[Frontiers in Bioscience 14, 2845-2856, January 1, 2009]

TNF-alpha enhances engraftment of mesenchymal stem cells into infarcted myocardium

Yong Sook Kim 1,2, Hye Jung Park 1, Moon Hwa Hong 1,2, Peter M. Kang 3, James P. Morgan 4, Myung Ho Jeong 1,2,5, Jeong Gwan Cho 2,5, Jong Chun Park 2,5, Youngkeun Ahn 1.2.5

1Cardiovascular Research Institute, Chonnam National University, Gwanju, South Korea, 2The Heart Center of Chonnam National University Hospital, Gwangju, South Korea, 3Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA, 4Division of Cardiovascular Medicine, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Brighton, MA 02135, USA, 5Clinical Trial Center, Chonnam National University Hospital, Gwangju, South Korea

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and Methods
3.1. MSC Isolation, culture, and labeling
3.2. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting
3.3. Analysis of BMP-2 expression by enzyme-linked immunosorbent assay (ELISA)
3.4. Cell adhesion and transmigration assay
3.5. Myocardial ischemia-reperfusion (IR) injury in a rat model
3.6. Adenoviral transduction
3.7. Optical bioluminescence imaging of MSC transplantation
3.8. Assessment of cardiac function
3.9. Histological examination 3.10. Statistical analysis
4. Results
4.1. TNF-a enhances MSC adhesion and migration in a BMP-2-, STAT-3, and NF-k B-dependent manner
4.2. TNF-a increases MSC adhesion and survival of ischemic myocardium
4.3. Treatment of MSC with TNF-a reduces collagen deposition and enhances recovery of cardiac function
5. Discussion
6. Acknowledgements
7. References

1. ABSTRACT

TNF-alpha released from ischemic heart after acute MI increases the production of other cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1). Activation of nuclear factor kappa B (NF-kappa B) by TNF-alpha , up-regulates the expression of molecules which are involved in inflammation and cell adhesion. For these reasons, we assessed the extent that treatment of MSC with tumor necrosis factor (TNF)-alpha modifies the characteristics of MSC, important to their engraftment in experimental myocardial infarct. Here, we show that pre-treatment of MSC prior to transplantation with tumor necrosis factor (TNF)-alpha increases adhesiveness, and migration of MSC in vitro and leads to increased expression of bone morphogenetic protein (BMP)-2 by MSC. Moreover, this treatment increases the rate of engraftment of MSC and improves recovery of cardiac function after myocardial infarction. These insights might provide better strategies for the treatment of myocardial infarction.