Administration of Granulocyte Colony-Stimulating Factor after Myocardial Infarction Enhances the Recruitment of Hematopoietic Stem Cell-Derived Myofibroblasts and Contributes to Cardiac Repair

¹ Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
² Department of Cardiac Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
³ Department of Medicine, and Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
⁴ Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
⁵ Division of Cardiology, Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.

^* To whom correspondence should be addressed. E-mail: hkawada{at}is.icc.u-tokai.ac.jp.

	Abstract

The administration of granulocyte colony-stimulating factor (G-CSF) after myocardial infarction (MI) improves cardiac function and survival rates in mice. It was also reported recently that bone marrow (BM)-derived c-kit⁺ cells or macrophages in the infarcted heart are associated with improvement of cardiac remodeling and function. These observations prompted us to examine whether BM-derived hematopoietic cells mobilized by G-CSF administration after MI play a beneficial role in the infarct region. A single hematopoietic stem cell from green fluorescent protein (GFP)-transgenic mice was used to reconstitute hematopoiesis in each experimental mouse. MI was then induced and the mice received G-CSF for 10 days. In the acute phase, a number of GFP⁺ cells showing the elongated morphology were found in the infarcted area. Most of these cells were positive for vimentin and -smooth muscle actin, but negative for CD45, indicating that they were myofibroblasts. The number of these cells was markedly enhanced by G-CSF administration, and the enhanced myofibroblast-rich repair was considered to lead to improvements of cardiac remodeling, function, and survival rate. Next, G-CSF-mobilized monocytes were harvested from the peripheral blood of GFP-transgenic mice and injected intravenously into the infarcted mice. Following this procedure, GFP⁺ myofibroblasts were observed in the infarcted myocardium. These results indicate that cardiac myofibroblasts are hematopoietic in origin and could arise from monocytes/macrophages. MI leads to the recruitment of monocytes, which differentiate into myofibroblasts in the infarct region. Administration of G-CSF promotes this recruitment and enhances cardiac protection.

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