Peroxisome proliferator-activated receptor gamma promotes exogenous mesenchymal stem cells to express connexin 43：its role and mechanism / 中国组织工程研究

ABSTRACT

BACKGROUND:Piglitazone, aperoxisome proliferator-activated receptor γ(PPAR-γ) agonist, has been demonstrated topromote survivalandcardiac differentiation ofexogenous bone marrow mesenchymal stem celsto improvecardiacfunction.In this study, we attempted to investigate whether pioglitazone couldinduce cardiac differentiation of endogenous bone marrow mesenchymal stem celsandimprove cardiacfunction, andmeanwhile, probed into the relevant mechanisms. OBJECTIVE:To compare the therapeutic efficacy ofpioglitazone combined with bone marrow mesenchymal stem cel transplantation, pioglitazone alone and phosphate buffer solution(PBS)and to investigatetherelevant mechanisms. METHODS:ThirtySprague-Dawley ratswith myocardial infarctioninducedby ligation of the left anterior descending coronary artery were randomized intocombined group (combination of bone marrow mesenchymal stem cels and pioglitazone), pioglitazone group andPBSgroup. Two weeks later, PKH26-labeled bone marrow mesenchymal stem cels inPBSorPBSalone wereinjected into the local infarct zone in the combinedgroup andthe other twogroups, respectively. Pioglitazone (3 mg/kg/d) was given by the oral gavage in the combinedand pioglitazone groups forcontinuous2weeks after cels transplantation. At 2weeks after treatment, cardiac functions were evaluated. In addition, expressions of PPAR-γ, connexin 43 and relative factors in transforming growth factor-β1/SMAD signaling pathway were examined in different areas of the left ventricle from each harvested heart. RESULTS AND CONCLUSION:There were no differences in the baseline parameters of cardiac function between the two groups.Twoweeksafter treatment, left ventricular end-diastolic diameter, left ventricular end-systolic diameter and left ventricular ejection fraction were significantlyimprovedin the combined groupcompared with the other two groups; the expression of PPAR-γ was significantly increased in different zones of the left ventriclein the combined andpioglitazone groups.In the combined group, there was a significantlyhigher expression of connexin 43, and the levels of transforming growth factor-β1, SMAD2 and SMAD3 were obviously attenuated in the infarctand marginal zones.However, no differences were found in the abovedeterminants between the pioglitazone andPBSgroups. To conclude, pioglitazone cannot induce the differentiation andproliferation of endogenous bone marrow mesenchymal stem cels, but pioglitazone combined with exogenous bone marrow mesenchymal stem cels can improve cardiac function post myocardial infarction.In this process,PPAR-γmight promote the connexin 43 expression inexogenous bone marrow mesenchymal stem celsviathe blockade oftransforming growth factor-β1/SMAD signaling pathway.