title: The use of cell-sheet technique eliminates arrhythmogenicity of skeletal myoblast-based therapy to the heart with enhanced therapeutic effects.
abstract: BACKGROUND
  Clinical application of skeletal myoblast transplantation has been curtailed due to arrhythmogenicity and inconsistent therapeutic benefits observed in previous studies. However, these issues may be solved by the use of a new cell-delivery mode. It is now possible to generate "cell-sheets" using temperature-responsive dishes without artificial scaffolds. This study aimed to validate the safety and efficacy of epicardial placement of myoblast-sheets (myoblast-sheet therapy) in treating heart failure.
  
  
  RESULTS
  After coronary artery ligation in rats, the same numbers of syngeneic myoblasts were transplanted by intramyocardial injection or cell-sheet placement. Continuous radio-telemetry monitoring detected increased ventricular arrhythmias, including ventricular tachycardia, after intramyocardial injection compared to the sham-control, while these were abolished in myoblast-sheet therapy. This effect was conjunct with avoidance of islet-like cell-cluster formation that disrupts electrical conduction, and with prevention of increased arrhythmogenic substrates due to exaggerated inflammation. Persistent ectopic donor cells were found in the lung only after intramyocardial injection, strengthening the improved safety of myoblast-sheet therapy. In addition, myoblast-sheet therapy enhanced cardiac function, corresponding to a 9.2-fold increase in donor cell survival, compared to intramyocardial injection. Both methods achieved reduced infarct size, decreased fibrosis, attenuated cardiomyocyte hypertrophy, and increased neovascular formation, in association with myocardial upregulation of a group of relevant molecules. The pattern of these beneficial changes was similar between two methods, but the degree was more substantial after myoblast-sheet therapy.
  
  
  CONCLUSIONS
  The cell-sheet technique enhanced safety and therapeutic efficacy of myoblast-based therapy, compared to the current method, thereby paving the way for clinical application.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Takuya
authors.initials: T
authors.lastname: Narita
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Shintani
authors.forename: Chiho
authors.initials: C
authors.lastname: Ikebe
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kaneko
authors.forename: Narumi
authors.initials: N
authors.lastname: Harada
authors.forename: Nomathamsanqa
authors.initials: N
authors.lastname: Tshuma
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Niall G
authors.initials: NG
authors.lastname: Campbell
authors.forename: Steven R
authors.initials: SR
authors.lastname: Coppen
authors.forename: Kenta
authors.initials: K
authors.lastname: Yashiro
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
authors.forename: Ken
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology / Q000517:prevention & control*; D018929:Cell Culture Techniques / Q000379:methods*; D005260:Female; D006333:Heart Failure / Q000503:physiopathology / Q000601:surgery*; D008297:Male; D032448:Myoblasts, Skeletal / Q000502:physiology / Q000637:transplantation*; D032383:Myocytes, Cardiac / Q000502:physiology / Q000637:transplantation*; D051381:Rats; D011917:Rats, Inbred Lew; D016896:Treatment Outcome