title: Attenuation of teratoma formation by p27 overexpression in induced pluripotent stem cells.
abstract: BACKGROUND
  Pluripotent stem cells, such as embryonic stem cells or induced pluripotent stem cells, have a great potential for regenerative medicine. Induced pluripotent stem cells, in particular, are suitable for replacement of tissue by autologous transplantation. However, tumorigenicity is a major risk in clinical application of both embryonic stem cells and induced pluripotent stem cells. This study explores the possibility of manipulating the cell cycle for inhibition of tumorigenicity.
  
  
  METHODS
  We genetically modified mouse induced pluripotent stem cells (miPSCs) to overexpress p27 tumor suppressor and examined their proliferation rate, gene expression, cardiac differentiation, tumorigenicity, and therapeutic potential in a mouse model of coronary artery ligation.
  
  
  RESULTS
  Overexpression of p27 inhibited cell division of miPSCs, and that inhibition was dependent on the expression level of p27. p27 overexpressing miPSCs had pluripotency characteristics but lost stemness earlier than normal miPSCs during embryoid body and teratoma formation. These cellular characteristics led to none or smaller teratoma when the cells were injected into nude mice. Transplantation of both miPSCs and p27 overexpressing miPSCs into the infarcted mouse heart reduced the infarction size and improved left ventricular function.
  
  
  CONCLUSIONS
  The overexpression of p27 attenuated tumorigenicity by reducing proliferation and earlier loss of stemness of miPSCs. The overexpression of p27 did not affect pluripotency and differentiation characteristics of miPSC. Therefore, regulation of the proliferation rate of miPSCs offers great therapeutic potential for repair of the injured myocardium.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, 45267-0529, USA. toru.matsuura@uc.edu.
authors.forename: Toru
authors.initials: T
authors.lastname: Matsu-ura
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, 45267-0529, USA. gyn078@poh.osaka-med.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, 45267-0529, USA. motoy@asahikawa-med.ac.jp.
authors.forename: Motoi
authors.initials: M
authors.lastname: Okada
authors.affiliation: Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Saitama, 351-0198, Japan. mikosiba@brain.riken.jp.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, 45267-0529, USA. Ashrafm2@uic.edu.|Department of Pharmacology, University of Illinois at Chicago College of Medicine, 835 South Wolcott Ave, Chicago, IL, 60612, USA. Ashrafm2@uic.edu.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ashraf
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D058732:Embryoid Bodies / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints; D015870:Gene Expression; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009203:Myocardial Infarction / Q000628:therapy; D009206:Myocardium / Q000473:pathology; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D013724:Teratoma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology
chemical_list: C493961:Cdkn1b protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27