm (PM) that provides a microenvironment for them to receive signals that direct their cell fates. Here, N-cadherin, which is weakly expressed by CPCs, plays a significant role by promoting the adhesion of CPCs within the AHF, regulating β-catenin levels in the cytoplasm to maintain high Wnt signaling and cardioproliferation while also preventing the premature differentiation of CPCs. On the contrary, strong expression of N-cadherin observed throughout matured myocardium is associated with downregulation of Wnt signaling due to β-catenin sequestration at the cell membrane, inhibiting cardioproliferation. As such, upregulation of Wnt signaling pathway to enhance cardiac tissue proliferation in mature cardiomyocytes can be explored as an interesting avenue for regenerative treatment to patients who have suffered from myocardial infarction. Methods: To investigate if Wnt signaling is able to enhance cellular proliferation of matured cardiomyocytes, we treated cardiomyocytes isolated from adult mouse heart and both murine and human ES cell-derived matured cardiomyocytes with N-cadherin antibody or CHIR99021 GSK inhibitor in an attempt to increase levels of cytoplasmic β-catenin. Immunostaining, western blot, and quantitative PCR for cell proliferation markers, cell cycling markers, and Wnt signaling pathway markers were used to quantitate re-activation of cardioproliferation and Wnt signaling. Results: N-cadherin antibody treatment releases sequestered β-catenin at N-cadherin-based adherens junction, resulting in an increased pool of cytoplasmic β-catenin, similar in effect to CHIR99021 GSK inhibitor treatment. Both treatments therefore upregulate Wnt signaling successfully and result in significant increases in matured cardiomyocyte proliferation. Conclusion: Although both N-cadherin antibody and CHIR99021 treatment resulted in increased Wnt signaling and cardioproliferation, CHIR99021 was found to be the more effective treatment method for human ES cell-derived cardiomyocytes. Therefore, we propose that CHIR99021 could be a potential therapeutic option for myocardial infarction patients in need of regeneration of cardiac tissue.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This work is supported by the Agency for Science, Technology and Research (Singapore) and by a grant from National Medical Research Council to B.S.S (NMRC/OFYIRG/0017/2016). This work is also partially supported by grants from National Natural Science Foundation of China to Y.F. (grant number 81871162 and 81570101), Guangdong Province Science and Technology Project (2017A020214005) and the Guangdong Science and Technology Project (201803010048). Beatrice Xuan Ho and Jeremy Kah Sheng Pang are supported by the National University of Singapore graduate scholarships.
Description:
ISSN:
1757-6512
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