Enzymatic self-assembly nanofibers anchoring mesenchymal stem cells induce cell spheroids and amplify paracrine function for myocardial infarction therapy

Transplantation of stem cells with biomaterials has proved to be an effective way to improve cell engraftment and survival in treating degenerative diseases. Owing to their structural resemblance to the extracellular matrix (ECM), synthetic biomaterials have been shown to mimic the native tissue microenvironment and support regeneration. Thus, they have been used extensively in tissue engineering to induce desirable cellular responses. However, it is challenging to develop synthetic materials for mimicking native ECM with dynamic processes like cell-mediated remodeling. Here, inspired by the natural unfolding of fibronectin to dynamic ECM remodeling, we designed an enzyme-instructed self-assembled peptide (Nap-pD-E7) that enables a sheet of mesenchymal stem cells (MSC) to form cell spheroids during the intercellular morphological transition of enzymatic self-assembly. Analysis showed that the supramolecular assemblies formed by phosphatase instructed partial dephosphorylation of Nap-pD-E7 interacted with ECM molecules in the intercellular space of MSC. Further studies revealed that Nap-pD-E7 assemblies significantly improved the gene expression of angiogenic factors and that conditioned medium from Nap-pD-E7–induced MSC spheroids promoted tube formation in human umbilical vein endothelial cells (HUVECs). Finally, transplantation of Nap-pD-E7 hydrogel encapsulated MSC spheroids to the murine infarcted myocardium could improve cell retention, promote tissue angiogenesis, attenuate ventricular remodeling, therefore ameliorate heart function. In conclusion, this approach using cell-responsive peptide assemblies mimicking cell-mediated remodeling of the ECM to modulate MSC functions is a feasible option for cell-based therapy.