title: A novel model of urinary tract differentiation, tissue regeneration, and disease: reprogramming human prostate and bladder cells into induced pluripotent stem cells.
abstract: BACKGROUND
  Primary culture and animal and cell-line models of prostate and bladder development have limitations in describing human biology, and novel strategies that describe the full spectrum of differentiation from foetal through to ageing tissue are required. Recent advances in biology demonstrate that direct reprogramming of somatic cells into pluripotent embryonic stem cell (ESC)-like cells is possible. These cells, termed induced pluripotent stem cells (iPSCs), could theoretically generate adult prostate and bladder tissue, providing an alternative strategy to study differentiation.
  
  
  OBJECTIVE
  To generate human iPSCs derived from normal, ageing, human prostate (Pro-iPSC), and urinary tract (UT-iPSC) tissue and to assess their capacity for lineage-directed differentiation.
  
  
  METHODS
  Prostate and urinary tract stroma were transduced with POU class 5 homeobox 1 (POU5F1; formerly OCT4), SRY (sex determining region Y)-box 2 (SOX2), Kruppel-like factor 4 (gut) (KLF4), and v-myc myelocytomatosis viral oncogene homolog (avian) (MYC, formerly C-MYC) genes to generate iPSCs.
  
  
  METHODS
  The potential for differentiation into prostate and bladder lineages was compared with classical skin-derived iPSCs. The student t test was used.
  
  
  CONCLUSIONS
  Successful reprogramming of prostate tissue into Pro-iPSCs and bladder and ureter into UT-iPSCs was demonstrated by characteristic ESC morphology, marker expression, and functional pluripotency in generating all three germ-layer lineages. In contrast to conventional skin-derived iPSCs, Pro-iPSCs showed a vastly increased ability to generate prostate epithelial-specific differentiation, as characterised by androgen receptor and prostate-specific antigen induction. Similarly, UT-iPSCs were shown to be more efficient than skin-derived iPSCs in undergoing bladder differentiation as demonstrated by expression of urothelial-specific markers: uroplakins, claudins, and cytokeratin; and stromal smooth muscle markers: α-smooth-muscle actin, calponin, and desmin. These disparities are likely to represent epigenetic differences between individual iPSC lines and highlight the importance of organ-specific iPSCs for tissue-specific studies.
  
  
  CONCLUSIONS
  IPSCs provide an exciting new model to characterise mechanisms regulating prostate and bladder differentiation and to develop novel approaches to disease modelling. Regeneration of bladder cells also provides an exceptional opportunity for translational tissue engineering.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, UK.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Moad
authors.forename: Deepali
authors.initials: D
authors.lastname: Pal
authors.forename: Anastasia C
authors.initials: AC
authors.lastname: Hepburn
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Williamson
authors.forename: Laura
authors.initials: L
authors.lastname: Wilson
authors.forename: Majlinda
authors.initials: M
authors.lastname: Lako
authors.forename: Lyle
authors.initials: L
authors.lastname: Armstrong
authors.forename: Simon W
authors.initials: SW
authors.lastname: Hayward
authors.forename: Omar E
authors.initials: OE
authors.lastname: Franco
authors.forename: Justin M
authors.initials: JM
authors.lastname: Cates
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Fordham
authors.forename: Stefan
authors.initials: S
authors.lastname: Przyborski
authors.forename: Jane
authors.initials: J
authors.lastname: Carr-Wilkinson
authors.forename: Craig N
authors.initials: CN
authors.lastname: Robson
authors.forename: Rakesh
authors.initials: R
authors.lastname: Heer
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002469:Cell Separation; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000502:physiology*; D007610:Kallikreins / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D017430:Prostate-Specific Antigen / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D023822:Tissue Engineering / Q000379:methods*; D014162:Transfection; D014513:Ureter / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D001743:Urinary Bladder / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D060165:Uroplakins / Q000378:metabolism
chemical_list: C410798:AR protein, human; D015415:Biomarkers; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D011944:Receptors, Androgen; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D060165:Uroplakins; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Androgen receptor; Bladder; Differentiation; KLF4; MYC (formerly cMYC); NANOG; POU5F1 (formerly OCT4); Pluripotent; Prostate; SOX2; Stem cells; Tissue engineering; Ureter; Urothelium