Thioredoxin-1 (Trx1) engineered mesenchymal stem cell therapy increased pro-angiogenic factors, reduced fibrosis and improved heart function in the infarcted rat myocardium.

Abstract

INTRODUCTION:

Engraftment of mesenchymal stem cells (MSCs) has emerged as a powerful candidate for mediating myocardial repair. In this study, we genetically modified MSCs with an adenovector encoding thioredoxin-1 (Ad.Trx1). Trx1 has been described as a growth regulator, a transcription factor regulator, a cofactor, and a powerful antioxidant. We explored whether engineered MSCs, when transplanted, are capable of improving cardiac function and angiogenesis in a rat model of myocardial infarction (MI).

METHODS:

Rat MSCs were cultured and divided into MSC, MSC+Ad.LacZ, and MSC+Ad.Trx1 groups. The cells were assayed for proliferation, and differentiation potential. In addition, rats were divided into control-sham (CS), control-MI (CMI), MSC+Ad.LacZ-MI (MLZMI), and MSC+Ad.Trx1-MI (MTrxMI) groups. MI was induced by left anterior descending coronary artery (LAD) ligation, and MSCs preconditioned with either Ad.LacZ or Ad.Trx1 were immediately administered to four sites in the peri-infarct zone.

RESULTS:

The MSC+Ad.Trx1 cells increased the proliferation capacity and maintained pluripotency, allowing them to divide into cardiomyocytes, smooth muscle, and endothelial cells. Western blot analysis, 4 days after treatment showed increased vascular endothelial growth factor (VEGF), heme oxygenase-1 (HO-1), and C-X-C chemokine receptor type 4 (CXCR4). Also capillary density along with myocardial function as examined by echocardiography was found to be increased. Fibrosis was reduced in the MTrxMI group compared to MLZMI and CMI. Visualization of Connexin-43 by immunohistochemistry confirmed increased intercellular connections in the MTrxMI rats compared to MLZMI.

CONCLUSION:

Engineering MSCs to express Trx1 may prove to be a strategic therapeutic modality in the treatment of cardiac failure.

• Authors: Sumanth C Suresh, Vaithinathan Selvaraju, Mahesh Thirunavukkarasu, Joshua W Goldman, Aaftab Husain, J Alexander Palesty, Juan A Sanchez, David W McFadden, Nilanjana Maulik
• Journal: International journal of cardiology (Int J Cardiol) Vol. 201 Pg. 517-28 (Dec 15 2015) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 26322599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Angiogenesis Inducing Agents
• Receptors, CXCR4
• TXN protein, human
• Vascular Endothelial Growth Factor A
• Thioredoxins
• Heme Oxygenase-1

Topics

• Angiogenesis Inducing Agents (metabolism)
• Animals
• Cell Differentiation
• Fibrosis (metabolism)
• Genetic Therapy (methods)
• Heme Oxygenase-1 (metabolism)
• Male
• Mesenchymal Stem Cell Transplantation (adverse effects, methods)
• Mesenchymal Stem Cells (cytology, physiology)
• Myocardial Infarction (metabolism, pathology, therapy)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (metabolism)
• Neovascularization, Physiologic (physiology)
• Rats
• Rats, Sprague-Dawley
• Receptors, CXCR4 (metabolism)
• Thioredoxins (biosynthesis, genetics, metabolism)
• Transfection
• Vascular Endothelial Growth Factor A (genetics, metabolism)