前列腺上皮干细胞转分化在BPH术后创面修复中的作用和分子机制研究

良性前列腺增生症（BPH）是老年男性最常见的疾病之一，经尿道内镜下前列腺手术是重要的治疗方式，且是解决尿路梗阻的最有效方法，然而术后仍可能发生下尿路刺激症状、感染、血尿及膀胱颈挛缩等并发症，严重影响手术疗效和患者生活质量。术后创面修复不良是导致一系列并发症的重要原因，但其中的机制及调控因素仍不明确。我们前期发现：术后新生尿路上皮来源于残存前列腺上皮转分化而非切缘尿路上皮爬行覆盖；炎性细胞因子和尿液刺激导致创面组织微环境改变；雄激素受体（AR）通路抑制创面再上皮化修复。为进一步研究创面修复机制，我们提出科学假说：BPH术后尿液-组织屏障被破坏，组织微环境改变，尿液刺激前列腺基质细胞表型改变，抑制AR通路，进而通过旁分泌途径促进前列腺上皮干细胞向尿路上皮细胞转分化。本项目拟通过动物模型、细胞示踪、单细胞测序、类器官培养等技术，阐明前列腺上皮干细胞转分化的分子机制，为术后并发症防治提供新的策略。

Benign prostatic hyperplasia (BPH) is one of the most common diseases in elderly men. Transurethral endoscopic resection of prostate is one of the most important strategy for BPH treatment, which is also the most effective way to relieve prostatic obstruction. However, postoperative complications such as lower urinary tract symptoms, infection, hematuria and bladder neck contracture may still occur, which seriously affect the curative effect and the quality of life of patients. Abnormal postoperative wound healing is an important cause of the series of complications, but the mechanisms and regulatory factors of the wound healing are still unclear. In our previous study, we have proven that the re-epithelialized urothelial cells during postoperative wound healing originated from the transdifferentiation of the residual prostate epithelial cells rather than migration of the urothelial cells from wound edge. Inflammatory cytokines and urine stimulation after surgery were able to induce the altlertion of the microenvironment of the prostatic wound. The activation of androgen receptor (AR) pathway delayed the re-epithelialization of the prostatic wound. To further study the mechanisms of the postoperative wound healing, we put forward a scientific hypothesis: the transurethral endoscopic resection of prostate destroyed the urine-tissue barrier, which resulted in alteration of the prostatic tissue microenvironment. The stimulation of urine and alerted cytokines changed the phenotype of the prostate stromal cells, and also inhibited the androgen-AR pathway, which finally promoted the transdifferentiation of the prostate epithelial stem/progenitor cells to urothelial cells through paracrinal manner. This project is aimed to elucidate the molecular mechanism of transdifferentiation of prostate epithelial stem/progenitor cells through animal models, cell lineage tracing, single cell sequencing, and organoid culture technique, and provide a new strategy for prevention and treatment of the postoperative complications.