Sorbitol-responsive in situ gel improves rat ischemic hearts: Supporting mesenchymal stem cell survival and enhancing paracrine effect.

Mesenchymal stem cells (MSCs) repair damaged myocardium by secreting biological factors and have shown only modest therapeutic efficacy in clinical trials. We recently developed a sorbitol-responsive in situ gelling material (SRG) solution, which increases viscosity by diffusing out pre-added sorbitol upon contact with heart tissue without external stimulation. Here, this study demonstrates that intramyocardial injection of MSC-loaded SRG (MSC/SRG) improves cardiac function and facilitates tissue repair following acute myocardial ischemia in rats, and the underlying mechanisms are elucidated. MSC/SRG is more effective than either MSC or SRG alone in preventing cardiac dysfunction and fibrotic remodeling while stimulating angiogenesis. The optimized SRG consists of 25 mg/mL boronic acid group-bearing polymer, 10 mg/mL polyvinyl alcohol, and 5 mg/mL sorbitol, which prolongs MSC survival and enhances their paracrine function in in vitro and in vivo assays. Sorbitol supplementation increases MSC proliferation, modulates cytokine secretion from MSCs in a concentration-dependent manner, and promotes angiogenesis in vitro. These findings suggest that the sorbitol in SRG supports MSC survival and enhances MSC paracrine activity. The SRG may facilitate the therapeutic potential of MSC and hydrogel-based interventions for myocardial ischemia.