CCR2-engineered mesenchymal stromal cells accelerate diabetic wound healing by restoring immunological homeostasis.

Abstract

Impaired wound healing presents great health risks to patients. While encouraging, the current clinical successes of mesenchymal stromal cell (MSC)-based therapies for tissue repair have been limited. Genetic engineering could endow MSCs with more robust regenerative capacities. Here, we identified that C-C motif chemokine receptor 2 (CCR2) overexpression enhanced the targeted migration and immunoregulatory potential of MSCs in response to C-C motif chemokine ligand 2 (CCL2) in vitro. Intravenously infusion of CCR2-engineered MSCs (MSCs^CCR2) exhibited improved homing efficiencies to injured sites and lungs of diabetic mice. Accordingly, MSC^CCR2 infusion inhibited monocyte infiltration, reshaped macrophage inflammatory properties, prompted the accumulation of regulatory T cells (Treg cells) in injured sites, and reshaped systemic immune responses via the lung and spleen in mouse diabetic wound models. In summary, CCR2-engineered MSCs restore immunological homeostasis to accelerate diabetic wound healing via their improved homing and immunoregulatory potentials in response to CCL2. Therefore, these findings provide a novel strategy to explore genetically engineered MSCs as tools to facilitate tissue repair in diabetic wounds.