title: Electrophysiological integration and action potential properties of transplanted cardiomyocytes derived from induced pluripotent stem cells.
abstract: OBJECTIVE
  Induced pluripotent stem cell-derived cardiomyocytes (iPSCM) are regarded as promising cell type for cardiac cell replacement therapy. We investigated long-term electrophysiological integration and maturation of transplanted iPSCM, which are essential for therapeutic benefit.
  
  
  RESULTS
  Murine iPSCM expressing enhanced green fluorescent protein and a puromycin resistance under control of the α-myosin heavy chain promoter were purified by antibiotic selection and injected into adult mouse hearts. After 6-12 days, 3-6 weeks, or 6-8 months, viable slices of recipient hearts were prepared. Slices were focally stimulated by a unipolar electrode placed in host tissue, and intracellular action potentials (APs) were recorded with glass microelectrodes in transplanted cells and neighbouring host tissue within the slices. Persistence and electrical integration of transplanted iPSCM into recipient hearts could be demonstrated at all time points. Quality of coupling improved, as indicated by a maximal stimulation frequency without conduction blocks of 5.77 ± 0.54 Hz at 6-12 days, 8.98 ± 0.38 Hz at 3-6 weeks and 10.82 ± 1.07 Hz at 6-8 months after transplantation. AP properties of iPSCM became more mature from 6-12 days to 6-8 months after transplantation, but still differed significantly from those of host APs.
  
  
  CONCLUSIONS
  Transplanted iPSCM can persist in the long term and integrate electrically into host tissue, supporting their potential for cell replacement therapy. Quality of electrical integration improves between 6-12 days and 6-8 months after transplantation, and there are signs of an electrophysiological maturation. However, even after 6-8 months, AP properties of transplanted iPSCM differ from those of recipient cardiomyocytes.
authors.affiliation: Department of Internal Medicine III, University Hospital of Cologne, Kerpener Str. 62, D-50937 Cologne, Köln, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Halbach
authors.forename: Gabriel
authors.initials: G
authors.lastname: Peinkofer
authors.forename: Sven
authors.initials: S
authors.lastname: Baumgartner
authors.forename: Martina
authors.initials: M
authors.lastname: Maass
authors.forename: Mirjam
authors.initials: M
authors.lastname: Wiedey
authors.forename: Klaus
authors.initials: K
authors.lastname: Neef
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krausgrill
authors.forename: Dennis
authors.initials: D
authors.lastname: Ladage
authors.forename: Azra
authors.initials: A
authors.lastname: Fatima
authors.forename: Tomo
authors.initials: T
authors.lastname: Saric
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hescheler
authors.forename: Jochen
authors.initials: J
authors.lastname: Müller-Ehmsen
mesh_terms: D000200:Action Potentials; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000637:transplantation*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000637:transplantation*; D018995:Myosin Heavy Chains / Q000235:genetics; D011401:Promoter Regions, Genetic; D013997:Time Factors; D014162:Transfection; D024723:Ventricular Myosins / Q000235:genetics
chemical_list: C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains
keywords: Conduction; Electrophysiology; Transplantation; iPSCM