Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, 23507, USA.
Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA, USA.
Sci Rep. 2024 Sep 9;14(1):21029. doi: 10.1038/s41598-024-71137-4.
Benign prostatic hyperplasia (BPH) is a prevalent age-related condition often characterized by debilitating urinary symptoms. Its etiology is believed to stem from hormonal imbalance, particularly an elevated estradiol-to-testosterone ratio and chronic inflammation. Our previous studies using a mouse steroid hormone imbalance model identified a specific increase in macrophages that migrated and accumulated in the prostate lumen where they differentiated into lipid-laden foam cells in mice implanted with testosterone and estradiol pellets, but not in sham animals. The current study focused on further characterizing the cellular heterogeneity of the prostate in this model as well as identifying the specific transcriptomic signature of the recruited foam cells. Moreover, we aimed to identify epithelia-derived signals that drive macrophage infiltration and luminal translocation. Male C57BL/6J mice were implanted with slow-release testosterone and estradiol pellets (T + E2) or sham surgery was performed and the ventral prostates were harvested two weeks later for scRNA-seq analysis. We identified Ear2 + and Cd72 + macrophages that were elevated in response to steroid hormone imbalance, whereas a Mrc1 + resident macrophage population did not change. In addition, an Spp1 + foam cell cluster was almost exclusively found in T + E2 mice. Further markers of foam cells were also identified, including Gpnmb and Trem2, and GPNMB was confirmed as a novel histological marker with immunohistochemistry. Foam cells were also shown to express known pathological factors Vegf, Tgfb1, Ccl6, Cxcl16 and Mmp12. Intriguingly, a screen for chemokines identified the upregulation of epithelia-derived Cxcl17, a known monocyte attractant, in T + E2 prostates suggesting that it might be responsible for the elevated macrophage number as well as their translocation to the lumen. Our study identified macrophage subsets that responded to steroid hormone imbalance as well as further confirmed a potential pathological role of luminal foam cells in the prostate. These results underscore a potential pathological role of the identified prostate foam cells and suggests CXCL17-mediated macrophage migration as a critical initiating event.
良性前列腺增生 (BPH) 是一种常见的与年龄相关的疾病，常表现为使人虚弱的尿路症状。其病因被认为源于激素失衡，特别是雌二醇与睾酮的比值升高和慢性炎症。我们之前使用雄性激素失衡的小鼠模型的研究发现，在移植了睾酮和雌二醇微球的小鼠前列腺管腔中，特定的巨噬细胞迁移并积累，这些巨噬细胞分化为富含脂质的泡沫细胞，但在假手术对照动物中没有。本研究旨在进一步描述该模型中前列腺的细胞异质性，并鉴定募集的泡沫细胞的特定转录组特征。此外，我们旨在鉴定上皮衍生的信号，这些信号驱动巨噬细胞浸润和管腔易位。雄性 C57BL/6J 小鼠植入缓释睾酮和雌二醇微球 (T+E2) 或接受假手术，两周后收获前列腺腹侧组织进行单细胞 RNA 测序分析。我们鉴定了对类固醇激素失衡有反应而升高的 Ear2+和 Cd72+巨噬细胞，而 Mrc1+固有巨噬细胞群没有变化。此外，在 T+E2 小鼠中几乎只发现了 Spp1+泡沫细胞簇。还鉴定了泡沫细胞的其他标记物，包括 Gpnmb 和 Trem2，并用免疫组织化学证实 GPNMB 是一种新的组织学标记物。泡沫细胞还表达了已知的病理因子 Vegf、Tgfb1、Ccl6、Cxcl16 和 Mmp12。有趣的是，趋化因子筛选发现 T+E2 前列腺中上皮衍生的趋化因子 Cxcl17 上调，Cxcl17 是已知的单核细胞趋化因子，提示它可能负责巨噬细胞数量的增加以及它们向管腔的易位。我们的研究鉴定了对类固醇激素失衡有反应的巨噬细胞亚群，并进一步证实了管腔泡沫细胞在前列腺中的潜在病理作用。这些结果强调了所鉴定的前列腺泡沫细胞的潜在病理作用，并提示 CXCL17 介导的巨噬细胞迁移是一个关键的起始事件。
