Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitors

Abstract

Guiding multipotent cells into distinct lineages and controlling their expansion remain fundamental challenges in developmental and stem cell biology. Members of the Wnt pathway control many pivotal embryonic events, often promoting self-renewal or expansion of progenitor cells. In contrast, canonical Wnt ligands are thought to negatively regulate cardiomyogenesis in several species. However, the cell-autonomous role of canonical Wnt signaling within precardiac mesoderm, through its obligatory transcriptional mediator, ␤-catenin, is unknown. Using tissue-specific in vivo genetic manipulation, we found that ␤-catenin is required for development of cardiac progenitors and is a positive regulator of proliferative expansion of such progenitor cells. At discrete windows of development in embryonic stem cells, activation of canonical Wnt signaling promoted expansion of cardiac progenitors after initial commitment and was required for cardiac differentiation. Together, these data provide in vivo and in vitro evidence that canonical Wnt signaling promotes the expansion of cardiac progenitors and differentiation of cardiomyocytes.cardiac development ͉ embryonic stem cells ͉ ␤-catenin ͉ second heart field

Genetics and Genetic Testing in Congenital Heart Disease

“…Similarly, mouse studies have demonstrated that Wnt signals are critical for early cardiac precursor induction and proliferation, but later become inhibitory 28,29 . As previously mentioned, a diverse array of cardiac transcription factors acts in concert with these signals to specify, differentiate, and pattern the developing heart.…”

β-Catenin downregulation attenuates ischemic cardiac remodeling through enhanced resident precursor cell differentiation

“…The earliest progenitor cell population corresponds to the FHF, which expresses Tbx5 during differentiation and gives rise to the LV (14). The second population identified by Islet-1 expression corresponds to the second heart field (SHF) from which right ventricle, atria, and outflow tract will arise (17,(19)(20)(21). Our findings of the coexpression of ␣MHC and specific cardiac transcription factors like GATA4, and Tbx5 characteristic for the LV, suggest the existence of an ␣MHC pos / cTnT neg cardiac committed FHF stem cell population in the adult heart.…”

The Multiple Phases and Faces of Wnt Signaling During Cardiac Differentiation and Development

“…In contrast, overexpressing a stabilized version of ␤-catenin under the control of the same enhancer resulted in enlarged ventricular chambers, more cells, and upregulated expression of cyclinD2. 82 Because both chambers were affected, these phenotypes strongly argue that in both cardiac lineages Wnt/␤-catenin signaling supports the expansion of committed cardiac progenitor cells. In contrast, deleting ␤-catenin using a Mesp1 driver mainly affected the SHF but not the FHF.…”

“…81 The overexpression of ␤-catenin, however, results in an expansion of SHF-derived structures. 79,82 These phenotypes were clearly linked to an effect of Wnt/␤-catenin signaling on cell proliferation. Also in the posterior part of the SHF Wnt signaling regulates cell proliferation.…”