Tgf-β1/cd105 signaling controls vascular network formation within growth factor sequestering hyaluronic acid hydrogels
Jha, Amit K.
Marcus, Sivan G.
Healy, Kevin E.
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Browne, Shane; Jha, Amit K. Ameri, Kurosh; Marcus, Sivan G.; Yeghiazarians, Yerem; Healy, Kevin E. (2018). Tgf-β1/cd105 signaling controls vascular network formation within growth factor sequestering hyaluronic acid hydrogels. PLOS ONE 13 (3),
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-beta 1) promoted proliferation of more clinically relevant human cardiospherederived 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-beta 1. Furthermore, production of nitric oxide (NO), VEGF, and a host of angiogenic factors were increased in the presence of TGF-beta 1. This response was dependent on the co-activity of CD105 (Endoglin) with the TGF-beta R2 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-beta 1/CD105 signaling.