Oxidative stress-induced Notch1 signaling promotes cardiogenic gene expression in mesenchymal stem cells

Stem Cell Research & Therapy

Michael E Davis²  Young-Sup Yoon²  Pao Lin Che¹  Karl D Pendergrass¹  Archana V Boopathy¹ 

[1] Parker H. Petit Institute for Bioengineering and Bioscience, Atlanta, GA 30332, USA;Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30332, USA

关键词: Notch1;    Mesenchymal stem cells;    Hydrogen peroxide;    Glucose oxidase;    Gene expression;    Cardiac progenitor cells;   

Others  :  847574
DOI  :  10.1186/scrt190

 received in 2012-10-31, accepted in 2013-04-08,  发布年份 2013

【 摘 要 】

Introduction

Administration of bone marrow-derived mesenchymal stem cells (MSCs) after myocardial infarction (MI) results in modest functional improvements. However; the effect of microenvironment changes after MI, such as elevated levels of oxidative stress on cardiogenic gene expression of MSCs, remains unclear.

Methods

MSCs were isolated from the bone marrow of adult rats and treated for 1 week with H₂O₂ (0.1 to 100 μM) or 48 hours with glucose oxidase (GOX; 0 to 5 mU/ml) to mimic long-term pulsed or short-term continuous levels of H₂O₂, respectively.

Results

In 100 μM H₂O₂ or 5 mU/ml GOX-treated MSCs, mRNA expression of selected endothelial genes (Flt1, vWF, PECAM1), and early cardiac marker (nkx2-5, αMHC) increased significantly, whereas early smooth muscle markers (smooth muscle α-actin and sm22α) and fibroblast marker vimentin decreased, as measured with real-time PCR. Interestingly, mRNA expression and activity of the cell-surface receptor Notch1 were significantly increased, as were its downstream targets, Hes5 and Hey1. Co-treatment of MSCs with 100 μM H₂O₂ and a γ-secretase inhibitor that prevents Notch signaling abrogated the increase in cardiac and endothelial genes, while augmenting the decrease in smooth muscle markers. Further, on GOX treatment, a significant increase in Wnt11, a downstream target of Notch1, was observed. Similar results were obtained with adult rat cardiac-derived progenitor cells.

Conclusions

These data suggest that H₂O₂- or GOX-mediated oxidative stress upregulates Notch1 signaling, which promotes cardiogenic gene expression in adult stem/progenitor cells, possibly involving Wnt11. Modulating the balance between Notch activation and H₂O₂-mediated oxidative stress may lead to improved adult stem cell-based therapies for cardiac repair and regeneration.

【 授权许可】

   
2013 Boopathy et al.; licensee BioMed Central Ltd.

【 图 表 】

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