Multipotent Basal Stem Cells, Maintained in Localized Proximal Niches, Support Directed Long-Ranging Epithelial Flows in Human Prostates
Mohammad Moad,
Edouard Hannezo,
Simon J. Buczacki,
Laura Wilson,
Amira El-Sherif,
David Sims,
Robert Pickard,
Nicholas A. Wright,
Stuart C. Williamson,
Doug M. Turnbull,
Robert W. Taylor,
Laura Greaves,
Craig N. Robson,
Benjamin D. Simons,
Rakesh Heer
Affiliations
Mohammad Moad
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4AD, UK
Edouard Hannezo
Cavendish Laboratory, Department of Physics, University of Cambridge, J.J. Thomson Avenue, Cambridge CB3 0HE, UK
Simon J. Buczacki
Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
Laura Wilson
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4AD, UK
Amira El-Sherif
Department of Histopathology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK
David Sims
Computational Genomics Analysis and Training (CGAT), MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK
Robert Pickard
Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Nicholas A. Wright
Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Stuart C. Williamson
Clinical and Experimental Pharmacology Group, University of Manchester, Manchester M13 9PL, UK
Doug M. Turnbull
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Robert W. Taylor
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Laura Greaves
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Craig N. Robson
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4AD, UK
Benjamin D. Simons
Cavendish Laboratory, Department of Physics, University of Cambridge, J.J. Thomson Avenue, Cambridge CB3 0HE, UK
Rakesh Heer
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4AD, UK
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.
