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

Authors
 Archana V Boopathy  ;  Karl D Pendergrass  ;  Pao Lin Che  ;  Young-Sup Yoon  ;  Michael E Davis 
Citation
 Stem Cell Research & Therapy, Vol.4(2) : 43, 2013 
Journal Title
 Stem Cell Research & Therapy 
Issue Date
2013
MeSH
Actins/metabolism ; Animals ; Bone Marrow Cells/cytology ; Cell Differentiation/drug effects ; Cells, Cultured ; Dipeptides/pharmacology ; Gene Expression/drug effects ; Glucose Oxidase/pharmacology ; Hydrogen Peroxide/toxicity ; Male ; Mesenchymal Stromal Cells/cytology* ; Mesenchymal Stromal Cells/drug effects ; Mesenchymal Stromal Cells/metabolism ; Myocardium/cytology ; Myocardium/metabolism ; Oxidative Stress*/drug effects ; RNA, Small Interfering/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Notch1/antagonists & inhibitors ; Receptor, Notch1/genetics ; Receptor, Notch1/metabolism* ; Signal Transduction/drug effects ; Stem Cells/cytology ; Stem Cells/drug effects ; Stem Cells/metabolism ; Wnt Proteins/metabolism
Abstract
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.
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DOI
10.1186/scrt190
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Yoon, Young Sup(윤영섭)
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/158453
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