Original article
Cardiovascular
Paracrine Action Enhances the Effects of Autologous Mesenchymal Stem Cell Transplantation on Vascular Regeneration in Rat Model of Myocardial Infarction

Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.
https://doi.org/10.1016/j.athoracsur.2005.02.072Get rights and content

Background

There are several reports that engrafted mesenchymal stem cells (MSCs) stimulate angiogenesis in the ischemic heart, but the mechanism remains controversial. We hypothesize that transplantation of MSCs enhances vascular regeneration through a paracrine action.

Methods

A transmural myocardial infarction was created by ligation of the left anterior descending coronary artery in rats. Those with an ejection fraction less than 0.70 1 week after myocardial infarction were included. Autologous MSCs (1 × 107; 0.2 mL) or culture medium (0.2 mL) was injected intramyocardially into the periinfarct zone (50 μL/injection at four sites; n = 20/group). At 2 weeks after transplantation, Western blot analysis was used to assay the paracrine factors and proapoptotic proteins. Echocardiography to assess heart function was performed on additional groups at 8 weeks after implantation.

Results

The angiogenic factors basic fibroblast growth factor, vascular endothelial growth factor, and stem cell homing factor (stromal cell-derived factor -1α) increased in the MSC-treated hearts compared with medium-treated hearts. This was accompanied by a downregulation of proapoptotic protein Bax in ischemic myocardium. Similarly, capillary density increased about 40% in MSC-treated hearts compared with medium-treated hearts (p = 0.001). Left ventricular contractility, indicated by fractional shortening, improved in MSC-treated hearts at 2 months after implantation (MSCs: 48.6% ± 19.9%; medium: 18.7% ± 6.4%; p = 0.004).

Conclusions

Autologous MSC transplantation attenuates left ventricular remodeling and improves cardiac performance. The major mechanism appears to be paracrine action of the engrafted cells, increasing angiogenesis and cytoprotection.

Section snippets

Material and Methods

All experiments were performed in accordance with the “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” prepared by the Institute of Laboratory Animal Resources, Commission on Life Science, National Research Council, and published by the National Academy Press, revised 1996.

Identification of Transplanted Mesenchymal Stem Cells

To identify grafted MSCs in the ischemic myocardium, MSCs were prelabeled with BrdU in the nucleus. 5-Bromo-2-deoxyruidine staining of MSCs demonstrated that 85% of MSCs were labeled with BrdU (Fig 1B). Transplanted cells were localized within the ischemic myocardium in MSC-transplanted hearts by means of immunohistochemical staining with monoclonal antibodies against BrdU (Fig 1C).

Capillary Density

Capillary density was quantified in the border zone of infarct area and compared between two groups. Mesenchymal

Comment

In this investigation, our data show that neovascularization induced in the ischemic myocardium is directly related to the paracrine action of engrafted MSCs in ischemic myocardium. The release of bFGF, VEGF, and SDF-1α leads to efficient vascular regeneration and also attenuates the apoptotic pathway. These paracrine actions account for reduced remodeling and recovery of cardiac performance.

We demonstrated that graft MSCs in ischemic myocardium secrete SDF-1α. This cytokine may have an effect

Acknowledgments

Yao Liang Tang is supported by an American Heart Association postdoctoral fellowship (0325378B). This work was supported by the National Institutes of Health MERIT Award HL 27339 (MIP). We are grateful for the expert technical assistance of Guoqian Huang, MD, Chuizheng Pan, and Xianhong Shu, MD.

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