Mesenchymal Stem Cells Shift Mitochondrial Dynamics and Enhance Oxidative Phosphorylation in Recipient Cells

Abstract

Mesenchymal stem cells (MSCs) are the most commonly used cells in tissue engineering and regenerative medicine. MSCs can promote host tissue repair through several different mechanisms including donor cell engraftment, release of cell signaling factors, and the transfer of healthy organelles to the host. In the present study, we examine the specific impacts of MSCs on mitochondrial morphology and function in host tissues. Employing in vitro cell culture of inherited mitochondrial disease and an in vivo animal experimental model of low-grade inflammation (high fat feeding), we show human-derived MSCs to alter mitochondrial function. MSC co-culture with skin fibroblasts from mitochondrial disease patients rescued aberrant mitochondrial morphology from a fission state to a more fused appearance indicating an effect of MSC co-culture on host cell mitochondrial network formation. In vivo experiments confirmed mitochondrial abundance and mitochondrial oxygen consumption rates were elevated in host tissues following MSC treatment. Furthermore, microarray profiling identified 226 genes with differential expression in the liver of animals treated with MSC, with cellular signaling, and actin cytoskeleton regulation as key upregulated processes. Collectively, our data indicate that MSC therapy rescues impaired mitochondrial morphology, enhances host metabolic capacity, and induces widespread host gene shifting. These results highlight the potential of MSCs to modulate mitochondria in both inherited and pathological disease states.

Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH

“…Indeed, in their niche, MSC energy metabolism may primarily rely on anaerobic glycolysis rather than oxidative phosphorylation [ 99 ]. Our results are consistent with data shown in a high-fat diet-fed mouse model, in which MSC transplants improved mitochondrial morphology and metabolic performance in the host liver [ 100 ]. This may describe a general mechanism of MSC action, since stem cell-derived donor mitochondria increased oxidative phosphorylation and ATP generation, and reduced ROS production in host cells like, e.g., myeloma cells [ 101 ], macrophages [ 102 ], cardiomyocytes [ 103 ], and airway epithelial cells [ 104 ].…”

Mesenchymal stem cells ameliorate lipid metabolism through reducing mitochondrial damage of hepatocytes in the treatment of post-hepatectomy liver failure

“…Meanwhile, under the effects of lipid peroxidation products and TNF-α on mitochondrial respiration, mitochondrial ROS oxidizes unsaturated FAs to cause lipid peroxidation. Lipid accumulation after hepatectomy can damage the ultrastructure of mitochondria and change the mitochondrial dynamics, thus reducing the activity of mitochondrial respiratory chain complex and β-oxidation function 35 . The damage of mitochondrial function further aggravates the steatosis after hepatectomy by reducing the β-oxidation of FA, forming a vicious circle, which is difficult to correct.…”

Therapeutic Potential of Mesenchymal Stem Cells in a Pre-Clinical Model of Diabetic Kidney Disease and Obesity

“…Reestablishment of redox balance implies preservation of the physiological and naturally produced ROS, intrinsically involved in cell signaling processes, instead of oxidative-agents ablation [ 48 ]. MSC therapy has the great potential to restitute redox state through mitochondrial modulation and anti-oxidative effects [ 49 ]. Our results indicated that MSCs induced the recovery of mitophagy-related genes PINK1 and PARKIN expressions, in addition to inducing the expression of TFAM, a gene related to the biogenesis process, which has important biological implications.…”