Open AccessTGF-β1/CD105 signaling controls vascular network formation within growth factor sequestering hyaluronic acid hydrogels
Author(s) -
Stephen Browne,
Amit K. Jha,
Kurosh Ameri,
Sivan G. Marcus,
Yerem Yeghiazarians,
Kevin E. Healy
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0194679
Subject(s) - hyaluronic acid , endoglin , transforming growth factor , vascular endothelial growth factor , self healing hydrogels , neovascularization , microbiology and biotechnology , growth factor , angiogenesis , transforming growth factor beta , regenerative medicine , chemistry , cell growth , cancer research , biology , immunology , stem cell , biochemistry , anatomy , receptor , vegf receptors , cd34 , organic chemistry
Cell-based strategies for the treatment of ischemic diseases are at the forefront of tissue engineering and regenerative medicine. Cell therapies purportedly can play a key role in the neovascularization of ischemic tissue; however, low survival and poor cell engraftment with the host vasculature following implantation limits their potential to treat ischemic diseases. To overcome these limitations, we previously developed a growth factor sequestering hyaluronic acid (HyA)-based hydrogel that enhanced transplanted mouse cardiosphere-derived cell survival and formation of vasculature that anastomosed with host vessels. In this work, we examined the mechanism by which HyA hydrogels presenting transforming growth factor beta-1 (TGF-β1) promoted proliferation of more clinically relevant human cardiosphere-derived cells (hCDC), and their formation of vascular-like networks in vitro . We observed hCDC proliferation and enhanced formation of vascular-like networks occurred in the presence of TGF-β1. Furthermore, production of nitric oxide (NO), VEGF, and a host of angiogenic factors were increased in the presence of TGF-β1. This response was dependent on the co-activity of CD105 (Endoglin) with the TGF-βR2 receptor, demonstrating its role in the process of angiogenic differentiation and vascular organization of hCDC. These results demonstrated that hCDC form vascular-like networks in vitro , and that the induction of vascular networks by hCDC within growth factor sequestering HyA hydrogels was mediated by TGF-β1/CD105 signaling.