Wnt inhibition promotes vascular specification of embryonic cardiac progenitors.

David E Reichman,Kenny Chao,David Redmond,Richard P Harvey,Makoto M Taketo,Limor Man,Zev Rosenwaks,Daylon James,Laura Park

doi:10.1242/dev.159905

Abstract

ABSTRACTSeveral studies have demonstrated a multiphasic role for Wnt signaling during embryonic cardiogenesis and developed protocols that enrich for cardiac derivatives during in vitro differentiation of human pluripotent stem cells (hPSCs). However, few studies have investigated the role of Wnt signaling in the specification of cardiac progenitor cells (CPCs) toward downstream fates. Using transgenic mice and hPSCs, we tracked endothelial cells (ECs) that originated from CPCs expressing NKX2.5. Analysis of EC-fated CPCs at discrete phenotypic milestones during hPSC differentiation identified reduced Wnt activity as a hallmark of EC specification, and the enforced activation or inhibition of Wnt reduced or increased, respectively, the degree of vascular commitment within the CPC population during both hPSC differentiation and mouse embryogenesis. Wnt5a, which has been shown to exert an inhibitory influence on Wnt signaling during cardiac development, was dynamically expressed during vascular commitment of hPSC-derived CPCs, and ectopic Wnt5a promoted vascular specification of hPSC-derived and mouse embryonic CPCs.

Highlights

One out of every three deaths in the USA results from cardiovascular disease (Roger et al, 2012)
We interrogated the role of the Wnt pathway in specifying endothelial derivatives of embryonic cardiac progenitor cells (CPCs) and demonstrated a differential influence of Wnt signaling in regulating the growth and vascular specification of CPCs during mouse cardiogenesis and cardiac differentiation of human pluripotent stem cells (hPSCs)
By combining recombinase-based fate mapping and cardiac-specific perturbations of Wnt signaling with in vitro modulation of Wnt signaling in hPSC differentiation cultures, we linked inhibition of Wnt signaling with acquisition of vascular fate, and identified a novel mechanism of cardiac neovascularization that is mediated by paracrine modulation of Wnt signaling in CPCs (Fig. 8)

Summary

Introduction

One out of every three deaths in the USA results from cardiovascular disease (Roger et al, 2012). Regenerative therapies represent a promising alternative to surgical and/or pharmacological interventions for. Autologous, tissue-resident cardiac progenitor cells (CPCs) have demonstrated modest benefit upon transplantation into patients following myocardial infarction (MI) (Bolli et al, 2011; Chugh et al, 2012), and cardiomyocytes differentiated from human pluripotent stem cells (hPSCs) and transplanted into small animal models of MI have shown favorable results (Laflamme et al, 2007; Shiba et al, 2012). Nonfatal ventricular arrhythmias have been noted in non-human primates engrafted with hPSC-derived cardiomyocytes (Chong et al, 2014), underscoring the challenge of achieving ordered intercalation of exogenous cells into injured cardiac tissue

Methods

Results

Conclusion