Boosting angiogenesis and functional vascularization in injectable dextran-hyaluronic acid hydrogels by endothelial-like mesenchymal stromal cells

Angiogenesis and neovascularization are fundamental for the success of clinically relevant-sized tissue-engineered (TE) constructs. The next generation of TE constructs relies on providing instructive materials combined with the delivery of angiogenic growth factors and cells to avoid tissue ischemia. However, the majority of materials and cell types screened so far show limited clinical relevance, either due to insufficient number of cells or due to the use of animal-derived matrixes. Here, we investigated whether endothelial-like cells derived from mesenchymal stromal cells (EL-MSCs) can be used for vascular TE in combination with injectable dextran-hyaluronic acid (Dex-g-HA) hydrogels. These hydrogels can be easily modified, as demonstrated by the incorporation of vascular endothelial growth factor (VEGF). We examined in vitro the reciprocal influences between cells and matrix. Dex-g-HA enabled higher EL-MSC metabolic rates associated with optimal cell sprouting in vitro compared to human umbilical vein endothelial cells. In vivo evaluation demonstrated the absence of an acute inflammatory response, and EL-MSCs incorporated within Dex-g-HA formed a functional vascular network integrated with the host vascular system. This work demonstrates that Dex-g-HA is an efficient delivery method of VEGF to induce angiogenesis. Additionally, functional neovascularization can be achieved in vitro and in vivo by the combination of Dex-g-HA with EL-MSC.