Moad Mohammad, Hannezo Edouard, Buczacki Simon J, Wilson Laura, El-Sherif Amira, Sims David, Pickard Robert, Wright Nicholas A, Williamson Stuart C, Turnbull Doug M, Taylor Robert W, Greaves Laura, Robson Craig N, Simons Benjamin D, Heer Rakesh
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4AD, UK.
Cavendish Laboratory, Department of Physics, University of Cambridge, J.J. Thomson Avenue, Cambridge CB3 0HE, UK; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Cell Rep. 2017 Aug 15;20(7):1609-1622. doi: 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.
散发性线粒体DNA突变作为克隆标记，有助于了解人体组织内干细胞的身份和谱系潜能。通过将定量克隆图谱与成年男性前列腺的三维重建相结合，我们发现多能基底干细胞局限于尿道旁导管中的离散微环境，在定向上皮迁移流中产生双能基底祖细胞。然后，基底祖细胞分散到整个腺网络中，分裂并分化以补充凋亡管腔细胞的损失。罕见的谱系受限管腔干细胞及其后代局限于近端导管，对上皮内稳态的贡献很小。从克隆图谱中进行原位细胞捕获，确定了基底干细胞中富含δ同源物1（DLK1），这在功能性球体分析中得到了验证。这项研究对前列腺干细胞和祖细胞的微环境组织和功能有了重要的认识，对疾病具有启示意义。
