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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 H 2 O 2  (0.1 to 100 μ M ) or 48 hours with glucose oxidase (GOX; 0 to 5 mU/ml) to mimic long-term pulsed or short-term continuous levels of H 2 O 2 , respectively.    Results  In 100 μ M  H 2 O 2  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 μ M  H 2 O 2  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 H 2 O 2 - 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 H 2 O 2 -mediated oxidative stress may lead to improved adult stem cell-based therapies for cardiac repair and regeneration.

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