Establishment of Regenerative Therapy for Patients with Left Ventricular Assist Device 〜Aiming to 'Bridge to Recovery〜

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1. Sheet-shaped myoblast implantation in dilated cardioyopathic hamstersMale 27-week-old BIO TO-2 (DCM) hamsters that showed moderate cardiac remodeling were used as recipients. Myoblasts isolated from BIO F1B hamsters were cultured on dishes coated with poly(N-isopropylacrylamide). Three different therapies were conducted : (1) sheet-shaped myoblast graft implantation (S group, n=29) ; (2) myoblast injection (M group, n=28) ; and (3) sham operation (C group, n=28). In the S group, two sheet-shaped myoblast grafts were implanted on the left ventricle (LV) wall, and in the M group, myoblasts were injected into the right ventricle (RV) and LV walls. After the sheet-shaped myoblast grafts were implanted, echocardiography demonstrated that the dilated LV dimension was significantly reduced, whereas the hearts in other groups showed a progression of LV dilation. The fractional shortening in the M and C groups decreased significantly while that in the S group was maintained at the preoperati … More ve level for 3 months after the operation. Histological examination demonstrated that in the S group, the LV wall thickness was increased, with viable myoblasts, and myocardial fibrosis was decreased compared with the other groups. Immunohistochemical staining demonstrated alpha-sarcoglycan and beta-sarcoglycan expression on the basement membrane of the cardiomyocytes in the S group but not in the other groups. The life expectancy was significantly prolonged in the S group. Sheet-shaped myoblast graft implantation improved cardiac performance and prolonged life expectancy, associated with a reduction in myocardial fibrosis and re-organization of the cytoskeletal proteins in DCM hamsters.2. Myobalst sheet implantation in pacing -induced canine modelTwelve dogs were given continuous ventricular pacing at 230 beats/min for 4weeks ; then the myoblast sheets (n=5) were grafted onto the left ventricular wall or a sham operation was performed (n=7). The number of cells was adjusted to 1.5〜2.5 x 10(6) cells per graft, and each dog received approximately 20 grafts. The cell sheets were easily grafted onto a large area of the left ventricular surface, and there were no serious sequelae. Four weeks after graft implantation, echocardiography demonstrated that the left ventricular ejection fraction and fractional shortening were significantly ameliorated with reduced left ventricular dilatation and increased wall thickness. Histologic evidence indicated the grafted myoblasts had survived, accompanied by a significant reduction in fibrosis and apoptosis, and a significant increase in proliferation.3. Suicide gene system regulates the effect of angiogenesis in infarcted rat heartWe developed human HGF (hHGF)-producing cells that regulated hHGF production using the thymidine kinase gene of Herpes Simplex Virus (TK) and the Ganciclovir (GCV) system. We tested whether these cells induced and regulated angiogenic effects in infarcted myocardium. NIH3T3 cells were stably transfected with an hHGF cDNA expression plasmid (NIH/HGF). Next, the NIH/HGF cells were stably transfected with TK (NIH/HGF/TK). The left anterior descending artery was ligated in the heart of severe combined immunodeficiency rats, and four materials were transplanted : 1) NIH/HGF (n=10), 2) NIH/HGF/TK, with orally administered GCV (n=10), 3) NIH3T3 (n=10), and 4) culture medium (n=10). In vitro, the proliferation of NIH/HGF/TK cells was suppressed by GCV. In vivo, significant increases in cardiac performance and angiogenesis were observed in the NIH/HGF and NIH/HGF/TK groups 4 weeks after transplantation. Although tumorous lesions were detected in the NIH/HGF group, their growth was completely controlled in the NIH/HGF/TK group. Angiogenic gene cell therapy using the TK-GCV suicide gene system induces and regulates angiogenesis under the control of cell growth. Less