In situ lineage tracking of human prostatic epithelial stem cell fate reveals a common clonal origin for basal and luminal cells

  1. Lookup NU author(s)
  2. Dr John Blackwood
  3. Dr Stuart Williamson
  4. Dr Laura Greaves
  5. Laura Wilson
  6. Dr Anastasia Hepburn
  7. Dr Raveen Sandher
  8. Professor Robert Pickard
  9. Professor Craig Robson
  10. Professor Doug Turnbull
  11. Professor Robert Taylor
  12. Dr Rakesh Heer
Author(s)Blackwood JK, Williamson SC, Greaves LC, Wilson L, Rigas AC, Sandher R, Pickard RS, Robson CN, Turnbull DM, Taylor RW, Heer R
Publication type Article
JournalJournal of Pathology
ISSN (print)0022-3417
ISSN (electronic)1096-9896
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Stem cells accumulate mitochondrial DNA (mtDNA) mutations resulting in an observable respiratory chain defect in their progeny, allowing the mapping of stem cell fate. There is considerable uncertainty in prostate epithelial biology where both basal and luminal stem cells have been described, and in this study the clonal relationships within the human prostate epithelial cell layers were explored by tracing stem cell fate. Fresh-frozen and formalin-fixed histologically-benign prostate samples from 35 patients were studied using sequential cytochrome c oxidase (COX)/succinate dehydrogenase (SDH) enzyme histochemistry and COX subunit I immunofluorescence to identify areas of respiratory chain deficiency; mtDNA mutations were identified by whole mitochondrial genome sequencing of laser-captured areas. We demonstrated that cells with respiratory chain defects due to somatic mtDNA point mutations were present in prostate epithelia and clonally expand in acini. Lineage tracing revealed distinct patterning of stem cell fate with mtDNA mutations spreading throughout the whole acinus or, more commonly, present as mosaic acinar defects. This suggests that individual acini are typically generated from multiple stem cells, and the presence of whole COX-deficient acini suggests that a single stem cell can also generate an entire branching acinar subunit of the gland. Significantly, a common clonal origin for basal, luminal and neuroendocrine cells is demonstrated, helping to resolve a key area of debate in human prostate stem cell biology.
PublisherJohn Wiley & Sons Ltd.
NotesSC Williamson is Joint First Author on this paper.
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