Reduced collagen deposition in infarcted myocardium facilitates induced pluripotent stem cell engraftment and angiomyogenesis for improvement of left ventricular function.

Abstract

OBJECTIVES:

The purpose of this study was to assess the effect of scar tissue composition on engraftment of progenitor cells into infarcted myocardium.

BACKGROUND:

Scar tissue formation after myocardial infarction creates a barrier that severely compromises tissue regeneration, limiting potential functional recovery.

METHODS:

In vitro: A tricell patch (Tri-P) was created from peritoneum seeded and cultured with induced pluripotent stem cell-derived cardiomyocytes, endothelial cells, and mouse embryonic fibroblasts. The expression of fibrosis-related molecules from mouse embryonic fibroblasts and infarcted heart was measured by Western blot and quantitative reverse transcriptase polymerase chain reaction. In vivo: A Tri-P was affixed over the entire infarcted area 7 days after myocardial infarction in mice overexpressing adenylyl cyclase 6 (AC6). Engraftment efficiency of progenitor cells in hearts of AC6 mice was compared with that of control wild-type (WT) mice using a combination of in vivo bioluminescence imaging, post-mortem ex vivo tissue analysis, and the number of green fluorescent protein-positive cells. Echocardiography of left ventricular (LV) function was performed weekly. Hearts were harvested for analysis 4 weeks after Tri-P application. Mouse embryonic fibroblasts were stimulated with forskolin before an anoxia/reoxygenation protocol. Fibrosis-related molecules were analyzed.

RESULTS:

In AC6 mice, infarcted hearts treated with Tri-P showed significantly higher bioluminescence imaging intensity and numbers of green fluorescent protein-positive cells than in WT mice. LV function improved progressively in AC6 mice from weeks 2 to 4 and was associated with reduced LV fibrosis.

CONCLUSIONS:

Application of a Tri-P in AC6 mice resulted in significantly higher induced pluripotent stem cell engraftment accompanied by angiomyogenesis in the infarcted area and improvement in LV function.

• Authors: Bo Dai, Wei Huang, Meifeng Xu, Ronald W Millard, Mei Hua Gao, H Kirk Hammond, Donald R Menick, Muhammad Ashraf, Yigang Wang
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 58 Issue 20 Pg. 2118-27 (Nov 08 2011) ISSN: 1558-3597 [Electronic] United States
• PMID: 22051336 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Collagen
• Adenylyl Cyclases
• adenylyl cyclase 6

Topics

• Adenylyl Cyclases (metabolism)
• Animals
• Cell Proliferation
• Cicatrix (physiopathology)
• Collagen (biosynthesis)
• Echocardiography
• Fibrosis
• Human Umbilical Vein Endothelial Cells
• Humans
• Luminescent Measurements
• Mice
• Mice, Transgenic
• Muscle Development
• Myocardial Infarction (pathology, therapy)
• Myocardium (metabolism, pathology)
• Neovascularization, Physiologic
• Pluripotent Stem Cells (physiology, transplantation)
• Rats
• Regeneration
• Ventricular Function, Left
• Ventricular Remodeling