A nitric oxide-releasing hydrogel for enhancing the therapeutic effects of mesenchymal stem cell therapy for hindlimb ischemia

Therapeutic angiogenesis with mesenchymal stem cells (MSCs) is promising for the clinical treatment of peripheral artery disease (PAD). However, the heterogeneous proangiogenic nature of MSCs is a key challenge in developing more effective treatments with MSCs for therapeutic angiogenesis purposes. Here, we propose to enhance the therapeutic function of human placenta-derived MSCs (hP-MSCs) in hindlimb ischemia therapy by using nitric oxide (NO)-releasing chitosan hydrogel (CS-NO). Our data showed that the co-transplantation of CS-NO hydrogel with hP-MSCs remarkably improved the grafting of hP-MSCs and ameliorated the functional recovery of ischemic hindlimbs. Moreover, we found that the neovascularization of damaged hindlimbs was significantly increased after co-transplanting CS-NO hydrogel and hP-MSCs, as confirmed by bioluminescence imaging (BLI). Further analysis revealed an endothelial-like status transformation of hP-MSCs in the presence of NO, which was identified as a potential mechanism contributing to the enhanced endothelium-protective and proangiogenic capacities of hP-MSCs that promote angiogenesis in mouse models of hindlimb ischemia. In conclusion, this study provides a promising approach for using NO hydrogel to improve the proangiogenic potency of MSCs in ischemic diseases, and the strategy used here facilitates the development of controlled-release scaffolds for enhancing the therapeutic efficiency of MSCs in angiogenic therapy. STATEMENT OF SIGNIFICANCE: The heterogeneous proangiogenic nature of mesenchymal stem cells (MSCs) is a key challenge in developing more effective treatments with MSCs for therapeutic angiogenesis purposes. In this study, we investigated whether nitric oxide (NO)-releasing chitosan hydrogel (CS-NO) could improve the proangiogenic potency of MSCs in ischemic diseases. Our results revealed an endothelial-like status transformation of human placenta-derived MSCs (hP-MSCs) in the presence of NO, which was identified as a potential mechanism contributing to the enhanced endothelium-protective and proangiogenic capacities of hP-MSCs that promote angiogenesis in mouse models of hindlimb ischemia. The strategy for enhancing the pro-angiogenic activity of MSCs with biomaterials provides a practical idea for overcoming the challenges associated with the clinical application of MSCs in therapeutic angiogenesis.