VE-cadherin functionalized injectable PAMAM/HA hydrogel promotes endothelial differentiation of hMSCs and vascularization

Abstract The functionalization of hydrogels for tissue engineering mainly focuses on the modification of hydrogels with extracellular matrices (ECM) and growth factors to promote vascularization by bio-mimicking vascular extracellular microenvironment. However, the lack of cell-cell interactions limit both the regulation in stem cell fate and the vascularization in the early stage of cell-hydrogel complex formation. In this study, a human vascular endothelial cadherin fusion protein (hVE-cad-Fc) is developed and employed for the functionalization of polyamidoamine/thiolated hyaluronic acid (PAMAM/HS-HA) hydrogel utilizing an Fc-binding polypeptide attached to the alkene modified PAMAM dendrimer (hVE-P/H). The hVE-P/H hydrogel enhances the adhesion and proliferation of human umbilical cord mesenchymal stem cells (hMSCs) as the RGD peptide functionalized hydrogel (R-P/H) does, and further significantly facilitates the reconstruction of vascular-promoting extracellular microenvironment through up-regulating the expression of endogenous VE-cadherin and the secretion of hMSCs, including growth factors (VEGF and ANG-1), ECM components (fibronectin and laminin), and immune-modulating factors (IDO and PGE2). Meanwhile, hMSCs-loaded hVE-P/H hydrogel effectively promotes not only the survival and endothelial differentiation of hMSCs independent of exogenous VEGF, but also the host cell recruitment, and the subsequent vascularization. Furthermore, the effects of the hVE-P/H hydrogel were considered to be imposed by activating the protein expressions of VE-cadherin/FAK/PI3K/AKT, VE-cadherin/VEGFR2/P-VEGFR2, and the VE-cadherin/YAP/P-YAP mediated cellular mechanotransduction by hVE-cad-Fc fusion protein. Therefore, functionalization of hydrogel with VE-cadherin is of great significance for the vascularization in tissue engineering and opens a new horizon for the design of cell-cell adhesion molecule-based advanced biomaterials.