Human prostate organoid generation and the identification of prostate development drivers using inductive rodent tissues

Mechanistic links between development and disease can be exploited to provide clues to the cellular signalling pathways that might become re-activated during adult pathogenesis such as those affecting the prostate. However, the mechanisms underpinning prostate development require further characterisation. Previously, our group developed novel methods to produce prostate organoids using induced pluripotent stem cells (iPSCs). Here, we show that the iPSCs can be fully differentiated into prostate organoids using neonatal rodent seminal vesicle mesenchyme (SVM) in vitro. Additionally, we elucidated molecular drivers of prostate induction through RNA-sequencing analyses of the rat urogenital sinus (the embryonic precursor of the prostate gland) as well as the neonatal seminal vesicles. We identified candidate drivers evident in the inductive mesenchyme and epithelium involved with prostate specification. Our top candidates included Spx, Trib3, Snai1, Snai2, Nrg2, and Lrp4. This work lays the foundations to further interrogate the reactivation of developmental genes in adulthood, leading to prostate disease.发育进程与疾病发生之间的机制性关联，可为阐明成年发病阶段（如前列腺相关疾病）中被重新激活的细胞信号通路提供重要线索。然而，支撑前列腺发育的具体机制仍有待进一步解析。此前，本团队开发了利用诱导多能干细胞（induced pluripotent stem cells, iPSCs）构建前列腺类器官的全新方法。本研究证实，通过体外添加新生啮齿类动物精囊间充质（seminal vesicle mesenchyme, SVM），可将iPSCs完全诱导分化为前列腺类器官。此外，我们通过对大鼠尿生殖窦（前列腺的胚胎前体）以及新生精囊开展RNA测序分析，阐明了前列腺诱导过程的分子驱动因子。我们在参与前列腺特化过程的诱导性间充质与上皮细胞中，鉴定出了潜在的驱动因子候选基因。筛选出的优先级最高的候选基因包括Spx、Trib3、Snai1、Snai2、Nrg2以及Lrp4。本研究为进一步探究成年个体中发育基因的重新激活（该过程与前列腺疾病的发生密切相关）奠定了坚实基础。