Distinctive Roles of Canonical and Noncanonical Wnt Signaling in Human Embryonic Cardiomyocyte Development.

Silvia Mazzotta,Andreia S Bernardo,Rory J Bonner,Stefan Hoppler,Kevin Docherty,Carlos Neves

doi:10.1016/j.stemcr.2016.08.008

Silvia Mazzotta, Andreia S Bernardo + Show 4 more

Open Access

https://doi.org/10.1016/j.stemcr.2016.08.008

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Abstract

SummaryWnt signaling is a key regulator of vertebrate heart development; however, specific roles for human cardiomyocyte development remain uncertain. Here we use human embryonic stem cells (hESCs) to analyze systematically in human cardiomyocyte development the expression of endogenous Wnt signaling components, monitor pathway activity, and dissect stage-specific requirements for canonical and noncanonical Wnt signaling mechanisms using small-molecule inhibitors. Our analysis suggests that WNT3 and WNT8A, via FZD7 and canonical signaling, regulate BRACHYURY expression and mesoderm induction; that WNT5A/5B, via ROR2 and noncanonical signaling, regulate MESP1 expression and cardiovascular development; and that later in development WNT2, WNT5A/5B, and WNT11, via FZD4 and FZD6, regulate functional cardiomyocyte differentiation via noncanonical Wnt signaling. Our findings confirm in human development previously proposed roles for canonical Wnt signaling in sequential stages of vertebrate cardiomyogenesis, and identify more precise roles for noncanonical signaling and for individual Wnt signal and Wnt receptor genes in human cardiomyocyte development.

Highlights

The human heart develops as the first functional organ in the embryo
Several studies in mouse and other experimental models have described diverse, and often opposing, effects of canonical and noncanonical Wnt signaling on subsequent cardiomyocyte differentiation, leading to the argument that the JNK-mediated noncanonical pathway may function in this context to antagonize canonical Wnt signaling (Abdul-Ghani et al, 2011; Cohen et al, 2012; reviewed by Hoppler et al, 2014)
Investigating Wnt Signaling during Human Cardiomyocyte Development Using human embryonic stem cells (hESCs) To study sequential stages of human cardiomyocyte development in vitro, we explored established hESC differentiation protocols

Summary

Introduction

The human heart develops as the first functional organ in the embryo. A well-known key regulator of vertebrate cardiomyocyte differentiation (Hoppler et al, 2014), acts through several molecular mechanisms (Hoppler and Nakamura, 2014): a b-catenin-dependent, so-called canonical pathway, and b-catenin-independent, so-called noncanonical pathways, among which a JNK-dependent pathway is prominent during heart development (Gessert and Kuhl, 2010; Gessert et al, 2008; Pandur et al, 2002a, 2002b). Canonical Wnt signaling has been shown to play multiple and conflicting roles at different stages of heart development (Gessert and Kuhl, 2010; Naito et al, 2006). Specific roles for Wnt signaling in human cardiomyocyte development remain unclear, regarding which endogenous Wnt ligands and Wnt receptors are involved

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