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J Thorac Cardiovasc Surg 2005;130:1333-1341
© 2005 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Repair of impaired myocardium by means of implantation of engineered autologous myoblast sheets

Imran A. Memon, MBBS, PhD a , * , Yoshiki Sawa, MD, PhD a , Norihide Fukushima, MD a , Goro Matsumiya, MD a , Shigeru Miyagawa, MD, PhD a , Satoshi Taketani, MD a , Satoru K. Sakakida, MD, PhD c , Haruhiko Kondoh, MD, PhD a , Alexey N. Aleshin, MD, PhD a , Tatsuya Shimizu, MD, PhD b , Teruo Okano, PhD b , Hikaru Matsuda, MD a

a Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
c Department of Molecular Pharmacology, Osaka University Graduate School of Medicine, Osaka, Japan
b Tokyo Women's Medical University, Institute of Advanced Biomedical Engineering and Science, Tokyo, Japan

Received for publication March 10, 2005; revisions received July 17, 2005; accepted for publication July 19, 2005.

* Address for reprints: Yoshiki Sawa, MD, Department of Surgery E1, Division of Cardiovascular Surgery, University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan (Email: i.memon{at}victorchang.unsw.edu.au).

OBJECTIVES: Autologous skeletal myoblast cell transplantation by means of the injection method is subject to the loss of intercellular communication, extracellular matrix, and cell numbers. We hypothesize that the implantation of skeletal myoblast cell sheets might be more advantageous in repairing the impaired heart by providing uniform and stable cell delivery with less cell loss and without disrupting the cell-cell microenvironment.

METHODS: Left anterior descending coronary artery–ligated Lewis rat hearts (2 weeks, total n = 173) received 1 x 107 autologous skeletal myoblasts by means of cell transplantation either through myoblast injection or implantation of 2 monolayer-constructed myoblast sheets (5 x 106 cells per sheet) or through medium injection. 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°C.

RESULTS: Echocardiographic results indicated higher improvement of cardiac performance in the myoblast sheet group than among the other groups until 8 weeks after cell transplantation. Histologic comparison revealed greater cellularity and abundant widespread neocapillaries within the noticeable uniform thickened wall in myoblast sheet group hearts only. Fibrosis was substantially reduced with skeletal myoblast sheet implantation compared with skeletal myoblast cell injection. Obviously higher numbers of hematopoietic stem cells (c-kit, stem cell antigen 1, and CD34) were observed in the myoblast sheet group infarct heart region. Reverse transcription–polymerase chain reaction results showed expression of stromal-derived factor 1, hepatocyte growth factor, and vascular endothelial growth factor as follows: myoblast sheets > myoblast injection > control.

CONCLUSIONS: Myoblast sheets repaired the impaired myocardium, reduced fibrosis, and prevented remodeling in association with recruitment of hematopoietic stem cells through the release of stromal-derived factor 1 and other growth factors. Our experiment indicates a therapy for patients with severe heart failure.

Abbreviations and Acronyms ANOVA = analysis of variance; BrdU = 5'-bromo-2'-deoxyuridine; Ctx = cell transplantation; EF = ejection fraction; HGF = hepatocyte growth factor; HSC = hematopoietic stem cell; LAD = left anterior descending coronary artery; LV = left ventricular; MHC = myosin heavy chain; MI group = myoblast cell suspension injection; MS group = myoblast cell sheet implantation; RT-PCR = reverse transcription–polymerase chain reaction; Sca-1 = stem cell antigen 1; SDF-1 = stromal-derived factor 1; VEGF = vascular endothelial growth factor




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