ABSTRACT
Figure 2a.1 Scheme of paracrine effects in stem/progenitor cell transplan-tation to the injured heart.
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differentiation of the transplanted cells contributes, at least in part, to improvement of cardiac function via the restoration of blood flow. On the other hand, an experimental model of acute myocardial infarct showed that injection of the supernatants of bone marrow mononuclear cell culture into the heart resulted in improvement of cardiac function, accompanied by increases in capillary density and reduction of infarct scar size [7]. Since the supernatants contained VEGF, FGF-1, IGF-1, and SDF-1 [8], these proteins are considered to promote proliferation and migration of cardiovascular and vascular smooth muscle cells in the host heart and consequently contribute to neovascularization. In addition, there is evidence that the host organ is not always the recipient of the cytokine actions, but host cells activated by transplantation therapy can produce protective proteins for self-repair. Cho et al. transplanted human EPCs into infarcted hearts of immunocompromised mice and found that, despite the rapid disappearance of human EPCs within one week, the levels of expression of angiogenic factors such as VEGF, FGF-2, HGF, and angiopoietin-1 remained high for more than two weeks, and this prolonged expression was attributed to host (mouse) cells, not transplanted (human) cells [9]. In other words, the secretion of proteins from the transplanted cells, or direct contact with the transplanted cells, promotes the production of angiogenic factors by host cells, which restores blood flow and consequently ameliorates cardiac dysfunction in myocardial infarct in mice. It was proven that transplanted cells in patients with peripheral vascular diseases promote angiogenesis, thereby alleviating subjective symptoms and contributing to limb salvage. Tateno et al. reported that transplanted peripheral blood-derived mononuclear cells promote the regeneration of local skeletal muscle, which then secretes angiogenic factors such as VEGF and IL-1b, thereby contributing to improvement of blood flow in the lower limbs [10]. Recently we have reported that Gr-1(+) myeloid cell-secreted GH mainly contributes to the improvement of cardiac function in several dilated cardiomyopathy models when bone marrow mononuclear cells are intravenously infused [11]. However, GH expression in Gr-1(+) cells was suppressed via humoral factor-mediated activin A in heart failure, which leads to marginal effects after infusion. Thus pretreatment to modulate the environmental cue in heart failure might enhance the function of cells for transplantation.
