In vivo cardiac cellular reprogramming efficacy is enhanced by angiogenic preconditioning of the infarcted myocardium with vascular endothelial growth factor.

Megumi Mathison, Robert P. Gersch, Ahmed Nasser, Sarit Lilo, Mallory Korman, Mitchell Fourman, Neil Hackett, Kenneth Shroyer, Jianchang Yang, Yupo Ma, Ronald Crystal, Todd K. Rosengart

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

In situ cellular reprogramming offers the possibility of regenerating functional cardiomyocytes directly from scar fibroblasts, obviating the challenges of cell implantation. We hypothesized that pretreating scar with gene transfer of the angiogenic vascular endothelial growth factor (VEGF) would enhance the efficacy of this strategy. Gata4, Mef2c, and Tbx5 (GMT) administration via lentiviral transduction was demonstrated to transdifferentiate rat fibroblasts into (induced) cardiomyocytes in vitro by cardiomyocyte marker studies. Fisher 344 rats underwent coronary ligation and intramyocardial administration of an adenovirus encoding all 3 major isoforms of VEGF (AdVEGF-All6A(+)) or an AdNull control vector (n=12/group). Lentivirus encoding GMT or a GFP control was administered to each animal 3 weeks later, followed by histologic and echocardiographic analyses. GMT administration reduced the extent of fibrosis by half compared with GFP controls (12 ± 2% vs 24 ± 3%, P<0.01) and reduced the number of myofibroblasts detected in the infarct zone by 4-fold. GMT-treated animals also demonstrated greater density of cardiomyocyte-specific marker beta myosin heavy chain 7(+) cells compared with animals receiving GFP with or without VEGF (P<0.01). Ejection fraction was significantly improved after GMT vs GFP administration (12 ± 3% vs -7 ± 3%, P<0.01). Eight (73%) GFP animals but no GMT animals demonstrated decreased ejection fraction during this interval (P<0.01). Also, improvement in ejection fraction was 4-fold greater in GMT/VEGF vs GMT/null animals (17 ± 2% vs 4 ± 1%, P<0.05). VEGF administration to infarcted myocardium enhances the efficacy of GMT-mediated cellular reprogramming in improving myocardial function and reducing the extent of myocardial fibrosis compared with the use of GMT or VEGF alone.

Original languageEnglish
JournalJournal of the American Heart Association
Volume1
Issue number6
DOIs
Publication statusPublished - 1 Dec 2012
Externally publishedYes

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Vascular Endothelial Growth Factor A
Myocardium
Cardiac Myocytes
Cicatrix
Fibrosis
Fibroblasts
Ventricular Myosins
Lentivirus
Myofibroblasts
Myosin Heavy Chains
Adenoviridae
Ligation
Cellular Reprogramming
Protein Isoforms
Genes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

In vivo cardiac cellular reprogramming efficacy is enhanced by angiogenic preconditioning of the infarcted myocardium with vascular endothelial growth factor. / Mathison, Megumi; Gersch, Robert P.; Nasser, Ahmed; Lilo, Sarit; Korman, Mallory; Fourman, Mitchell; Hackett, Neil; Shroyer, Kenneth; Yang, Jianchang; Ma, Yupo; Crystal, Ronald; Rosengart, Todd K.

In: Journal of the American Heart Association, Vol. 1, No. 6, 01.12.2012.

Research output: Contribution to journalArticle

Mathison, Megumi ; Gersch, Robert P. ; Nasser, Ahmed ; Lilo, Sarit ; Korman, Mallory ; Fourman, Mitchell ; Hackett, Neil ; Shroyer, Kenneth ; Yang, Jianchang ; Ma, Yupo ; Crystal, Ronald ; Rosengart, Todd K. / In vivo cardiac cellular reprogramming efficacy is enhanced by angiogenic preconditioning of the infarcted myocardium with vascular endothelial growth factor. In: Journal of the American Heart Association. 2012 ; Vol. 1, No. 6.
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abstract = "In situ cellular reprogramming offers the possibility of regenerating functional cardiomyocytes directly from scar fibroblasts, obviating the challenges of cell implantation. We hypothesized that pretreating scar with gene transfer of the angiogenic vascular endothelial growth factor (VEGF) would enhance the efficacy of this strategy. Gata4, Mef2c, and Tbx5 (GMT) administration via lentiviral transduction was demonstrated to transdifferentiate rat fibroblasts into (induced) cardiomyocytes in vitro by cardiomyocyte marker studies. Fisher 344 rats underwent coronary ligation and intramyocardial administration of an adenovirus encoding all 3 major isoforms of VEGF (AdVEGF-All6A(+)) or an AdNull control vector (n=12/group). Lentivirus encoding GMT or a GFP control was administered to each animal 3 weeks later, followed by histologic and echocardiographic analyses. GMT administration reduced the extent of fibrosis by half compared with GFP controls (12 ± 2{\%} vs 24 ± 3{\%}, P<0.01) and reduced the number of myofibroblasts detected in the infarct zone by 4-fold. GMT-treated animals also demonstrated greater density of cardiomyocyte-specific marker beta myosin heavy chain 7(+) cells compared with animals receiving GFP with or without VEGF (P<0.01). Ejection fraction was significantly improved after GMT vs GFP administration (12 ± 3{\%} vs -7 ± 3{\%}, P<0.01). Eight (73{\%}) GFP animals but no GMT animals demonstrated decreased ejection fraction during this interval (P<0.01). Also, improvement in ejection fraction was 4-fold greater in GMT/VEGF vs GMT/null animals (17 ± 2{\%} vs 4 ± 1{\%}, P<0.05). VEGF administration to infarcted myocardium enhances the efficacy of GMT-mediated cellular reprogramming in improving myocardial function and reducing the extent of myocardial fibrosis compared with the use of GMT or VEGF alone.",
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AU - Lilo, Sarit

AU - Korman, Mallory

AU - Fourman, Mitchell

AU - Hackett, Neil

AU - Shroyer, Kenneth

AU - Yang, Jianchang

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AU - Crystal, Ronald

AU - Rosengart, Todd K.

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