Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs

Abstract

Mesenchymal stem cells (MSCs) and macrophages are fundamental components of the stem cell niche and function coordinately to regulate haematopoietic stem cell self-renewal and mobilization. Recent studies indicate that mitophagy and healthy mitochondrial function are critical to the survival of stem cells, but how these processes are regulated in MSCs is unknown. Here we show that MSCs manage intracellular oxidative stress by targeting depolarized mitochondria to the plasma membrane via arrestin domain-containing protein 1-mediated microvesicles. The vesicles are then engulfed and re-utilized via a process involving fusion by macrophages, resulting in enhanced bioenergetics. Furthermore, we show that MSCs simultaneously shed micro RNA-containing exosomes that inhibit macrophage activation by suppressing Toll-like receptor signalling, thereby de-sensitizing macrophages to the ingested mitochondria. Collectively, these studies mechanistically link mitophagy and MSC survival with macrophage function, thereby providing a physiologically relevant context for the innate immunomodulatory activity of MSCs.

Extracellular RNA profiles with human age

“…Furthermore, our pathway analysis identified mitochondrial dysfunction and oxidative phosphorylation among the top canonical pathways. Cells have been found to shed lysosome‐like vesicles and entire mitochondria into EVs through a mitophagy‐dependent mechanism (Phinney et al., 2015). In fact, mesenchymal stem cells use this mechanism to release mitochondria in EVs in response to oxidative stress (Phinney et al., 2015).…”

“…Cells have been found to shed lysosome‐like vesicles and entire mitochondria into EVs through a mitophagy‐dependent mechanism (Phinney et al., 2015). In fact, mesenchymal stem cells use this mechanism to release mitochondria in EVs in response to oxidative stress (Phinney et al., 2015). Here, perhaps the higher levels of mitochondrial RNAs in serum with age may be a consequence of mitochondrial dysfunction and higher levels of oxidative stress that occur with age.…”

Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer

“…MSC-derived EVs alone are capable of recapitulating many of the beneficial effects of MSC whole-cell therapy (25)(26)(27)(28). Phinney and colleagues observed the transfer of MSC mitochondria and miRNAs via EVs to human macrophages in a model of silicosis and found that mitochondria enhanced macrophage bioenergetics, whereas miRNAs suppressed Toll-like receptor signaling (24). They observed that normoxia (21% oxygen) induced oxidative stress, thereby promoting mitophagy in MSCs.…”

“…Recently, EVs have emerged as an important component of the MSC secretory repertoire. MSC-derived EVs may contain a diverse cargo, including proteins, mRNAs, microRNAs (miRNAs), and mitochondria, the functional effects of which remain largely unknown (9,(23)(24)(25). MSC-derived EVs alone are capable of recapitulating many of the beneficial effects of MSC whole-cell therapy (25)(26)(27)(28).…”

Therapeutic and diagnostic applications of extracellular vesicles

“…As another example, MSC EVs are also successfully investigated in refractory graft-versus-host disease [99]. The exact mechanism behind the therapeutic effect of MSC-derived EVs remains largely obscure and is a topic of intensive investigation [100]. It is however known that stem cell EVs are enriched in signaling proteins, including cytokines, chemokines, interleukins and growth factors [101].…”