Regenerative abilities of mesenchymal stem cells through mitochondrial transfer

Abstract

The past decade has witnessed an upsurge in studies demonstrating mitochondrial transfer as one of the emerging mechanisms through which mesenchymal stem cells (MSCs) can regenerate and repair damaged cells or tissues. It has been found to play a critical role in healing several diseases related to brain injury, cardiac myopathies, muscle sepsis, lung disorders and acute respiratory disorders. Several studies have shown that various mechanisms are involved in mitochondrial transfer that includes tunnel tube formation, micro vesicle formation, gap junctions, cell fusion and others modes of transfer. Few studies have investigated the mechanisms that contribute to mitochondrial transfer, primarily comprising of signaling pathways involved in tunnel tube formation that facilitates tunnel tube formation for movement of mitochondria from one cell to another. Various stress signals such as release of damaged mitochondria, mtDNA and mitochondrial products along with elevated reactive oxygen species levels trigger the transfer of mitochondria from MSCs to recipient cells. However, extensive cell signaling pathways that lead to mitochondrial transfer from healthy cells are still under investigation and the changes that contribute to restoration of mitochondrial bioenergetics in recipient cells remain largely elusive. In this review, we have discussed the phenomenon of mitochondrial transfer from MSCs to neighboring stressed cells, and how this aids in cellular repair and regeneration of different organs such as lung, heart, eye, brain and kidney. The potential scope of mitochondrial transfer in providing novel therapeutic strategies for treatment of various pathophysiological conditions has also been discussed.

Keywords: Mesenchymal stem cells; Mitochondrial transfer mechanism; Regenerative medicine.

Fig. 1

Striking difference between mitochondria of Human MSCs and JEG-3 Cell Line as observed under Transmission Electron Microscope (TECNAI 200 Kv, Fei, Electron Optics). a Human BM-MSCs cells: Mitochondria are fewer in number, spherical, condensed with underdeveloped cristae and display cytoplasmic localization. Scale Bar: 0.2 μm (b) JEG-3 Cell Line, mitochondria are branched, tubular, elongated and well-organized cristae, more in number and peri-nuclear in localization. Scale Bar: 0.5 μm

Fig. 2

Different modes of mitochondrial transfer from MSCs to injured or damaged cells. These include transfer through intracellular nanotubes, gap junctions, cell fusion, microvesicles and direct uptake of isolated mitochondria

Fig. 3

Mechanisms of Mitochondrial Transfer. An overview of mitochondrial transfer mechanisms has been shown with expression of Miro1 protein and tunnel tube formation signaling pathways along with signaling that trigger mitochondrial release from MSCs to injured cell under stress

Fig. 4

Mitochondria stained with MitoTracker Green FM (Thermo Fisher Scientific) in human BM-MSCs were transfered to Antimycin A treated (a) U87-MG and (b) rat cardiomyocyte. Confocal imaging was done on Leica TCS SP5 using software LAS AF