Year-end Sale % OFF 
Abstract
IntroductionAdministration 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.MethodsMSCs 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.ResultsIn 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.ConclusionsThese 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.
Highlights
Administration of bone marrow-derived mesenchymal stem cells (MSCs) after myocardial infarction (MI) results in modest functional improvements
H2O2 or glucose oxidase treatment increases early endothelial gene expression in MSCs To determine whether H2O2 or glucose oxidase (GOX)mediated oxidative stress regulates endothelial gene expression, bone marrow-derived MSCs were cultured in media containing hydrogen peroxide (H2O2; 0 to 100 μM) for 1 week or glucose oxidase (GOX; 0 to 5 mU/ml) for 48 hours
The mRNA expression of VEGF receptor Fms-related tyrosine kinase 1 (Flt1), vWF, and PECAM1 after exposure to H2O2 or GOX was quantified with qRT-PCR
Summary
Administration of bone marrow-derived mesenchymal stem cells (MSCs) after myocardial infarction (MI) results in modest functional improvements. Myocardial infarction (MI) leads to irreversible damage to the myocardium and progressive loss of function, eventually leading to heart failure. Many therapies attempt to improve functionality of the heart, the only in cardiac function after MI either by endogenous bone marrow [5] or by augmenting this endogenous MSC response via injection of Granulocyte-macrophage colony-stimulating factor (GM-CSF) and other stem cell-mobilizing factors [6]. Effects of ROS on cardiac cell death, remodeling, and function are well studied, stem and progenitor cells that could be used for potential regeneration have both adaptive and maladaptive responses to oxidative stress. Pinpointing the exact signals modulated by ROS, leading to alterations in MSC differentiation, is of great therapeutic interest
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
