Diabetic Impairment of C-Kit+ Bone Marrow Stem Cells Involves the Disorders of Inflammatory Factors, Cell Adhesion and Extracellular Matrix Molecules

Bone marrow stem cells from diabetes mellitus patients exhibit functional impairment, but the relative molecular mechanisms responsible for this impairment are poorly understood. We investigated the mechanisms responsible for diabetes-related functional impairment of bone marrow stem cells by extensively screening the expression levels of inflammatory factors, cell cycle regulating molecules, extracellular matrix molecules and adhesion molecules. Bone marrow cells were collected from type 2 diabetic (db/db) and healthy control (db/m+) mice, and c-kit+ stem cells were purified (purity>85%) for experiments. Compared with the healthy control mice, diabetic mice had significantly fewer c-kit+ stem cells, and these cells had a lower potency of endothelial differentiation; however, the production of the angiogenic growth factor VEGF did not differ between groups. A pathway-focused array showed that the c-kit+ stem cells from diabetic mice had up-regulated expression levels of many inflammatory factors, including Tlr4, Cxcl9, Il9, Tgfb1, Il4, and Tnfsf5, but no obvious change in the expression levels of cell cycle molecules. Interestingly, diabetes-related alterations of the extracellular matrix and adhesion molecules were varied; Pecam, Mmp10, Lamc1, Itgb7, Mmp9, and Timp4 were up-regulated, but Col11a1, Fn1, Admts2, and Itgav were down-regulated. Some of these changes were also confirmed at the protein level by flow cytometry analysis. In conclusion, c-kit+ bone marrow stem cells from diabetic mice exhibited an extensive enhancement of inflammatory factors and disorders of the extracellular matrix and adhesion molecules. Further intervention studies are required to determine the precise role of each molecule in the diabetes-related functional impairment of c-kit+ bone marrow stem cells

Seasonal variation of non-shivering thermogenesis (NST) during mild cold exposure

Background: The physiological function of non-shivering thermogenesis (NST) has been investigated in recent years, and some studies have discussed the importance of NST with respect to human cold adaptation. The present study aimed to clarify individual and seasonal variations in NST that occurred as a result of mild cold exposure.Methods: Seventeen male university students participated in the present study during summer and winter. The climate chamber used was programmed so that ambient temperature dropped from 28°C to 16°C over an 80-min period. Physiological parameters of test subjects were recorded during the experiments.Results: Increases in oxygen intake (VO2) during cold exposure were significantly greater without shivering in winter than they were in summer. Respiratory exchange ratio (RER) was significantly lower during thermoneutral baseline and cold exposure in winter than it was during the same periods in summer. In addition, there was a significant negative correlation between ΔVO2 and ΔRER.Conclusions: Increase of VO2 without shivering indicated increase of NST, and decrease of RER depends on the metabolization of fat in winter. These results suggested that NST activity was activated by seasonal acclimatization, and individual variation of NST depends on individual variation of fat metabolism

Relationship between mitochondrial haplogroup and seasonal changes of physiological responses to cold

Background: Physiological responses to cold exhibit individual variation that can be affected by various factors, such as morphological characteristics, seasonal changes, and lifestyle; however, the genetic factors associated with this variation remain unclear. Recent studies have identified mtDNA as a potential genetic factor affecting cold adaptation. In addition, non-shivering thermogenesis (NST), a process closely related to mitochondrial dynamics, has also been suggested as an important factor affecting human response to cold. The present study aimed to clarify the relationship between mitochondrial haplogroup and NST during periods of mild cold exposure.Methods: Seventeen healthy university students (D: n = 8, non-D: n = 9) participated in the present study during summer and winter. A climate chamber was programmed so that ambient temperature inside dropped from 28°C to 16°C over the course of an 80-minute period. Physiological parameters were recorded throughout the course of the experiments.Results: Increases in VO2 were significantly greater during periods of cold exposure in winter than they were during periods of cold exposure in summer, and individuals from the D group exhibited greater winter values of ΔVO2 than individuals from the non-D group.Tre was significantly lower during periods of rest and cold exposure in winter; however, no significant difference was observed between Tre values of individuals in the D and non-D groups. In addition, although T-dist was significantly lower during periods of rest in winter than it was during those same periods in summer, no significant seasonal differences in values of T-dist were observed during periods of cold exposure.Conclusions: Results of the present study indicated that NST was greater in winter, and that the D group exhibited greater NST than the non-D group during winter. Despite the differences between groups in NST, no significant differences in rectal and skin temperatures were found between groups in either season. Therefore, it was supposed that mitochondrial DNA haplogroups had a greater effect on variation in energy expenditure involving NST than they had on insulative responses. Future studies are necessary in order to investigate more multiple candidate genes related to human cold adaptation and to elucidate the relationship between gene polymorphism and physiological polytypism