In Situ Reprogramming to Transdifferentiate Fibroblasts into Cardiomyocytes Using Adenoviral Vectors: Implications for Clinical Myocardial Regeneration

Abstract Objective The reprogramming of cardiac fibroblasts into induced cardiomyocytes (iCMs) improves ventricular function in myocardial infarction models. Only integrating persistent expression vectors have thus far been used to induce reprogramming, potentially limiting its clinical applicabilit...

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Published in:The Journal of thoracic and cardiovascular surgery 2017-02, Vol.153 (2), p.329-339.e3
Main Authors: Mathison, Megumi, MD, PhD, Singh, Vivek P., PhD, Chiuchiolo, Maria J., PhD, Sanagasetti, Deepthi, MS, Mao, Yun, MD, Patel, Vivekkumar B., MD, Yang, Jianchang, MD, PhD, Kaminsky, Stephen M., PhD, Crystal, Ronald G., MD, Rosengart, Todd K., MD
Format: Article
Language:English
Subjects:
adenoviral vector
Cardiothoracic Surgery
gene therapy
in situ cardiac reprogramming
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Summary:Abstract Objective The reprogramming of cardiac fibroblasts into induced cardiomyocytes (iCMs) improves ventricular function in myocardial infarction models. Only integrating persistent expression vectors have thus far been used to induce reprogramming, potentially limiting its clinical applicability. We therefore tested the reprogramming potential of non-integrating, acute expression adenoviral vectors. Methods Adenoviral (Ad) or lentivirus vectors encoding Gata4 (G), Mef2c (M) and Tbx5 (T) were validated in vitro . Sprague Dawley rats then underwent coronary ligation and Ad-mediated administration of vascular endothelial growth factor to generate infarct prevascularization. Three weeks later, animals received Ad or lentivirus encoding G, M, or T (AdGMT or LentiGMT) or an equivalent dose of a null vector (n=11, 10, and 10, respectively). Outcomes were analyzed by echocardiography, MRI and histology. Results Ad and lentivirus vectors provided equivalent G, M, and T expression in vitro. AdGMT and LentiGMT both likewise induced expression of the cardiomyocyte marker cardiac troponin T in approximately 6% of cardiac fibroblasts vs
ISSN:0022-5223
1097-685X
DOI:10.1016/j.jtcvs.2016.09.041