title: Addition of mesenchymal stem cells enhances the therapeutic effects of skeletal myoblast cell-sheet transplantation in a rat ischemic cardiomyopathy model.
abstract: BACKGROUND
  Functional skeletal myoblasts (SMBs) are transplanted into the heart effectively and safely as cell sheets, which induce functional recovery in myocardial infarction (MI) patients without lethal arrhythmia. However, their therapeutic effect is limited by ischemia. Mesenchymal stem cells (MSCs) have prosurvival/proliferation and antiapoptotic effects on co-cultured cells in vitro. We hypothesized that adding MSCs to the SMB cell sheets might enhance SMB survival post-transplantation and improve their therapeutic effects.
  
  
  RESULTS
  Cell sheets of primary SMBs of male Lewis rats (r-SMBs), primary MSCs of human female fat tissues (h-MSCs), and their co-cultures were generated using temperature-responsive dishes. The levels of candidate paracrine factors, rat hepatocyte growth factor and vascular endothelial growth factor, in vitro were significantly greater in the h-MSC/r-SMB co-cultures than in those containing r-SMBs only, by real-time PCR and enzyme-linked immunosorbent assay (ELISA). MI was generated by left-coronary artery occlusion in female athymic nude rats. Two weeks later, co-cultured r-SMB or h-MSC cell sheets were implanted or no treatment was performed (n=10 each). Eight weeks later, systolic and diastolic function parameters were improved in all three treatment groups compared to no treatment, with the greatest improvement in the co-cultured cell sheet transplantation group. Consistent results were found for capillary density, collagen accumulation, myocyte hypertrophy, Akt-signaling, STAT3 signaling, and survival of transplanted cells of rat origin, and were related to poly (ADP-ribose) polymerase-dependent signal transduction.
  
  
  CONCLUSIONS
  Adding MSCs to SMB cell sheets enhanced the sheets' angiogenesis-related paracrine mechanics and, consequently, functional recovery in a rat MI model, suggesting a possible strategy for clinical applications.
authors.affiliation: 1 Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine , Suita, Japan .
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shudo
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Hanayuki
authors.initials: H
authors.lastname: Ohkura
authors.forename: Satsuki
authors.initials: S
authors.lastname: Fukushima
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Saito
authors.forename: Motoko
authors.initials: M
authors.lastname: Shiozaki
authors.forename: Naomasa
authors.initials: N
authors.lastname: Kawaguchi
authors.forename: Nariaki
authors.initials: N
authors.lastname: Matsuura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Shimizu
authors.forename: Teruo
authors.initials: T
authors.lastname: Okano
authors.forename: Akifumi
authors.initials: A
authors.lastname: Matsuyama
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D048430:Cell Shape; D002470:Cell Survival; D018925:Chemokines / Q000096:biosynthesis; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000637:transplantation*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic; D051381:Rats; D011917:Rats, Inbred Lew; D011923:Rats, Nude; D020127:Recovery of Function; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018925:Chemokines; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor