Spatial transcriptomics identifies candidate stromal drivers of benign prostatic hyperplasia.
Spatial transcriptomics identifies candidate stromal drivers of benign prostatic hyperplasia.
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空间转录组学鉴定了良性前列腺增生的候选基质驱动因素。
DOI：
10.1172/jci.insight.176479
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发表时间：
2024
期刊：
影响因子：
8
通讯作者：
Pollack,JonathanR
中科院分区：
文献类型：
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作者：
Pollack,AnnaS;Kunder,ChristianA;Brazer,Noah;Shen,Zhewei;Varma,Sushama;West,RobertB;Cunha,GeraldR;Baskin,LaurenceS;Brooks,JamesD;Pollack,JonathanR
良性前列腺增生（BPH）是老年男性前列腺移行区的结节性增生，导致尿潴留和排尿问题，可能无法治疗。几十年前，John McNeal提出BPH起源于成年前列腺基质对胚胎诱导活性的“重新唤醒”，这刺激了新的导管增殖和分支形态发生。在这里，通过激光显微切割和邻近增生分支导管的BPH间质的转录谱分析，我们确定了可能介导前列腺上皮间质诱导的分泌因子和同时发生的过程。最主要的基质因子是胰岛素样生长因子1（IGF 1）和CXC趋化因子配体13（CXCL 13），我们通过RNA原位杂交证实了它们在BPH成纤维细胞中共表达，沿着的是相邻上皮上的同源受体（IGF 1 R和CXCR 5）。与此相反，IGF 1，而不是CXCL 13表达在人胚胎前列腺基质。最后，我们证明了IGF 1是在3D培养中产生BPH-1细胞球状体和患者来源的BPH细胞类器官所必需的。我们的研究结果部分支持了对BPH病因的历史推测，并提供了我们认为是针对推动BPH的潜在过程的合理治疗的新分子靶点。
Benign prostatic hyperplasia (BPH) is the nodular proliferation of the prostate transition zone in older men, leading to urinary storage and voiding problems that can be recalcitrant to therapy. Decades ago, John McNeal proposed that BPH originates with the “reawakening” of embryonic inductive activity by adult prostate stroma, which spurs new ductal proliferation and branching morphogenesis. Here, by laser microdissection and transcriptional profiling of the BPH stroma adjacent to hyperplastic branching ducts, we identified secreted factors likely mediating stromal induction of prostate glandular epithelium and coinciding processes. The top stromal factors were insulin-like growth factor 1 (IGF1) and CXC chemokine ligand 13 (CXCL13), which we verified by RNA in situ hybridization to be coexpressed in BPH fibroblasts, along with their cognate receptors (IGF1R and CXCR5) on adjacent epithelium. In contrast, IGF1 but not CXCL13 was expressed in human embryonic prostate stroma. Finally, we demonstrated that IGF1 is necessary for the generation of BPH-1 cell spheroids and patient-derived BPH cell organoids in 3D culture. Our findings partially support historic speculations on the etiology of BPH and provide what we believe to be new molecular targets for rational therapies directed against the underlying processes driving BPH.