Cardiosphere-Derived Cells Require Endoglin for Paracrine-Mediated Angiogenesis.

Derek Gilchrist,Benjamin J. Davison,Esha Singh,Rachael E. Redgrave,Alexander Medvinsky,Muhammad M. Amirrasouli,Helen M. Arthur,Simon Tual-Chalot,Darroch Hall

doi:10.1016/j.stemcr.2017.04.015

Abstract

SummaryClinical trials of stem cell therapy to treat ischemic heart disease primarily use heterogeneous stem cell populations. Small benefits occur via paracrine mechanisms that include stimulating angiogenesis, and increased understanding of these mechanisms would help to improve patient outcomes. Cardiosphere-derived-cells (CDCs) are an example of these heterogeneous stem cell populations, cultured from cardiac tissue. CDCs express endoglin, a co-receptor that binds specific transforming growth factor β (TGFβ) family ligands, including bone morphogenetic protein 9 (BMP9). In endothelial cells endoglin regulates angiogenic responses, and we therefore hypothesized that endoglin is required to promote the paracrine pro-angiogenic properties of CDCs. Cre/LoxP technology was used to genetically manipulate endoglin expression in CDCs, and we found that the pro-angiogenic properties of the CDC secretome are endoglin dependent both in vitro and in vivo. Importantly, BMP9 pre-treatment of endoglin-depleted CDCs restores their pro-angiogenic paracrine properties. As BMP9 signaling is normally required to maintain endoglin expression, we propose that media containing BMP9 could be critical for therapeutic CDC preparation.

Highlights

Stem cells have both differentiation capacities and paracrine effects that can be harnessed to promote tissue regeneration
The majority of CDCs at passage 2 (P2) express endoglin, the proportion of endoglin-positive CDCs reduces at later passages
To determine the role of endoglin, we prepared CDCs from mice in which Endoglin can be depleted by Cre/LoxP technology

Summary

SUMMARY

Clinical trials of stem cell therapy to treat ischemic heart disease primarily use heterogeneous stem cell populations. Cardiosphere-derived-cells (CDCs) are an example of these heterogeneous stem cell populations, cultured from cardiac tissue. CDCs express endoglin, a co-receptor that binds specific transforming growth factor b (TGFb) family ligands, including bone morphogenetic protein 9 (BMP9). In endothelial cells endoglin regulates angiogenic responses, and we hypothesized that endoglin is required to promote the paracrine pro-angiogenic properties of CDCs. Cre/LoxP technology was used to genetically manipulate endoglin expression in CDCs, and we found that the pro-angiogenic properties of the CDC secretome are endoglin dependent both in vitro and in vivo. BMP9 pre-treatment of endoglin-depleted CDCs restores their pro-angiogenic paracrine properties. As BMP9 signaling is normally required to maintain endoglin expression, we propose that media containing BMP9 could be critical for therapeutic CDC preparation

INTRODUCTION

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DISCUSSION

EXPERIMENTAL PROCEDURES