Joseph Diya B, Henry Gervaise H, Malewska Alicia, Iqbal Nida S, Ruetten Hannah M, Turco Anne E, Abler Lisa L, Sandhu Simran K, Cadena Mark T, Malladi Venkat S, Reese Jeffrey C, Mauck Ryan J, Gahan Jeffrey C, Hutchinson Ryan C, Roehrborn Claus G, Baker Linda A, Vezina Chad M, Strand Douglas W
Department of Urology, UT Southwestern Medical Center, Dallas, Texas.
Department of Bioinformatics, UT Southwestern Medical Center, Dallas, Texas.
Prostate. 2020 Aug;80(11):872-884. doi: 10.1002/pros.24020. Epub 2020 Jun 4.
Castration-insensitive epithelial progenitors capable of regenerating the prostate have been proposed to be concentrated in the proximal region based on facultative assays. Functional characterization of prostate epithelial populations isolated with individual cell surface markers has failed to provide a consensus on the anatomical and transcriptional identity of proximal prostate progenitors.
Here, we use single-cell RNA sequencing to obtain a complete transcriptomic profile of all epithelial cells in the mouse prostate and urethra to objectively identify cellular subtypes. Pan-transcriptomic comparison to human prostate cell types identified a mouse equivalent of human urethral luminal cells, which highly expressed putative prostate progenitor markers. Validation of the urethral luminal cell cluster was performed using immunostaining and flow cytometry.
Our data reveal that previously identified facultative progenitors marked by Trop2, Sca-1, KRT4, and PSCA are actually luminal epithelial cells of the urethra that extend into the proximal region of the prostate, and are resistant to castration-induced androgen deprivation. Mouse urethral luminal cells were identified to be the equivalent of previously identified human club and hillock cells that similarly extend into proximal prostate ducts. Benign prostatic hyperplasia (BPH) has long been considered an "embryonic reawakening," but the cellular origin of the hyperplastic growth concentrated in the periurethral region is unclear. We demonstrate an increase in urethral luminal cells within glandular nodules from BPH patients. Urethral luminal cells are further increased in patients treated with a 5-α reductase inhibitor.
Our data demonstrate that cells of the proximal prostate that express putative progenitor markers, and are enriched by castration in the proximal prostate, are urethral luminal cells and that these cells may play an important role in the etiology of human BPH.
基于兼性分析，能够再生前列腺的去势不敏感上皮祖细胞被认为集中在近端区域。使用单个细胞表面标志物分离的前列腺上皮细胞群体的功能特征未能就近端前列腺祖细胞的解剖学和转录特征达成共识。
在这里，我们使用单细胞RNA测序来获得小鼠前列腺和尿道中所有上皮细胞的完整转录组图谱，以客观地识别细胞亚型。与人前列腺细胞类型的全转录组比较确定了小鼠中相当于人尿道腔细胞的细胞，其高度表达假定的前列腺祖细胞标志物。使用免疫染色和流式细胞术对尿道腔细胞簇进行验证。
我们的数据显示，先前鉴定的以Trop2、Sca-1、KRT4和PSCA为标记的兼性祖细胞实际上是延伸至前列腺近端区域的尿道腔上皮细胞，并且对去势诱导的雄激素剥夺具有抗性。小鼠尿道腔细胞被确定相当于先前鉴定的同样延伸至前列腺近端导管的人球部和小丘细胞。良性前列腺增生（BPH）长期以来一直被认为是一种“胚胎觉醒”，但集中在尿道周围区域的增生性生长的细胞起源尚不清楚。我们证明了BPH患者腺结节内尿道腔细胞增加。在接受5-α还原酶抑制剂治疗的患者中，尿道腔细胞进一步增加。
我们的数据表明，在前列腺近端表达假定祖细胞标志物并在前列腺近端因去势而富集的细胞是尿道腔细胞，并且这些细胞可能在人类BPH的病因学中起重要作用。
