Intracellular delivery of nitric oxide enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction

Cell therapy by autologous mesenchymal stem cells (MSCs) is a clinically
acceptable strategy for treating various diseases. Unfortunately, the
therapeutic efficacy is largely affected by the low quality of MSCs
collected from patients. Herein, we showed that the gene expression of
MSCs from patients with diabetes was differentially regulated compared to
that of MSCs from healthy controls. Then, MSCs were genetically engineered
to catalyse an NO prodrug to release NO intracellularly. Compared to
extracellular NO conversion, intracellular NO delivery effectively
prolonged survival and enhanced the paracrine function of MSCs, as
demonstrated by in vitro and in vivo assays. The enhanced therapeutic
efficacy of engineered MSCs combined with intracellular NO delivery was
further confirmed in mouse and rat models of myocardial infarction, and a
clinically relevant cell administration paradigm through secondary
thoracotomy has been attempted.