Sox17 drives functional engraftment of endothelium converted from non-vascular cells

Chaitanya R. Badwe,Raphael Lis,Olivier Elemento,Balvir Kunar,Masataka Yokoyama,Shahin Rafii,Michael Ginsberg,Brisa Palikuqi,Joseph M. Scandura,William Schachterle

doi:10.1038/ncomms13963

Abstract

Transplanting vascular endothelial cells (ECs) to support metabolism and express regenerative paracrine factors is a strategy to treat vasculopathies and to promote tissue regeneration. However, transplantation strategies have been challenging to develop, because ECs are difficult to culture and little is known about how to direct them to stably integrate into vasculature. Here we show that only amniotic cells could convert to cells that maintain EC gene expression. Even so, these converted cells perform sub-optimally in transplantation studies. Constitutive Akt signalling increases expression of EC morphogenesis genes, including Sox17, shifts the genomic targeting of Fli1 to favour nearby Sox consensus sites and enhances the vascular function of converted cells. Enforced expression of Sox17 increases expression of morphogenesis genes and promotes integration of transplanted converted cells into injured vessels. Thus, Ets transcription factors specify non-vascular, amniotic cells to EC-like cells, whereas Sox17 expression is required to confer EC function.

Highlights

Transplanting vascular endothelial cells (ECs) to support metabolism and express regenerative paracrine factors is a strategy to treat vasculopathies and to promote tissue regeneration
Clustering and PCA analyses of transcriptional profiles indicated that active myrAkt1 (Akt) signalling did not broadly enhance EC gene expression, we found that Akt signalling refined the Fli[1] genomic binding site purview of RACVECs, making it more similar to Akt-LECs and LSECs (Fig. 3d and Supplementary Fig. 3d)
We found that 337 genes were downregulated and 30% of these genes were found in the set of genes that were reduced in Akt-RACVECs

Summary

Introduction

Transplanting vascular endothelial cells (ECs) to support metabolism and express regenerative paracrine factors is a strategy to treat vasculopathies and to promote tissue regeneration. Ets transcription factors specify non-vascular, amniotic cells to EClike cells, whereas Sox[17] expression is required to confer EC function. Enforced expression of Sox[17] in RACVECs enabled converted cells to form stable vascular networks in vitro and in vivo, and obviated the need for constitutive Akt signalling. Sox[17] is not required to activate a broad set of EC genes in amniotic cells, after initial EC gene induction by Ets factors, subsequent Sox[17] gene regulation is required to generate long-lasting engraftable and stable ECs. As vascular engraftment after transplantation is necessary for both the angiogenic and instructive functions of ECs in orchestrating organ repair, our approach identifies a key TF network governing EC transplantation and provides an important step towards EC-directed therapy

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