Progenitor cell therapy in a porcine acute myocardial infarction model induces cardiac hypertrophy, mediated by paracrine secretion of cardiotrophic factors including TGFbeta1.
Administration of endothelial progenitor cells (EPC) is a promising therapy for post-infarction cardiac repair. However, the mechanisms that underlie apparent beneficial effects on myocardial remodeling are unclear. In a porcine model of acute myocardial infarction, we investigated the therapeutic effects of a mixed population of culture modified peripheral blood mononuclear cells (termed hereafter porcine EPC). Porcine EPC were isolated using methods identical to those previously adopted for harvest of EPC in human cell therapy studies. In addition the therapeutic effects of paracrine factors secreted by these cells was evaluated in vitro and in vivo. Intracoronary injection of autologous porcine EPC was associated with increased infarct territory mass and improved regional ventricular systolic function at 2 months compared to control. Treatment with conditioned media derived from autologous EPC was associated with similar improved effects on infarct territory mass and function. Histologic analysis of the infarct territory revealed significantly increased cardiomyocyte size in EPC and conditioned media treated groups, when compared to controls. A paracrine EPC effect was also verified in a pure myocardial preparation in which cardiomyocytes devoid of fibroblast, neuronal and vascular elements directly responded by increasing cell mass when exposed to the same conditioned media. Analysis of conditioned media revealed elevated levels of TGFbeta1 (human 267.3+/-11.8 pg/ml, porcine 57.1+/-6.1 pg/ml), a recognized mediator of hypertrophic signaling in the heart. Neutralizing antibodies to TGFbeta1 attenuated the pro-hypertrophic effect of conditioned media, and use of recombinant TGFbeta1 added to fresh media replicated the pro-hypertrophic effects of conditioned media in vitro. These data demonstrate the potential of paracrine factors secreted from endothelial progenitor cells to induce cardiomyocyte hypertrophy contributing to increased infarct territory LV mass, with favorable medium term effects on regional function following myocardial infarction.
Doyle
Brendan
B
Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Sorajja
Paul
P
Hynes
Brian
B
Kumar
Arun H S
AH
Araoz
Phillip A
PA
Stalboerger
Paul G
PG
Miller
Dylan
D
Reed
Cynthia
C
Schmeckpeper
Jeffrey
J
Wang
Shaohua
S
Liu
Chunsheng
C
Terzic
Andre
A
Kruger
David
D
Riederer
Stephen
S
Caplice
Noel M
NM
D000818:Animals; D001681:Biological Assay; D006332:Cardiomegaly / Q000209:etiology* / Q000503:physiopathology; D048429:Cell Size; D064987:Cell- and Tissue-Based Therapy; D017077:Culture Media, Conditioned; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology; D005434:Flow Cytometry; D006334:Heart Function Tests; D006352:Heart Ventricles / Q000033:anatomy & histology / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D009203:Myocardial Infarction / Q000150:complications* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000473:pathology; D009929:Organ Size; D019899:Paracrine Communication; D010641:Phenotype; D051381:Rats; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D034421:Sus scrofa; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D017077:Culture Media, Conditioned; D053773:Transforming Growth Factor beta1