Moad, M. and Pal, D. and Hepburn, A.C. and Williamson, S.C. and Wilson, L. and Lako, M. and Armstrong, L. and Hayward, S.W. and Franco, O.E. and Cates, J.M. and Fordham, S.E. and Przyborski, S. and Carr-Wilkinson, J. and Robson, C.N. and Heer, R. (2013) 'A novel model of urinary tract differentiation, tissue regeneration, and disease : reprogramming human prostate and bladder cells into induced pluripotent stem cells.', European urology., 64 (5). pp. 753-761.
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. Design, setting, and participants: 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. Outcome measurements and statistical analysis: The potential for differentiation into prostate and bladder lineages was compared with classical skin-derived iPSCs. The student t test was used. Results and limitations: 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.
|Keywords:||Prostate, Bladder, Differentiation, Pluripotent, Stem cells, Tissue engineering, Ureter, Urothelium, Androgen receptor, POU5F1 (formerly OCT4), SOX2, KLF4, MYC (formerly cMYC), NANOG.|
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|Publisher Web site:||http://dx.doi.org/10.1016/j.eururo.2013.03.054|
|Publisher statement:||This article is available under the terms of the Creative Commons Attribution License (CC BY). You may copy and distribute the article, create extracts, abstracts and new works from the article, alter and revise the article, text or data mine the article and otherwise reuse the article commercially (including reuse and/or resale of the article) without permission from Elsevier. You must give appropriate credit to the original work, together with a link to the formal publication through the relevant DOI and a link to the Creative Commons user license above. You must indicate if any changes are made but not in any way that suggests the licensor endorses you or your use of the work.|
|Date accepted:||25 March 2013|
|Date deposited:||27 July 2015|
|Date of first online publication:||November 2013|
|Date first made open access:||No date available|
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