Abstract
Mesenchymal stem cell (MSC) transplantation after ischemia/reperfusion (I/R) injury reduces infarct size and improves cardiac function. We used mouse ventricular myocytes (VMs) in an in vitro model of I/R to determine the mechanism by which MSCs prevent reperfusion injury by paracrine signaling. Exposure of mouse VMs to an ischemic challenge depolarized their mitochondrial membrane potential (Ψmito), increased their diastolic Ca(2+), and significantly attenuated cell shortening. Reperfusion of VMs with Ctrl tyrode or MSC-conditioned tyrode (ConT) resulted in a transient increase of the Ca(2+) transient amplitudes in all cells. ConT-reperfused cells exhibited a decreased number early after depolarization (EADs) (ConT: 6.3% vs. Ctrl: 28.4%) and prolonged survival (ConT: 58% vs. Ctrl: 33%). Ψmito rapidly recovered in Ctrl as well as ConT-treated VMs on reperfusion; however, in Ctrl solution, an exaggerated hyperpolarization of Ψmito was determined that preceded the collapse of Ψmito. The ability of ConT to attenuate the hyperpolarization of Ψmito was suppressed on inhibition of the PI3K/Akt signaling pathway or IK,ATP. However, protection of Ψmito was best mimicked by the reactive oxygen species (ROS) scavenger mitoTEMPO. Analysis of ConT revealed a significant antioxidant capacity that was linked to the presence of extracellular superoxide dismutase (SOD3) in ConT. In conclusion, MSC ConT protects VMs from simulated I/R injury by its SOD3-mediated antioxidant capacity and by delaying the recovery of Ψmito through Akt-mediated opening of IK,ATP. These changes attenuate reperfusion-induced ROS production and prevent the opening of the permeability transition pore and arrhythmic Ca(2+) release.
Highlights
The benefit of transplantation of bone marrowderived mesenchymal stem cells (MSCs) after cardiac infarction has been evaluated in many preclinical and clinical studies [1,2]
We have previously demonstrated that MSC-derived conditioned tyrode (ConT) significantly enhances cell survival of isolated ventricular myocytes (VMs) in culture [22]
To determine whether this translates into the protection of VMs during simulated I/R injury, we monitored intracellular Ca2 + transients from isolated, fieldstimulated VMs that were loaded with Fluo-4/AM
Summary
The benefit of transplantation of bone marrowderived mesenchymal stem cells (MSCs) after cardiac infarction has been evaluated in many preclinical and clinical studies [1,2]. Potential mechanisms of MSC-mediated protection from ischemic injury are the differentiation of MSCs into cardiomyocytes, the stimulation of cardiac stem cell proliferation, and/or cells that enhance vascularization [3]. The low retention rate of MSCs after transplantation and their low propensity to differentiate into a cardiac phenotype [4] make it unlikely that cell replacement is the primary mechanism of benefit. Since MSCs secrete an array of cytokines and growth factors, recent research has focused on the relevance of paracrine signaling in MSC-mediated cardioprotection [5]. For vascular endothelial growth factor [7], transforming growth factor [8], and tumor necrosis factor [9], it could be demonstrated that changes in their secretion level correlate with modifications in the MSCinduced signaling
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