Abstract
Cardiac stem cells (CSCs) have emerged as one of the most promising stem cells for cardiac protection. Recently, exosomes from bone marrow-derived mesenchymal stem cells (BMSCs) have been found to facilitate cell proliferation and survival by transporting various bioactive molecules, including microRNAs (miRs). In this study, we found that BMSC-derived exosomes (BMSC-exos) significantly decreased apoptosis rates and reactive oxygen species (ROS) production in CSCs after oxidative stress injury. Moreover, a stronger effect was induced by exosomes collected from BMSCs cultured under hypoxic conditions (Hypoxic-exos) than those collected from BMSCs cultured under normal conditions (Nor-exos). We also observed greater miR-214 enrichment in Hypoxic-exos than in Nor-exos. In addition, a miR-214 inhibitor or mimics added to modulate miR-214 levels in BMSC-exos revealed that exosomes from miR-214-depleted BMSCs partially reversed the effects of hypoxia-induced exosomes on oxidative damage in CSCs. These data further confirmed that miR-214 is the main effector molecule in BMSC-exos that protects CSCs from oxidative damage. miR-214 mimic and inhibitor transfection assays verified that CaMKII is a target gene of miR-214 in CSCs, with exosome-pretreated CSCs exhibiting increased miR-214 levels but decreased CaMKII levels. Therefore, the miR-214/CaMKII axis regulates oxidative stress-related injury in CSCs, such as apoptosis, calcium homeostasis disequilibrium, and excessive ROS accumulation. Collectively, these findings suggest that BMSCs release miR-214-containing exosomes to suppress oxidative stress injury in CSCs through CaMKII silencing.
Highlights
The endogenous myocardial repair response to injury has been reported to be involved in the activation and differentiation of resident cardiac stem cells (CSCs) [1,2,3], and preclinical and clinical studies have provided abundant evidence for the ability of Cardiac stem cells (CSCs) to improve cardiac function [4,5,6,7,8]
Considering the potential role of bone marrow-derived mesenchymal stem cells (BMSCs)-exos in cardioprotection and the effects of miR-214 on regulating oxidative stress-mediated injury at the translational level in many cell types, we focused on investigating whether miR-214 expression in BMSC-exos is sensitive to hypoxic stimulation and whether miR-214-enriched exosomes play a protective role against H2O2-induced CSC apoptosis and reactive oxygen species (ROS) production and participate in Ca2+ homeostasis by targeting calmodulin-dependent protein kinase II (CaMKII)
CSCs purified by using anti-rabbit secondary antibodyconjugated magnetic beads [5, 30] were stained with the anti-C-kit antibody and counterstained with DAPI to visualize nuclei
Summary
The endogenous myocardial repair response to injury has been reported to be involved in the activation and differentiation of resident cardiac stem cells (CSCs) [1,2,3], and preclinical and clinical studies have provided abundant evidence for the ability of CSCs to improve cardiac function [4,5,6,7,8] Despite this impressive cardiac repair capacity of CSCs, the poor survival and low retention of CSCs hinder functional improvements and cardiac outcomes [7, 9, 10]. Over the past few years, several experimental studies have demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs) release specialized nanosized membranous vesicles, termed exosomes, that improve cardiac function in the damaged heart [14]. These membrane-bound vesicles with a 30–100 nm diameter are released from many cell types and deliver many bioactive molecules, including microRNAs (miRs) and long noncoding RNAs (lncRNAs) as well as Oxidative Medicine and Cellular Longevity
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