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.
Highlights
Identified as plastic-adherent cells, mesenchymal stem cells (MSCs) are non-hematopoietic stem cells that are capable of differentiating into a multitude of cell lineages (Colter et al, 2000; Maijenburg et al, 2012)
To examine the effect of Mesenchymal stem cells (MSCs) using an in vitro model of mitochondrial dysfunction, skin fibroblasts from patients with long-standing, well-characterized mitochondrial disease, and matched healthy controls underwent contact co-culture with MSCs
As identified in previously published work, bi-directional transfer of labeled mitochondrial components was identified (Shi et al, 2010; Bernardo and Fibbe, 2012; Islam et al, 2012) (Video S1). These results indicate MSCs induce morphologic shifts in a cell culture model of mitochondrial dysfunction, and that this may be a result of bi-directional mitochondrial transfer
Summary
Identified as plastic-adherent cells, mesenchymal stem cells (MSCs) are non-hematopoietic stem cells that are capable of differentiating into a multitude of cell lineages (Colter et al, 2000; Maijenburg et al, 2012). Little is known about the impact of MSC therapy on mitochondrial function and morphology. Mitochondrial function or the ability to generate energy through OXPHOS (oxidative phosphorylation) is vital for cell homeostasis and its dysfunction has been linked to the pathogenesis of most chronic diseases (Pieczenik and Neustadt, 2007). Relevant to the studies presented in this manuscript, mitochondrial dysfunction is a key contributor to the perpetuation of metabolic inflammation caused by nutrient excess. This is accomplished, in part, through the inability to utilize excess fatty acids through inhibition of enzymatic function and the generation of excessive oxidative stress (Hotamisligil, 2006; Gregor and Hotamisligil, 2011; Satapati et al, 2015). Besides OXPHOS, mitochondrial dysfunction is present in the examination of mitochondrial morphology, the balance of mitochondrial network formation, and fission and fusion
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