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. Here, 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 catalyze 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.

Endothelium-Mimetic Surface Modification Improves Antithrombogenicity and Enhances Patency of Vascular Grafts in Rats and Pigs.

We first identified thrombomodulin (TM) and endothelial nitric oxide (NO) synthase as key factors for the antithrombogenic function of the endothelium in human atherosclerotic carotid arteries. Then, recombinant TM and an engineered galactosidase responsible for the conversion of an exogenous NO prodrug were immobilized on the surface of the vascular grafts. Surface modification by TM and NO cooperatively enhanced the antithrombogenicity and patency of vascular grafts. Importantly, we found that the combination of TM and NO also promoted endothelialization, whereas it reduced adverse intimal hyperplasia, which is critical for the maintenance of vascular homeostasis, as confirmed in rat and pig models.

Enzyme-responsive hybrid prodrug of nitric oxide and hydrogen sulfide for heart failure therapy.

A hybrid prodrug was synthesized to realize the combined delivery of nitric oxide and hydrogen sulfide. The NO-H2S donor can release nitric oxide and hydrogen sulfide step by step in response to the endogenous enzymes ß-galactosidase and carbonic anhydrase, providing potent therapeutic efficacy for heart failure post- myocardial infarction.

MSC-derived sEV-loaded hyaluronan hydrogel promotes scarless skin healing by immunomodulation in a large skin wound model.

Designing hydrogel-based constructs capable of adjusting immune cell functions holds promise for skin tissue regeneration. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have attracted increasing attention owing to their anti-inflammatory and proangiogenic effects. Herein, we constructed a biofunctional hydrogel in which MSC-derived sEVs were incorporated into the injectable hyaluronic acid hydrogel, thus endowing the hydrogel with immunomodulatory effects. When implanted onto the wound site in a mouse large skin injury model, this functional hydrogel facilitates wound healing and inhibits scar tissue formation by driving macrophages towards an anti-inflammatory and anti-fibrotic (M2c) phenotype. Further investigation showed that the M2c-like phenotype induced by MSC-derived sEVs markedly inhibited the activation of fibroblasts, which could result in scarless skin wound healing. Taken together, these results suggest that modulation of the immune response is a promising and efficient approach to prevent fibrotic scar formation.