Please use this identifier to cite or link to this item: https://doi.org/10.1186/s13287-018-1086-8
Title: Wnt/β-catenin-mediated signaling re-activates proliferation of matured cardiomyocytes
Authors: Fan, Y.
Ho, B.X.
Pang, J.K.S.
Pek, N.M.Q.
Hor, J.H.
Ng, S.-Y. 
Soh, B.-S. 
Keywords: 6 [[2 [[4 (2,4 dichlorophenyl) 5 (4 methyl 1h imidazol 2 yl) 2 pyrimidinyl]amino]ethyl]amino]nicotinonitrile
beta catenin
cell marker
nerve cell adhesion molecule
protein antibody
Wnt protein
beta catenin
cadherin
Cdh2 protein, mouse
messenger RNA
pyridine derivative
pyrimidine derivative
adult
animal cell
Article
cardiac muscle cell
cell activation
cell maturation
cell proliferation
controlled study
cytoplasm
human
immunohistochemistry
mouse
nonhuman
polymerase chain reaction
priority journal
quantitative analysis
signal transduction
upregulation
Western blotting
Wnt signaling
animal
cardiac muscle
cardiac muscle cell
cell differentiation
cell line
cell nucleus
cell proliferation
cytology
deficiency
disease model
genetics
human embryonic stem cell
metabolism
pathology
phenotype
protein transport
Wnt signaling
Adult
Animals
beta Catenin
Cadherins
Cell Differentiation
Cell Line
Cell Nucleus
Cell Proliferation
Disease Models, Animal
Human Embryonic Stem Cells
Humans
Mice
Myocardium
Myocytes, Cardiac
Phenotype
Protein Transport
Pyridines
Pyrimidines
RNA, Messenger
Up-Regulation
Wnt Signaling Pathway
Issue Date: 2018
Publisher: BioMed Central Ltd.
Citation: Fan, Y., Ho, B.X., Pang, J.K.S., Pek, N.M.Q., Hor, J.H., Ng, S.-Y., Soh, B.-S. (2018). Wnt/β-catenin-mediated signaling re-activates proliferation of matured cardiomyocytes. Stem Cell Research and Therapy 9 (1) : 338. ScholarBank@NUS Repository. 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 ?-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. © 2018 The Author(s).
Source Title: Stem Cell Research and Therapy
URI: https://scholarbank.nus.edu.sg/handle/10635/174516
ISSN: 17576512
DOI: 10.1186/s13287-018-1086-8
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