Matrix Viscoelasticity Controls Differentiation of Human Blood Vessel Organoids into Arterioles and Promotes Neovascularization in Myocardial Infarction

Abstract Stem cell‐derived blood vessel organoids are embedded in extracellular matrices to stimulate vessel sprouting. Although vascular organoids in 3D collagen I‐Matrigel gels are currently available, they are primarily capillaries composed of endothelial cells (ECs), pericytes, and mesenchymal stem‐like cells, which necessitate mature arteriole differentiation for neovascularization. In this context, the hypothesis that matrix viscoelasticity regulates vascular development is investigated in 3D cultures by encapsulating blood vessel organoids within viscoelastic gelatin/β‐CD assembly dynamic hydrogels or methacryloyl gelatin non‐dynamic hydrogels. The vascular organoids within the dynamic hydrogel demonstrate enhanced angiogenesis and differentiation into arterioles containing smooth muscle cells. The dynamic hydrogel mechanical microenvironment promotes vascular patterning and arteriolar differentiation by elevating notch receptor 3 signaling in mesenchymal stem cells and downregulating platelet‐derived growth factor B expression in ECs. Transplantation of vascular organoids in vivo, along with the dynamic hydrogel, leads to the reassembly of arterioles and restoration of cardiac function in infarcted hearts. These findings indicate that the viscoelastic properties of the matrix play a crucial role in controlling the vascular organization and differentiation processes, suggesting an exciting potential for its application in regenerative medicine.