An immunometabolic patch facilitates mesenchymal stromal/stem cell therapy for myocardial infarction through a macrophage-dependent mechanism.

ABSTRACT

Mesenchymal stromal/stem cells (MSCs) have emerged as a promising approach against myocardial infarction. Due to hostile hyperinflammation, however, poor retention of transplanted cells seriously impedes their clinical applications. Proinflammatory M1 macrophages, which rely on glycolysis as their main energy source, aggravate hyperinflammatory response and cardiac injury in ischemic region. Here, we showed that the administration of an inhibitor of glycolysis, 2-deoxy-d-glucose (2-DG), blocked the hyperinflammatory response within the ischemic myocardium and subsequently extended effective retention of transplanted MSCs. Mechanistically, 2-DG blocked the proinflammatory polarization of macrophages and suppressed the production of inflammatory cytokines. Selective macrophage depletion abrogated this curative effect. Finally, to avoid potential organ toxicity caused by systemic inhibition of glycolysis, we developed a novel chitosan/gelatin-based 2-DG patch that directly adhered to the infarcted region and facilitated MSC-mediated cardiac healing with undetectable side effects. This study pioneered the application of an immunometabolic patch in MSC-based therapy and provided insights into the therapeutic mechanism and advantages of this innovative biomaterial.