TGF-β1/CD105 signaling controls vascular network formation within growth factor sequestering hyaluronic acid hydrogels

Abstract

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.

S-endoglin expression is induced in hyperoxia and contributes to altered pulmonary angiogenesis in bronchopulmonary dysplasia development

“…To date, most studies published on endoglin have focused on L-endoglin, although L-endoglin and S-endoglin are co-expressed and distinguishable in vivo 32,36,37,[39][40][41][42][43]48,[50][51][52] . This finding explains the contradictory results in the quantitative expression of endoglin in experimental BPD models or postmortem BPD patients in which the total quantity of endoglin has been evaluated 9,11,18,25,32,40,42,45,53 .…”

“…Evidence indicates that L-endoglin, the predominant isoform in ECs, promotes EC proliferation via TGFβ-ALK1 signalling, whereas S-endoglin acts as an antagonist of L-endoglin via activation of the TGFβ-ALK5 pathway 32,33,36,37 .To date, most studies published on endoglin have focused on L-endoglin. It has been found that L-endoglin enhances ALK1-Smad1/5 signalling in ECs, leading to proliferation and migration, which are the main characteristics of the activation phase of angiogenesis 15,18,20,22,[38][39][40][41][42][43] . However, a role of S-endoglin during endothelial senescence was recently described 36,37 .…”

“…Transforming growth factor β (TGFβ) plays a pivotal role during lung development and angiogenesis through the regulation of endothelial cell (EC) growth, differentiation, migration, senescence, and extracellular matrix (ECM) production [15][16][17][18][19] . TGFβ-mediated signalling is initiated by binding to a TGFβ specific membrane receptor complex in ECs that contains 3 types of receptors: type I and type II serine/threonine kinase receptors and a co-receptor or TGFβ type III receptor named endoglin, also known as CD105.…”

“…TGFβ-mediated signalling is initiated by binding to a TGFβ specific membrane receptor complex in ECs that contains 3 types of receptors: type I and type II serine/threonine kinase receptors and a co-receptor or TGFβ type III receptor named endoglin, also known as CD105. These receptors propagate the signal to the downstream nuclear effectors, Smads, by phosphorylation 16,18,[20][21][22] . Phosphorylated Smads bind to the common Smad4 protein, translocate into the nucleus and regulate the transcription of their target genes.…”

Biomaterials for Sequestration of Growth Factors and Modulation of Cell Behavior

“…The affinitybound TGF-β1 induces an initial response on progenitor cells, which is then amplified by the sequestering of proangiogenic GFs produced endogenously in response to the initial stimulation. [101][102][103] This provides a good example of the emerging trends of ECM-inspired microenvironment manipulation for control of stem/progenitor cell behavior. To prepare these gels, HA was modified with acrylate groups while heparin was thiolated, with thiol-ene chemistry being used to link the two polymeric components.…”