The Modulation Effects And Mechanism Of Different Tissues Derived Mesenchymal Stem Cells On Adiposity, Glucose Metabolism

Mesenchymal stem cells (MSC), a subset of multipotential adult stem cells,possess two basic characteristics of self-renewal and multilineage differentiationpotential. These cells could home to damaged and inflamed tissues and are veryattractive candidates in stem cell-based strategies for tissue repair and gene therapy.MSC have been isolated from multiple human tissues, such as bone marrow(BM-MSC), subcutaneous adipose tissue (AD-MSC), umbilical cord (UC-MSC) andplacenta. MSC have some characteristics of immune cells, including apro-inflammatory phenotype, antibacterial properties, and expression of Toll-likereceptor proteins. In present study, we showed that MSC display a “short-termmemory” effect when exposed to environment stimuli and danger signals. In otherwords, MSC could maintain the effect to transient environmental stimuli for a shortperiod of time and responded more intensely to the same stimulus upon a secondround exposure. Based on this finding, different pre-treatment strategies can greatlyenhance the therapeutic potential of MSC for different diseases.Following the short-term memory effect of MSC, we can deduce that MSCisolated from different tissues may have different characteristics. The differences mayreflect in two aspects:(1) the gene expression profiles of MSC derived from differenttissues may differ greatly;(2) MSC from different sources may react differently to thesame stimulation. We treated the umbilical cord and the adipose derived MSC with ahigh concentration of sugar and fatty acid, and found that the proliferation ofUC-MSC was inhibited markedly, while the proliferation of AD-MSC was less or noaffected. We have also analyzed global gene expression profiles of AD-MSC andUC-MSC, and found that about1500genes were differentially expressed in AD-MSCand UC-MSC. In addition, Twenty-eight genes were upregulated or downregulated inAD-MSC after sugar and fatty acid pretreated, while only four genes wereupregulated in UC-MSC. In conclusion, AD-MSC have a stronger capacity than UC-MSC to endure the high sugar and fatty acid environment.The above results verified the theory of short-term memory MSC, and which alsosuggested that AD-MSC and UC-MSC may have different effects on glucose and lipidmetabolism regulation.To test the hypothesis, we chose the Leprdb/dbmice as T2DM model, andevaluated the therapeutic effects of AD-MSC and UC-MSC. The possible mechanismsinvolved were also explored. The cells were adminstrated by i.p. for there times, andeach adminstration was7days apart. Both AD-MSC and UC-MSC treatmentramarkably ameliorated the hyperglycemia and improved the glucose utilization of theanimals. However, only AD-MSC treatment reduced the mice body weight andplasma lipid concentration, diminished the adipocytes size, upregulated the lipolyticenzyme HSL and downregulated the fatty acid synthetase ACC1in adipose tissues.These effects ofAD-MSC were confirmed in diet-induced obesity (DIO) mice model.Previous reports have indicated that inflammation is one of most important riskfactors for glucose/lipid metabolism disorder. We found that the concentration ofserum inflammatory factor TNF-α, IL-1β and IL-6were significantly higher in db/dbmice than the normal mice, and MSC adminstration markedly reduced the seruminflammatory factor levels. So we analyzed the mechanism on immumodulatory ofMSC, and found that galectin-3, a protein that modulated system metabolicinflammation, played an important role on the immune regulation of MSC. The resultssuggest that MSC may regulate the body’s metabolic inflammation through thegalectin-3.In conclusion, we evaluated the role of MSC in glucose/lipid metabolism andprovided some mechanistic insights into its glucose-and lipid-lowering effects.