Progenitor cell therapy in a porcine acute myocardial infarction model induces cardiac hypertrophy, mediated by paracrine secretion of cardiotrophic factors including TGFβ1

Brendan Doyle, Paul Sorajja, Brian Hynes, Arun H S Kumar, Philip A Araoz, Paul G. Stalboerger, Dylan Miller, Cynthia Reed, Jeffrey Schmeckpeper, Shaohua Wang, Chunsheng Liu, Andre Terzic, David Kruger, Stephen J Riederer, Noel M. Caplice

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Abstract

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 TGFβ1 (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 TGFβ1 attenuated the pro-hypertrophic effect of conditioned media, and use of recombinant TGFβ1 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.

Original languageEnglish (US)
Pages (from-to)941-951
Number of pages11
JournalStem Cells and Development
Volume17
Issue number5
DOIs
StatePublished - Oct 2008

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Cardiomegaly
Cell- and Tissue-Based Therapy
Swine
Stem Cells
Myocardial Infarction
Conditioned Culture Medium
Cardiac Myocytes
Therapeutic Uses
Endothelial Progenitor Cells
Ventricular Function
Neutralizing Antibodies
Infarction
Hypertrophy
Blood Vessels
Blood Cells
Fibroblasts
Injections
Therapeutics

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Hematology

Cite this

Progenitor cell therapy in a porcine acute myocardial infarction model induces cardiac hypertrophy, mediated by paracrine secretion of cardiotrophic factors including TGFβ1. / Doyle, Brendan; Sorajja, Paul; Hynes, Brian; Kumar, Arun H S; Araoz, Philip A; Stalboerger, Paul G.; Miller, Dylan; Reed, Cynthia; Schmeckpeper, Jeffrey; Wang, Shaohua; Liu, Chunsheng; Terzic, Andre; Kruger, David; Riederer, Stephen J; Caplice, Noel M.

In: Stem Cells and Development, Vol. 17, No. 5, 10.2008, p. 941-951.

Research output: Contribution to journalArticle

Doyle, Brendan ; Sorajja, Paul ; Hynes, Brian ; Kumar, Arun H S ; Araoz, Philip A ; Stalboerger, Paul G. ; Miller, Dylan ; Reed, Cynthia ; Schmeckpeper, Jeffrey ; Wang, Shaohua ; Liu, Chunsheng ; Terzic, Andre ; Kruger, David ; Riederer, Stephen J ; Caplice, Noel M. / Progenitor cell therapy in a porcine acute myocardial infarction model induces cardiac hypertrophy, mediated by paracrine secretion of cardiotrophic factors including TGFβ1. In: Stem Cells and Development. 2008 ; Vol. 17, No. 5. pp. 941-951.
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AU - Sorajja, Paul

AU - Hynes, Brian

AU - Kumar, Arun H S

AU - Araoz, Philip A

AU - Stalboerger, Paul G.

AU - Miller, Dylan

AU - Reed, Cynthia

AU - Schmeckpeper, Jeffrey

AU - Wang, Shaohua

AU - Liu, Chunsheng

AU - Terzic, Andre

AU - Kruger, David

AU - Riederer, Stephen J

AU - Caplice, Noel M.

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N2 - 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 TGFβ1 (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 TGFβ1 attenuated the pro-hypertrophic effect of conditioned media, and use of recombinant TGFβ1 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.

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