Background: The efficacy of cell transplantation has been reported to be modest for heart failure and adjuvant drug combined with cell therapy may be one of options to improve the effectiveness in cell therapy. Peroxisome proliferator-activated receptor (PPAR)γ has been already reported to enhance cytokine production in Adipose tissue-derived regenerative cells (ADRCs). We hypothesized that combined administration of PPARγ agonist and ADRCs may enhance APN paracrine effects, leading further functional recovery in the rat chronic myocardial infarction (MI) model through anti-inflammation mechanism.
Methods and Results: ADRCs were isolated from adipose tissue of adult Lewis rat by the gradient-centrifugation, and embedded in bio-compatible fibrin-glue to produce ADRC-fibrin-glue sheet (FS). In vitro study the ADRC-FS released APN (21.7±0.9 ng/5x106cells/day) or VEGF (85±21 ng/5x106cells/day), which were significantly enhanced with PPARγ agonist (51±3.9 and 113±35 ng/5x106cells/day, P<0.05, respectively) as assessed by ELISA, in vitro. Transplantation of ADRC-FS(group A), or ADRC-FS mixed with PGZ(group AP) on the epicardium or sham operation was performed in syngeneic Lewis rats that were subjected to LAD ligation 2 weeks prior to the treatment (n=20 each). At 8 weeks after the transplantation, in the group AP ejection fraction was significantly increased compared with the group A and the sham group (group AP vs A vs S=63±7.9, 55±2.6, and 35±2.4%, P<0.05 respectively). Moreover, diameter of myocytes and capillary density were significantly improved in the group A and AP than the sham group. In AP group, significantly larger number of M2-polarized macrophage were detected in the implanted site and those cells existed for significantly longer duration compared with the other group. Quantitative RT-PCR results showed that the APN and IL-10 transcription were significantly higher and IL-6 was notably lower in the group A and AP (n=10 each) than in the group S (n=10) for 2 week after implantation.
Conclusions: Combined administration with PPARγ-agonist and ADRSCs activated M2-polarized macrophage with enhancement in APN paracrine effects in rat infarction model, promising new approach in cell therapy for patients with ischemic cardiomyopathy.