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, a team led by researchers at the Scripps Research Institute 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, they 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.
(a–d) Differential interference contrast (DIC) fluorescence overlay of live human MSCs expressing fluorescent proteins that target mitochondria (green) and phagosomes (red) shows mitochondria being loaded into phagosomes (arrows), which are then shuttled to the plasma membrane for extrusion (also see Supplementary Movie 1). (e–h) Inset shows a representative macrophage interacting with a human MSC. This interaction is shown as a time sequence (5 min intervals) in the lower images and in Supplementary Movie 3. The inset demarcates the area in the human MSC plasma membrane where the membrane blebs outwards and accumulates vesicles. Macrophages nibble the surface of human MSCs and uptake mitochondrial laden phagosomes from blebs budding (arrows) from the plasma membrane of the human MSCs. Scale bars, 10 μ.