Vellky Jordan E, Wu Yaqi, Moline Daniel, Drnevich Jenny, Maienschein-Cline Mark, Valyi-Nagy Klara, Kajdacsy-Balla Andre, Vander Griend Donald J
Department of Pathology, The University of Illinois at Chicago, Chicago, IL, USA.
Committee on Development, Regeneration, and Stem Cell Biology (DRSB), The University of Chicago, Chicago, IL, USA.
J Pathol. 2024 Feb;262(2):212-225. doi: 10.1002/path.6227. Epub 2023 Nov 20.
Despite evidence of genetic signatures in normal tissue correlating with disease risk, prospectively identifying genetic drivers and cell types that underlie subsequent pathologies has historically been challenging. The human prostate is an ideal model to investigate this phenomenon because it is anatomically segregated into three glandular zones (central, peripheral, and transition) that develop differential pathologies: prostate cancer in the peripheral zone (PZ) and benign prostatic hyperplasia (BPH) in the transition zone (TZ), with the central zone (CZ) rarely developing disease. More specifically, prostatic basal cells have been implicated in differentiation and proliferation during prostate development and regeneration; however, the contribution of zonal variation and the critical role of basal cells in prostatic disease etiology are not well understood. Using single-cell RNA sequencing of primary prostate epithelial cultures, we elucidated organ-specific, zone-specific, and cluster-specific gene expression differences in basal cells isolated from human prostate and seminal vesicle (SV). Aggregated analysis identified ten distinct basal clusters by Uniform Manifold Approximation and Projection. Organ specificity compared gene expression in SV with the prostate. As expected, SV cells were distinct from prostate cells by clustering, gene expression, and pathway analysis. For prostate zone specificity, we identified two CZ-specific clusters, while the TZ and PZ populations clustered together. Despite these similarities, differential gene expression was identified between PZ and TZ samples that correlated with gene expression profiles in prostate cancer and BPH, respectively. Zone-specific profiles and cell type-specific markers were validated using immunostaining and bioinformatic analyses of publicly available RNA-seq datasets. Understanding the baseline differences at the organ, zonal, and cellular level provides important insight into the potential drivers of prostatic disease and guides the investigation of novel preventive or curative treatments. Importantly, this study identifies multiple prostate basal cell populations and cell type-specific gene signatures within prostate basal epithelial cells that have potential critical roles in driving prostatic diseases. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
尽管有证据表明正常组织中的基因特征与疾病风险相关，但前瞻性地识别潜在后续病变的基因驱动因素和细胞类型在历史上一直具有挑战性。人类前列腺是研究这一现象的理想模型，因为它在解剖学上被分为三个腺区（中央区、外周区和移行区），这些区域会发生不同的病变：外周区（PZ）发生前列腺癌，移行区（TZ）发生良性前列腺增生（BPH），而中央区（CZ）很少发生疾病。更具体地说，前列腺基底细胞在前列腺发育和再生过程中的分化和增殖中发挥了作用；然而，区域差异的贡献以及基底细胞在前列腺疾病病因中的关键作用尚未得到充分了解。通过对原发性前列腺上皮培养物进行单细胞RNA测序，我们阐明了从人类前列腺和精囊（SV）分离的基底细胞中器官特异性、区域特异性和簇特异性的基因表达差异。通过均匀流形近似和投影的聚合分析确定了十个不同的基底细胞簇。器官特异性比较了精囊中与前列腺中的基因表达。正如预期的那样，通过聚类、基因表达和通路分析，精囊细胞与前列腺细胞不同。对于前列腺区域特异性，我们确定了两个中央区特异性簇，而移行区和外周区群体聚集在一起。尽管有这些相似之处，但在外周区和移行区样本之间发现了差异基因表达，分别与前列腺癌和良性前列腺增生的基因表达谱相关。使用免疫染色和对公开可用RNA测序数据集的生物信息学分析验证了区域特异性谱和细胞类型特异性标记。了解器官、区域和细胞水平的基线差异为前列腺疾病的潜在驱动因素提供了重要见解，并指导了新型预防或治疗方法的研究。重要的是，本研究确定了前列腺基底上皮细胞内的多个前列腺基底细胞群体和细胞类型特异性基因特征，它们在驱动前列腺疾病中可能具有关键作用。© 2023作者。《病理学杂志》由约翰·威利父子有限公司代表大不列颠及爱尔兰病理学会出版。
