Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 985850, USA.
Department of Health and Kinesiology, University of Nebraska at Omaha, Omaha, NE, USA.
Cell Death Dis. 2020 Mar 13;11(3):186. doi: 10.1038/s41419-020-2367-6.
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.
为提高再生治疗中移植干细胞的存活率，提供有利的微环境至关重要。高血糖会促进干细胞死亡，从而损害糖尿病心脏中的心肌再生。了解高血糖诱导干细胞死亡的分子机制对于改善糖尿病患者的心肌再生非常重要。基质金属蛋白酶-9（MMP9）是一种胶原酶，在糖尿病心脏中上调，而 MMP9 的缺失可减少非糖尿病性心肌梗死心脏的梗死面积。在本研究中，我们旨在研究 MMP9 是否是体外人心脏干细胞（hCSC）中高血糖诱导细胞死亡的介质。我们创建了 MMP9 hCSC 来验证假设，即 MMP9 通过促进 hCSC 中的细胞焦亡和细胞凋亡来介导高血糖诱导的氧化应激和细胞死亡，而 MMP9 的缺失则可减轻这种作用。我们发现，高血糖通过促进细胞焦亡和细胞凋亡诱导 hCSC 中的氧化应激和细胞死亡，而在 MMP9 hCSC 中则可预防这种作用。这些发现揭示了 MMP9 在介导干细胞死亡方面的新的细胞内作用，并提供了一个平台来评估 MMP9 抑制是否可以改善 hCSC 在急性高血糖微环境中的存活，至少在干细胞治疗中。
