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Tissue-Specific Stem Cells
Article first published online: 25 FEB 2013
Copyright © 2013 AlphaMed Press
Volume 31, Issue 3, pages 547–559, March 2013
How to Cite
Clarkin, C. E., King, A. J., Dhadda, P., Chagastelles, P., Nardi, N., Wheeler-Jones, C. P. and Jones, P. M. (2013), Activin Receptor-Like Kinase 5 Inhibition Reverses Impairment of Endothelial Cell Viability by Endogenous Islet Mesenchymal Stromal Cells. STEM CELLS, 31: 547–559. doi: 10.1002/stem.1305
Author contributions: C.C.: conception and design, collection of data, data analysis and interpretation, and manuscript writing; A.J.K. and P.C.: provision of study material and final approval of manuscript; P.D.: collection of data; N.N.: provision of study material and final approval of manuscript; C.P.W.-J. and P.J.: conception and design, data interpretation, and manuscript writing. C.P.W.J. and P.M.J. contributed equally to this article.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS December 19, 2012.
- Issue published online: 25 FEB 2013
- Article first published online: 25 FEB 2013
- Accepted manuscript online: 19 DEC 2012 02:04AM EST
- Manuscript Accepted: 21 NOV 2012
- Manuscript Revised: 6 NOV 2012
- Manuscript Received: 30 JUL 2012
- Diabetes UK and The Diabetes Foundation
- Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil for fundingm
- Islet mesenchymal stromal cell;
- Endothelial cell;
- Transforming growth factor-β
Following islet transplantation, islet graft revascularization is compromised due to loss of endothelial cells (ECs) during islet culture. TGF-β signaling pathways are essential for vascular homeostasis but their importance for islet EC function is unclear. We have identified a population of multipotent mesenchymal stromal cells (MSCs) within islets and investigated how modulation of TGF-β signaling by these cells influences islet EC viability. Cultured islets exhibited reduced expression of EC markers (VEGFR2, VE-cadherin and CD31), which was associated with diminished but sustained expression of endoglin a marker of both ECs and MSCs. Double fluorescent labeling of islets in situ with the EC marker CD31 disclosed a population of CD31-negative cells which were positive for endoglin. In vitro coculture of microvascular ECs with endoglin-positive, CD31-negative islet MSCs reduced VEGFR2 protein expression, disrupted EC angiogenic behavior, and increased EC detachment. Medium conditioned by islet MSCs significantly decreased EC viability and increased EC caspase 3/7 activity. EC:MSC cocultures showed enhanced Smad2 phosphorylation consistent with altered ALK5 signaling. Pharmacological inhibition of ALK5 activity with SB431542 (SB) improved EC survival upon contact with MSCs, and SB-treated cultured islets retained EC marker expression and sensitivity to exogenous VEGF164. Thus, endoglin-expressing islet MSCs influence EC ALK5 signaling in vitro, which decreases EC viability, and changes in ALK5 activity in whole cultured islets contribute to islet EC loss. Modifying TGF-β signaling may enable maintenance of islet ECs during islet isolation and thus improve islet graft revascularization post-transplantation. STEM CELLS2013;31:547–559