Rosuvastatin-loaded injectable immunomodulatory hydrogel mitigates local immune response against transplanted stem cells and promotes heart repair in vivo

In clinical trials allogeneic mesenchymal stem cells (MSCs) from young and healthy donors have shown promise to repair the heart following a heart attack. However, immune rejection of transplanted MSCs has prevented the clinical translation of stem cells-based therapies for cardiac patients. Therefore, strategies to improve survival of implanted stem cells in the heart would be of immense therapeutic value. This study presents the development of a novel immunomodulatory chitosan-rosuvastatin (CR) hydrogel loaded with MSCs for cardiac repair. The hydrogel showed excellent 3 dimensional (3D) structure and porosity, and was found to support the growth of MSCs. In an in vivo rat model of myocardial infarction (MI), the immunomodulatory CR hydrogel provided physical bulk, improved the retention of MSCs and cardiac function at 4 weeks after MI. The RNA sequencing data demonstrate that rosuvastatin improved the "stemness" of MSCs and reduced the activation of T-cells, downregulated T_H1 polarization in response to inflammatory stress in the infarcted heart. Therefore, the current study presents a new paradigm in improving clinical effectiveness of stem cell therapy for cardiac repair by modulating local immune response in the heart against transplanted stem cells using a novel immunomodulatory CR hydrogel.