Pioglitazone strengthen therapeutic effect of adipose-derived regenerative cells against ischemic cardiomyopathy through enhanced expression of adiponectin and modulation of macrophage phenotype

Daisuke Mori,Norikazu Maeda,Koichi Tomita,Koichi Toda,Satsuki Fukushima,Iichiro Shimomura,Ryohei Matsuura,Nagako Sougawa,Shigeru Miyagawa,Yoshiki Sawa,Takayoshi Ueno,Toru Kuratani

doi:10.1186/s12933-019-0829-x

Abstract

BackgroundThe efficacy of cell transplantation in heart failure is reportedly modest, but adjuvant drugs combined with cell therapy may improve this efficacy. Peroxisome proliferator-activated receptor (PPAR)γ, one of the hypoglycemic medicine for diabetes mellitus, reportedly enhances cytokine production in adipose tissue-derived regenerative cells (ADRCs). We hypothesized that combined administration of PPARγ agonists and ADRCs may enhance the paracrine effects of adiponectin (APN), leading to functional recovery in a chronic myocardial infarction (MI) model.MethodsADRCs were isolated from adipose tissues of adult rats by gradient centrifugation and embedded in bio-compatible fibrin-glue to produce ADRCs grafts. In the in vitro study, the ADRCs grafts released APN, which was significantly enhanced by the PPARγ agonist (PGZ, pioglitazone). Transplantation of ADRCs grafts (group A), ADRCs mixed with PGZ (group AP), APN knockdown-ADRCs (group Si) or PGZ (group P) onto the epicardium or a sham operation (group C) was performed (n = 10–20 per group).ResultsThe AP group showed significant improvement in ejection fraction compared to that in the other groups. In the AP group, a significantly larger number of M2-polarized macrophages was detected and existed for a significantly longer duration in the infarct area. Furthermore, comparing Si group and P group, western blotting of T-cadherin revealed that exogenous APN and local expression of T-cadherin were essential to this histological change and recovery of cardiac function.ConclusionsCombined administration of PPARγ agonist and ADRSCs activated M2-polarized macrophages with enhancement of APN paracrine effects and lead to better cardiac function in a rat infarction model.

Highlights

Ischemic cardiomyopathy is a major cause of death and is an independent predictor of mortality in all cardiomyopathy types [1, 2]
Mesenchymal system stem cells, and bone-marrow stem cells have been reported as candidates for cell therapy in ischemic cardiomyopathy, they are clinically ineffective in treating severe heart failure [5]
We investigated whether PPARγ agonists act as adjuvants to adipose tissue-derived regenerative cells (ADRCs) therapy in a rat ischemic cardiomyopathy model via enhanced cytokine secretion

Summary

Introduction

Ischemic cardiomyopathy is a major cause of death and is an independent predictor of mortality in all cardiomyopathy types [1, 2]. Treatment strategies, such as heart transplantation or ventricular assist device implantation, have been used to treat patients with severe heart failure; problems such as scarcity of donors and serious complications have hindered the success of these treatment strategies [3]. The efficacy of cell transplantation in heart failure is reportedly modest, but adjuvant drugs combined with cell therapy may improve this efficacy. Peroxisome proliferator-activated receptor (PPAR)γ, one of the hypoglycemic medicine for diabetes mellitus, reportedly enhances cytokine production in adipose tissue-derived regenerative cells (ADRCs). We hypothesized that combined administration of PPARγ agonists and ADRCs may enhance the paracrine effects of adiponectin (APN), leading to functional recovery in a chronic myocardial infarction (MI) model

Methods

Results

Discussion

Conclusion