The Renewal and Differentiation of Isl1+ Cardiovascular Progenitors Are Controlled by a Wnt/β-Catenin Pathway

Abstract

Isl1(+) cardiovascular progenitors and their downstream progeny play a pivotal role in cardiogenesis and lineage diversification of the heart. The mechanisms that control their renewal and differentiation are largely unknown. Herein, we show that the Wnt/beta-catenin pathway is a major component by which cardiac mesenchymal cells modulate the prespecification, renewal, and differentiation of isl1(+) cardiovascular progenitors. This microenvironment can be reconstituted by a Wnt3a-secreting feeder layer with ES cell-derived, embryonic, and postnatal isl1(+) cardiovascular progenitors. In vivo activation of beta-catenin signaling in isl1(+) progenitors of the secondary heart field leads to their massive accumulation, inhibition of differentiation, and outflow tract (OFT) morphogenic defects. In addition, the mitosis rate in OFT myocytes is significantly reduced following beta-catenin deletion in isl1(+) precursors. Agents that manipulate Wnt signals can markedly expand isl1(+) progenitors from human neonatal hearts, a key advance toward the cloning of human isl1(+) heart progenitors.

Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling

“…Phase-contrast images of E18.5 embryos and hearts from WT and Tet3 KO mice showed no obvious developmental abnormalities of cardiac or other tissues. Nevertheless, qPCR and immunostaining analysis of the whole hearts from WT and Tet3 KO embryos (E18.5) showed an increase of the cardiac progenitor marker Isl-1, a target gene of Wnt/β-catenin signaling (44) in the Tet3 KO heart, especially in the right ventricle (Fig. S5).…”

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

“…32,33 Also, differentiation of Isl1 ϩ cardiac progenitors was inhibited by the addition of Wnt3a-conditioned media. 84 Interestingly, the above-mentioned overexpression of constitutively active ␤-catenin by use of a SHF-specific enhancer of the Mef2c gene resulted in massive accumulation of Isl1-positive progenitor cells attributable not only to increased proliferation but also to a massive inhibition of terminal differentiation. 84 A novel extracellular inhibitor of Wnt/␤-catenin signaling was identified recently as IGFBP-4 (insulin-like growth factors binding protein).…”

“…84 Interestingly, the above-mentioned overexpression of constitutively active ␤-catenin by use of a SHF-specific enhancer of the Mef2c gene resulted in massive accumulation of Isl1-positive progenitor cells attributable not only to increased proliferation but also to a massive inhibition of terminal differentiation. 84 A novel extracellular inhibitor of Wnt/␤-catenin signaling was identified recently as IGFBP-4 (insulin-like growth factors binding protein). In Xenopus, it was shown that IGFBP-4 binds to Frizzled and LRP6, thereby preventing binding of a Wnt ligand.…”

Chemical Biology of Pluripotent Stem Cells: Focus on Cardiomyogenesis

“…In contrast, late addition of BIO (starting at day 5) completely abolished the expression of cardiac markers and the appearance of spontaneously contracting embryoid bodies [56]. Interestingly, the same compound BIO was identified in a HTS screen for small molecules that expand postnatal Isl1+ cardiovascular progenitor cells [58], and it was also shown to promote proliferation of neonatal and adult rat cardiomyocytes [59]. These intriguing results suggest that small molecule Wnt pathway activators like BIO may one day be used as pharmacological agents to restore function in the diseased heart.…”