Xenotransplantation of human mesenchymal stem cells alters host gene expression following prolonged high fat feeding

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BackgroundInitially identified as plastic‐adherent cells, human mesenchymal stem cells (hMSCs) are non‐hematopoietic stem cells which are capable of differentiating into a multitude of cell lineages. Over the past decade the number of clinical trials involving hMSCs has steadily increased, resulting in hMSCs being the most commonly used cells in tissue engineering and regenerative medicine. Known to preferentially home to sites of injury and inflammation, administered hMSCs have exhibited promotion of host tissue repair through donor cell engraftment, release of cell signaling factors, and transfer of healthy organelles. As such, enhanced hMSC engraftment to host tissues and improved therapeutic potential may be induced by a state of low‐grade inflammation. Here we induce low‐grade inflammation through excessive nutrient consumption, achieved through prolonged high fat feeding.PurposeTo examine the impact of hMSC treatment on the liver tissue of mice following a prolonged high fat feeding regiment.MethodsAt 4 weeks of age, mice were placed on a high fat diet (60% kcal fat) for 20 weeks in order to elicit an obese phenotype. Following dietary manipulation, mice were randomly divided into two groups: hMSC treatment (HFM; n = 8) or saline control (HFS; n = 8). Mitochondrial metabolism, microarray gene expression profiling, and metabolomic profiling of host liver tissue were specifically highlighted for their important role in the obese phenotype.ResultsAs a measure of mitochondrial metabolic activity, maximal complex I oxygen consumption (supported by the addition of ADP) was higher in HFM animals (p<0.05). The marker of mitochondrial abundance, citrate synthase, was also elevated following hMSC administration (p<0.05). Microarray gene expression profiling identified 226 genes with significant differential expression between groups ‐ fold change (±1.2) and p‐value (<0.01). Specific gene networks and pathway analysis commonly identified cellular signalling and actin cytoskeleton regulation as upregulated processes in HFM mice (p<0.01).ConclusionsOur data indicate that xenogeneic hMSC treatment improves metabolic capacity of host liver and results in widespread host gene shifting. The upregulation of cell signaling and actin cytoskeleton regulation may provide mechanistic insight into how hMSCs impart their ability to migrate to areas of inflammation and transfer organelles to host tissues.Support or Funding InformationThis study was supported by NSERC (JS). This research was supported by PhD funding to CN from MitoCanada and Alberta Innovates – Health Solutions.