Developing an Injectable Nanofibrous Extracellular Matrix Hydrogel With an Integrin αvβ3 Ligand to Improve Endothelial Cell Survival, Engraftment and Vascularization

Abstract

Endothelial cell (EC) transplantation via injectable collagen hydrogel has received much attention as a potential treatment for various vascular diseases. However, the therapeutic effect of transplanted ECs is limited by their poor viability, which partially occurs as a result of cellular apoptosis triggered by the insufficient cell-extracellular matrix (ECM) engagement. Integrin binding to the ECM is crucial for cell anchorage to the surrounding matrix, cell spreading and migration, and further activation of intracellular signaling pathways. Although collagen contains several different types of integrin binding sites, it still lacks sufficient specific binding sites for ECs. Previously, using one-bead one-compound (OBOC) combinatorial technology, we identified LXW7, an integrin αvβ3 ligand, which possessed a strong binding affinity to and enhanced functionality of ECs. In this study, to improve the EC-matrix interaction, we developed an approach to molecularly conjugate LXW7 to the collagen backbone, via a collagen binding peptide SILY, in order to increase EC specific integrin binding sites on the collagen hydrogel. Results showed that in the in vitro 2-dimensional (2D) culture model, the LXW7-treated collagen surface significantly improved EC attachment and survival and decreased caspase 3 activity in an ischemic-mimicking environment. In the in vitro 3dimensional (3D) culture model, LXW7-modified collagen hydrogel significantly improved EC spreading, proliferation, and survival. In a mouse subcutaneous implantation model, LXW7-modified collagen hydrogel improved the engraftment of transplanted ECs and supported ECs to form vascular network structures. Therefore, LXW7-functionalized collagen hydrogel has shown promising potential to improve vascularization in tissue regeneration and may be used as a novel tool for EC delivery and the treatment of vascular diseases.

Proangiogenic Collagen-Binding Glycan Therapeutic Promotes Endothelial Cell Angiogenesis

“…In this study, we built upon the DS–SILY therapeutic by further functionalizing with an angiogenic peptide to stimulate angiogenesis through integrin-mediated VEGF pathway activation. The cyclic octapeptide LXW7 has been shown to specifically target the αvβ3 integrin on ECs when tethered to a surface and can induce targeted and controlled angiogenesis through VEGFR2 phosphorylation . We hypothesized that by combining the collagen-binding decorin mimetic with the proangiogenic peptide (LXW7–DS–SILY), we could capitalize on the ability of DS–SILY to suppress collagen matrix degradation and promote angiogenesis indirectly through integrin-mediated VEGFR2 phosphorylation.…”

Infantile hemangioma models: is the needle in a haystack?

“…These implants formed a block-like structure after 4 weeks, similar to an expanded vascular plexus. This model is one of the most promising models for research in the fields of angiogenesis, 3D cell culture, vascular growth factors, and cell-to-cell communication [ 103 , 104 ]. It resembles the progression of IH observed in infants and young children, from the proliferative to the regressive stage.…”

Fabrication of Vascular Grafts Using Poly(ε-Caprolactone) and Collagen-Encapsuled ADSCs for Interposition Implantation of Abdominal Aorta in Rhesus Monkeys

“…Collagen has been served as a biodegradable scaffold material and extensively employed in research on vascular regeneration studies, supporting and promoting angiogenesis . Prior research has shown that collagen regulates the migration and adhesion of endothelial cells by furnishing cell adhesion sites and facilitating cell-to-cell interactions. , Through binding to cell receptors, collagen initiates a cascade of cellular signaling pathways that impact various functions, including the survival, proliferation, and migration of vascular endothelial cells. , Additionally, collagen can modulate inflammatory responses, contributing to wound healing and the reconstruction of endothelial function . ADSCs are a type of multipotent stem cell found in adipose tissue, possessing the potential for multilineage differentiation.…”

“…30,31 Through binding to cell receptors, collagen initiates a cascade of cellular signaling pathways that impact various functions, including the survival, proliferation, and migration of vascular endothelial cells. 32,33 Additionally, collagen can modulate inflammatory responses, contributing to wound healing and the reconstruction of endothelial function. 34 ADSCs are a type of multipotent stem cell found in adipose tissue, possessing the potential for multilineage differentiation.…”