Mitohormesis in Hypothalamic POMC Neurons Mediates Regular Exercise-Induced High-Turnover Metabolism.

Low-grade mitochondrial stress can promote health and longevity, a phenomenon termed mitohormesis. Here, we demonstrate the opposing metabolic effects of low-level and high-level mitochondrial ribosomal (mitoribosomal) stress in hypothalamic proopiomelanocortin (POMC) neurons. POMC neuron-specific severe mitoribosomal stress due to Crif1 homodeficiency causes obesity in mice. By contrast, mild mitoribosomal stress caused by Crif1 heterodeficiency in POMC neurons leads to high-turnover metabolism and resistance to obesity. These metabolic benefits are mediated by enhanced thermogenesis and mitochondrial unfolded protein responses (UPRmt) in distal adipose tissues. In POMC neurons, partial Crif1 deficiency increases the expression of ß-endorphin (ß-END) and mitochondrial DNA-encoded peptide MOTS-c. Central administration of MOTS-c or ß-END recapitulates the adipose phenotype of Crif1 heterodeficient mice, suggesting these factors as potential mediators. Consistently, regular running exercise at moderate intensity stimulates hypothalamic MOTS-c/ß-END expression and induces adipose tissue UPRmt and thermogenesis. Our findings indicate that POMC neuronal mitohormesis may underlie exercise-induced high-turnover metabolism.

Placenta-Derived Mesenchymal Stem Cells Restore the Ovary Function in an Ovariectomized Rat Model via an Antioxidant Effect.

Oxidative stress is one of the major etiologies of ovarian dysfunction, including premature ovarian failure (POF). Previous reports have demonstrated the therapeutic effects of human placenta-derived mesenchymal stem cells (PD-MSCs) in an ovariectomized rat model (OVX). However, their therapeutic mechanism in oxidative stress has not been reported. Therefore, we investigated to profile the exosome of serum and demonstrate the therapeutic effect of PD-MSCs transplantation for the ovary function. We established an OVX model by ovariectomy and PD-MSCs transplantation was conducted by intravenous injection. Additionally, various factors in the exosome were profiled by LC-MS analysis. As a result, the transplanted PD-MSCs were engrafted into the ovary and the existence of antioxidant factors in the exosome. A decreased expression of oxidative stress markers and increased expression of antioxidant markers were shown in the transplantation (Tx) in comparison to the non-transplantation group (NTx) (*p < 0.05). The apoptosis factors were decreased, and ovary function was improved in Tx in comparison to NTx (*p < 0.05). These results suggest that transplanted PD-MSCs restore the ovarian function in an OVX model via upregulated antioxidant factors. These findings offer new insights for further understanding of stem cell therapy for reproductive systems.

Human adipose-derived stem cells attenuate inflammatory bowel disease in IL-10 knockout mice.

Inflammatory bowel disease (IBD) is a complex immunological disorder characterized by chronic inflammation caused mainly by unknown factors. The interleukin-10 knockout (IL-10 KO) mouse is a well-established murine model of IBD which develops spontaneous intestinal inflammation that resembles Crohn's disease. In the present study, human adipose-derived mesenchymal stem cells (hAMSCs) were administrated to IL-10 KO mice to evaluate the anti-inflammatory effects of hAMSCs that may attenuate the progress of or treat IBD. After IBD was induced by feeding the IL-10 KO mouse a 125-250 ppm piroxicam mixed diet for 1 week, 2×10(6) hAMSCs were injected into the peritoneum and the mice were switched to a normal diet. After 1 week, the mice were sacrificed and tissue samples were harvested. Tissue scores for inflammation and inflammation-related genes expression were determined. The hAMSC-treated group showed significantly reduced inflammatory changes in histological analysis. Reverse transcription-PCR analysis showed that RANTES, Toll-like receptor 9, and IL-4 expression levels were not significantly different between the groups while IL-12, INF-γ, and TNF-α levels were significantly decreased in the hAMSC treated group. hAMSC attenuated IBD in the IL-10 KO mice by suppressing inflammatory cytokine expression, was mediated by the type 1 helper T cell pathway. Even though only a single injection of hAMSCs was delivered, the effect influenced chronic events associated with inflammatory changes and demonstrated that hAMSCs are a powerful candidate for IBD therapy.

Optimal supplementation of dexamethasone for clinical purposed expansion of mesenchymal stem cells for bone repair.

BACKGROUND: Although mesenchymal stem cells (MSCs) are generally considered to represent a very promising tool for bone repair, no optimal protocol has yet been developed for the isolation and expansion of these cells for large-scale clinical applications. METHODS: Mesenchymal stem cells were supplemented with four different concentrations of dexamethasone: 0 M (Con), 0.2 × 10(-8) M (D0.2), 1.0 × 10(-8) M (D1.0) and 5.0 × 10(-8) M (D5.0); and analyzed every week for 5 weeks (P1-P5). Cells were analyzed via an alkaline phosphatase assay, DNA quantification, Oil Red stain, and flow cytometry for CD105 and CD90. Additionally, P3 and P5 cells were subcutaneously transplanted into nude mice after seeding in ceramic cubes. RESULTS: Proliferation of the cells was significantly higher in the D0.2 group. Alkaline phosphatase activities remained at low levels in the Con and D0.2 groups, but increased to high levels in the D1.0 and D5.0 groups as time elapsed. CD105 expression at P5 was lower than at P1, P2 and P3. Adipocyte differentiation was highest at P3. At the 8th week, in vivo bone formation was enhanced by the MSCs in a dexamethasone-supplemented culture for 3 or 5 weeks, and D0.2 was also higher than Con. CONCLUSIONS: The supplementation of MSCs under low-level rather than physiological concentrations (2 × 10(-9) M) of dexamethasone facilitates the culture expansion of these cells for osteogenic purposes by enhancing cell proliferation without diverse differentiation, and also promotes bone formation after in vivo transplantation.