Multipotent Basal Stem Cells, Maintained in Localized Proximal Niches, Support Directed Long-Ranging Epithelial Flows in Human Prostates
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Moad, M., Hannezo, E., Buczacki, S., Wilson, L., El-Sherif, A., Sims, D., Pickard, R., et al. (2017). Multipotent Basal Stem Cells, Maintained in Localized Proximal Niches, Support Directed Long-Ranging Epithelial Flows in Human Prostates. Cell Reports, 20 (7), 1609-1622. https://doi.org/10.1016/j.celrep.2017.07.061
Sporadic mitochondrial DNA mutations serve as clonal marks providing access to the identity and lineage potential of stem cells within human tissues. By combining quantitative clonal mapping with 3D reconstruction of adult human prostates, we show that multipotent basal stem cells, confined to discrete niches in juxta-urethral ducts, generate bipotent basal progenitors in directed epithelial migration streams. Basal progenitors are then dispersed throughout the entire glandular network, dividing and differentiating to replenish the loss of apoptotic luminal cells. Rare lineage-restricted luminal stem cells, and their progeny, are confined to proximal ducts and provide only minor contribution to epithelial homeostasis. In situ cell capture from clonal maps identified delta homolog 1 (DLK1) enrichment of basal stem cells, which was validated in functional spheroid assays. This study establishes significant insights into niche organization and function of prostate stem and progenitor cells, with implications for disease.
DLK1, Notch, basal, branch, epithelium, luminal, niche, organoids, prostate, prostate cancer, stem cell
This work was supported by grants from The Royal College of Surgeons of England and a Cancer Research UK Clinician Scientist Fellowship (C10169/A12173). This work was also supported by the Wellcome Trust (grant 098357/Z/12/Z to B.D.S. and grant 110326/Z/15/Z to E.H.). E.H. is funded by a Junior Research Fellowship from Trinity College, Cambridge, a Sir Henry Wellcome Fellowship from the Wellcome Trust and acknowledges the Bettencourt-Schueller Young Researcher Prize for support. L.C.G., D.M.T., and R.W.T. are supported by the Wellcome Trust Centre Strategic Award (096919/Z/11/Z). R.W.T. is also supported by the Medical Research Council (MRC) Centre for Neuromuscular Diseases (G0601943), the Lily Foundation, and the UK National Health Service (NHS) Highly Specialised “Rare Mitochondrial Disorders of Adults and Children” Service. L.C.G. and D.M.T. receive support from the Newcastle University Centre for Ageing and Vitality funded by the Biotechnology and Biological Sciences Research Council (BBSRC), the Engineering and Physical Sciences Research Council (EPSRC), the Economic and Social Research Council (ESRC), and MRC as part of the cross-council Lifelong Health and Wellbeing Initiative.
Wellcome Trust (098357/Z/12/Z)
WELLCOME TRUST (110326/Z/15/Z)
External DOI: https://doi.org/10.1016/j.celrep.2017.07.061
This record's URL: https://www.repository.cam.ac.uk/handle/1810/267466
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