Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties

Abstract

Mesenchymal stem cells (MSCs) protect tissues against cell death induced by ischemia/reperfusion insults. This therapeutic effect seems to be controlled by physiological cues released by the local microenvironment following injury. Recent lines of evidence indicate that MSC can communicate with their microenvironment through bidirectional exchanges of mitochondria. In particular, in vitro and in vivo studies report that MSCs rescue injured cells through delivery of their own mitochondria. However, the role of mitochondria conveyed from somatic cells to MSC remains unknown. By using a co-culture system consisting of MSC and distressed somatic cells such as cardiomyocytes or endothelial cells, we showed that mitochondria from suffering cells acted as danger-signaling organelles that triggered the anti-apoptotic function of MSC. We demonstrated that foreign somatic-derived mitochondria were engulfed and degraded by MSC, leading to induction of the cytoprotective enzyme heme oxygenase-1 (HO-1) and stimulation of mitochondrial biogenesis. As a result, the capacity of MSC to donate their mitochondria to injured cells to combat oxidative stress injury was enhanced. We found that similar mechanisms – activation of autophagy, HO-1 and mitochondrial biogenesis – occurred after exposure of MSC to exogenous mitochondria isolated from somatic cells, strengthening the idea that somatic mitochondria alert MSC of a danger situation and subsequently promote an adaptive reparative response. In addition, the cascade of events triggered by the transfer of somatic mitochondria into MSC was recapitulated in a model of myocardial infarction in vivo. Specifically, MSC engrafted into infarcted hearts of mice reduced damage, upregulated HO-1 and increased mitochondrial biogenesis, while inhibition of mitophagy or HO-1 failed to protect against cardiac apoptosis. In conclusion, our study reveals a new facet about the role of mitochondria released from dying cells as a key environmental cue that controls the cytoprotective function of MSC and opens novel avenues to improve the effectiveness of MSC-based therapies.

Blood contains circulating cell‐free respiratory competent mitochondria

“…38 In particular, the mitochondria transfer between differentiated and mesenchymal stem cells was observed in cardiomyocytes and endothelial cells as a means to rescue injured tissues. 39 Similarly, mitochondria are able to be internalized by different types of cells, by macro pinocytosis which is an endocytic pathway specific for large vesicles. 40 Clinical transplantation of mitochondria between cells is an active area of research but the specific mechanisms and critical factors involved in natural mitochondria transfer between the donor cells and recipient cells remain to be fully characterized.…”

Concise Review: Mesenchymal Stem Cells Derived from Human Pluripotent Cells, an Unlimited and Quality-Controllable Source for Therapeutic Applications

“…Mitochondrial transfer of hiPS‐MSCs effectively protects corneal epithelial cells from mitochondrial damage . Rodriguez and coworkers demonstrated that MSCs can sense mitochondria released from damaged cells as danger signals to activate their rescue properties, thus acting as both sensors and rescuers of the tissue injury .…”

Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging

“…Beside increased mitophagy, MSCs have adopted a particular strategy to accomplish this goal, i.e., they outsource mitophagy to bystander macrophages in the niche, at the same time delivering miRNA to inhibit macrophage activation that may occur since mitochondria may trigger a pattern recognition receptor reactivity [115]. On the other hand, MSCs may sense mitochondria released from damaged somatic cells as a signal to increase their modulatory activity [116].…”