Progenitor-like LSCmed cells are enriched in the prostates of Pb-PRL mice, a preclinical model of benign prostate hyperplasia

The prostate epithelium is made of basal and luminal cells. We recently identified in wild type mouse prostates a rare population of luminal progenitor-like cells that we called LSCmed according to their FACS profile (Lin-/Sca-1+/CD49fmed). LSCmed defines non-secretory luminal cells that exhibit a specific transcriptomic profile enriched in stemness markers (Psca, Tacstd2, Cd44, Sox2, Sca-1), and are able to generate organoids in vitro and glandular epithelium in vivo. Importantly, LSCmed cells are tolerant to androgen deprivation. Here we investigated the prevalence of these cells in probasin-prolactin (Pb-PRL) mice, a model of benign prostate hyperplasia (BPH). We show that LSCmed prevalence is increased from ± 5% of epithelial cells in the prostate of WT mice, to ± 20% of epithelial cells in premalignant prostate tumors of Pb-PRL mice. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene-expression profile is different from luminal and basal/stem cells, but shares markers of each. LSCmed cells show molecular similarity with Club cells of the human prostate. Club cells have been proposed to be urethral cells that extend into the proximal ducts of the prostate transition zone, where BPH develops. Club cells are enriched in human BPH compared to healthy prostate, and this phenotype is aggravated by inhibitors of 5-alpha reductase treatment, which was proposed to result from luminal cell reprogramming into Club-like cells. Together, these observations suggest that cells exhibiting LSCmed/Club-like features may contribute to BPH development and therapeutic resistance.

前列腺上皮由基底细胞与腔细胞共同构成。我们近期在野生型小鼠前列腺中鉴定出一类稀有腔祖细胞样群体，依据其荧光激活细胞分选（Fluorescence-Activated Cell Sorting, FACS）谱（Lin-/Sca-1+/CD49fmed）将其命名为LSCmed。LSCmed为非分泌型腔细胞，其转录组特征独特，富集干性标志物（Psca、Tacstd2、Cd44、Sox2、Sca-1），可在体外形成类器官、在体内生成腺上皮。尤为关键的是，LSCmed细胞对雄激素剥夺具有耐受性。本研究探究了此类细胞在前列腺珠蛋白-催乳素（Pb-PRL）小鼠——一种良性前列腺增生（benign prostate hyperplasia, BPH）模型——中的占比。结果显示，LSCmed在野生型小鼠前列腺上皮细胞中的占比约为5%，而在Pb-PRL小鼠的癌前前列腺肿瘤中，其占比提升至约20%。转录组分析表明，LSCmed是一类独特的细胞类群：其基因表达谱既区别于腔细胞与基底/干细胞，又同时兼具二者的标志物特征。LSCmed细胞与人类前列腺的克拉拉细胞（Club cell）具有分子相似性。此前研究提出，克拉拉细胞是一类尿道细胞，可延伸至前列腺移行带的近端导管——这正是良性前列腺增生（BPH）的发生部位。相较于健康前列腺组织，克拉拉细胞在人类BPH样本中富集，而5-α还原酶抑制剂治疗会加剧这一表型，该现象被认为源于腔细胞重编程为类克拉拉细胞。综上，上述观察结果提示，具备LSCmed/类克拉拉细胞特征的细胞可能参与BPH的发生发展，并与治疗耐药性的产生相关。