MMP9 mediates acute hyperglycemia-induced human cardiac stem cell death by upregulating apoptosis and pyroptosis in vitro

Santosh K Yadav,Tyler N Kambis,Paras K Mishra,Sumit Kar,Song Y Park

doi:10.1038/s41419-020-2367-6

Santosh K Yadav, Tyler N Kambis + Show 3 more

Open Access

https://doi.org/10.1038/s41419-020-2367-6

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Abstract

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.

Highlights

Stem cells have potential to differentiate into multiple cell types, which is crucial for cardiac repair in regenerative therapy
The basal level of caspase-3 activity remained unaffected by HG treatment or JNK inhibition in Matrix metalloproteinase-9 (MMP9)−/− human cardiac stem cells (hCSCs) (Fig. 4h), which suggests that MMP9 is upstream to JNK signaling. These findings demonstrates the role of SAPK/JNK signaling in HG-induced apoptosis in hCSCs, and revealed that MMP9 mediates apoptosis in hCSCs
We found that hyperglycemia upregulates oxidative stress-induced cell death via apoptosis and pyroptosis in hCSCs, which is mediated by MMP9

Summary

Introduction

Stem cells have potential to differentiate into multiple cell types, which is crucial for cardiac repair in regenerative therapy. A key challenge in stem cell therapy is death of transplanted stem cells in the damaged tissue microenvironment. This problem is amplified by diabetes mellitus (DM) where stem cell death is exacerbated by oxidative stress due to hyperglycemic microenvironment[1]. It is important to investigate the molecular mechanisms underlying hyperglycemiainduced cell death of human cardiac stem cells (hCSCs), which is far poorly understood. Matrix metalloproteinases (MMPs) play crucial roles in signaling pathways of migration, proliferation, and differentiation of stem cells[5].

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