Providing a conducive microenvironment is critical to increase survival of transplanted stem cells in regenerative therapy. Hyperglycemia promotes stem cell death impairing cardiac regeneration in the diabetic heart. Understanding the molecular mechanisms of high glucose-induced stem cell death is important for improving cardiac regeneration in diabetic patients. Matrix metalloproteinase-9 (MMP9), a collagenase, is upregulated in the diabetic heart, and ablation of MMP9 decreases infarct size in the non-diabetic myocardial infarction heart. In the present study, we aim to investigate whether MMP9 is a mediator of hyperglycemia-induced cell death in human cardiac stem cells (hCSCs) in vitro. We created MMP9^−/− hCSCs to test the hypothesis that MMP9 mediates hyperglycemia-induced oxidative stress and cell death via apoptosis and pyroptosis in hCSCs, which is attenuated by the lack of MMP9. We found that hyperglycemia induced oxidative stress and increased cell death by promoting pyroptosis and apoptosis in hCSCs, which was prevented in MMP9^−/− hCSCs. These findings revealed a novel intracellular role of MMP9 in mediating stem cell death and provide a platform to assess whether MMP9 inhibition could improve hCSCs survival in stem cell therapy at least in acute hyperglycemic microenvironment.

提供有益的微环境对于再生疗法中增加移植干细胞的存活率至关重要。高血糖症会促进干细胞死亡，损害糖尿病心脏的心脏再生。了解高糖诱导的干细胞死亡的分子机制对于改善糖尿病患者的心脏再生至关重要。糖尿病患者心脏中的胶原酶基质金属蛋白酶9（MMP9）被上调，而MMP9的消融可减少非糖尿病性心肌梗塞心脏的梗塞面积。在本研究中，我们旨在研究MMP9是否是体外高血糖诱导的人心脏干细胞（hCSCs）细胞死亡的介体。我们创建了MMP9 ^-/-hCSCs用于检验以下假设：MMP9通过hCSCs中的细胞凋亡和细胞凋亡而介导高血糖诱导的氧化应激和细胞死亡，而MMP9的缺乏则减弱了这种情况。我们发现高血糖症可通过促进hCSCs的细胞凋亡和凋亡来诱导氧化应激并增加细胞死亡，而这在MMP9 ^-/- hCSCs中是可以预防的。这些发现揭示了MMP9在介导干细胞死亡中的新型细胞内作用，并为评估MMP9抑制是否至少在急性高血糖微环境下的干细胞治疗中可以改善hCSCs生存提供了平台。