Layered implantation of myoblast sheets attenuates cardiac remodeling of infarcted heart
Naosumi Sekiya1, Shigeru Miyagawa1, Goro Matsumiya1, Takaya Hoashi1, Tatsuya Shimizu2, Teruo Okano2, Yoshiki Sawa1; 1Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan; 2Tokyo Women’s Medical University, Tokyo, Japan
Comment on this Abstract
Objective: We have shown that autologous myoblast sheets constructed with tissue-engineering technique improve the function of impaired heart. In this study, we evaluated the effect of the layered myoblast sheets to clarify the optimal number of cell sheets to efficiently improve cardiac function.
Methods: Myoblast sheets were constructed with temperature-responsive, polymer-grafted cell-culture dishes, which release the confluent cells from the dish surface at less than 20 degrees centigrade. After two weeks from LAD ligation, sixty Lewis rats had implantation of myoblast sheets (3×106 cells per sheet) on the infarcted area. Rats were divided into the following 4 groups depending on the number of layered myoblast sheets (n=15, in each group), S1 group: one layer, S3 group: three layers, S5 group: five layers and Sham group. We examined cardiac function by echocardiography and pressure-volume analysis with a conductance catherter and examined histology and mRNA expression of growth factors (hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), stromal cell-derived factor-1 (SDF-1), midkine, thymosin b4, b10) by real time RT-PCR.
Results: Grafted anterior wall thickness significantly increased in dose dependent manner. In functional assessment, Ejection fraction (EF) of S5 and S3 at 4 and 8 weeks significantly improved. The dilatation of end diastolic area (EDA) at 8 weeks in S5 was significantly reduced than other groups. In catheterization study at 8 weeks, ESPVR of S3, S5 groups significantly improved. All the angiogenic and myocardial protective factor mRNA expressions were most upregulated in S5 group than those in the other groups. In histological examination, %fibrosis most decreased in S5, vascular density increased and the dilatation of cell attenuated in S5 and S3 groups. In Elastica-Masson stain, elastic fibers were massively expressed in infarcted area and implanted sheets in S3, S5 groups with significantly more elastin gene expressing.
Conclusion: Five layered myoblast sheets implantation seems to be favorable with better improvement of cardiac function, induction of angiogenesis, less fibrosis, and less hypertrophy. Elastic fibers were possibly derived from myoblast sheets and might play a mechanically protective role for attenuating cardiac remodeling.
Cardiac function and histological data
| Sham | S1 | S3 | S5 |
| Wall thickness(mm) | 0.38±0.01 | 0.44±0.03 | 0.81±0.09*† | 0.96±0.04*† |
| LVEF(%)at 4 weeks | 38.6±1.3 | 38.5±2.8 | 45.3±1.4*† | 51.3±1.6*†# |
| LVEF(%)at 8 weeks | 34.6±2.2 | 38.2±5.8 | 43.7±1.9*† | 47.8±2.8*† |
| EDA(mm2)at 8 weeks | 1.02±0.02 | 0.99±0.04 | 0.96±0.02 | 0.91±0.05* |
| ESPVR(mmHg/ml) | 719±180 | 726±65 | 1831±276*† | 2071±361*† |
| %fibrosis(%) | 6.62±0.30 | 6.48±0.23 | 4.58±0.16*† | 2.48±0.15*†# |
| Vascular density(/mm2) | 3.71±0.41 | 4.32±0.38 | 12.54±0.80*† | 11.42±0.61*† |
| Cell diameter(μm) | 20.23±0.13 | 19.72±0.13 | 17.21±0.12*† | 17.56±0.14*† |
* P<.05 vs Sham group, † P<.05 vs S1 group, # P<.05 vs S3 group
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