| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
It has been held for decades that organ systems with regenerative ability are maintained by populations of cells called stem cells which are able to self-renew and generate committed progenies. These stem cells are also believed to be organ/tissue specific. However, this dogma was recently challenged by a number of reports. We first examined myocardial regeneration by cytokine mobilized-bone marrow (BM) cells in mice. We demonstrated that granulocyte colony-stimulating factor (G-CSF) improved cardiac function and survival rate, and BM-derived cells could regenerate infarcted myocardial tissue, differentiating into cardiomyocytes, by using mice whose BM had been replaced with genetically marked BM cells. Since crude BM contain both hematopoietic and non-hematopoietic stem cells, we next assessed the origin of the BM cells which are capable of regenerating cardiomyocytes ; we used clonal studies to determine the origin of BM-derived cardiomyocytes. Our results suggested that the origin of the vast majority of BM-derived cardiomyocytes is mesenchymal stem cells (MSC). However, the number of regenerated cardiomyocytes derived from MSCs was considered to be too small to solely account for the beneficial effect of G-CSF on cardiac remodeling. Then, we focused on the effect of hematopoietic stem cells (HSCs) in the myocardial regeneration. As a result, we found that cardiac myofibroblasts/fibroblasts derive from HSCs and that G-CSF treatment markedly increases the number of HSCs-derived myofibroblasts/fibroblasts in the infarcted area, which reinforced the infarcted ventricular wall, resulting in improved cardiac remodeling, function, and survival. Further, we also demonstrated that monocytes/macrophages could be the precursors of myofibroblasts/ fibroblasts.; MI recruits monocytes which differentiate into myofibroblasts in the infarct region, and administration of G-CSF promotes the recruitment resulting in enhanced cardiac protection.
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