Castration-induced stromal remodeling disrupts the reconstituted prostate epithelial structure
Castration-induced stromal remodeling disrupts the reconstituted prostate epithelial structure
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DOI：
10.1038/s41374-019-0352-4
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发表时间：
2020-05-01
影响因子：
5
通讯作者：
Sugimura, Yoshiki
中科院分区：
文献类型：
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作者：
Kajiwara, Shinya;Ishii, Kenichiro;Sugimura, Yoshiki
作者研究了去势诱导的间质重塑和随后上皮-间质相互作用的异常激活对重建的人前列腺样上皮的影响。他们证明，去势诱导的基质重塑破坏了重建的上皮结构，诱导tenascin- c阳性成纤维细胞的出现，并伴有tgf - β信号的激活。前列腺基质结构的改变可能导致基底膜和上皮细胞极性的丧失。正常的前列腺上皮结构是通过与平滑肌细胞的稳态相互作用来维持的。然而，间质结构改变在前列腺增生性疾病中很常见，导致前列腺上皮结构异常。在实验中，雄激素水平的降低可诱导间质重塑，即平滑肌细胞被成纤维细胞或肌成纤维细胞取代。在这项研究中，我们研究了去势诱导的基质重塑和随后上皮-基质相互作用的异常激活对重建的人前列腺样上皮结构的影响。我们使用人前列腺上皮细胞系BPH-1和胎鼠泌尿生殖窦间充质进行体内实验，生成异型组织重组，形成人前列腺样上皮结构（即实体上皮索和管状上皮索）。宿主小鼠在移植后12周被阉割（阉割），并在阉割后14天植入双氢睾酮颗粒（雄激素替代治疗；ART）。去势组纤维化面积和无基底膜前列腺上皮结构破坏（BM）的百分比呈时间依赖性成比例增加，但ART抑制。在去势组，无基底膜的前列腺上皮结构破坏周围的间质中有大量tenascin-C （TNC）阳性成纤维细胞。BPH-1细胞与人原代培养的前列腺成纤维细胞共培养可增加tgf - β 1的分泌。在与BPH-1细胞共培养的成纤维细胞中，TNC mRNA表达增加，tgf - β RI激酶抑制剂抑制TNC mRNA表达。此外，在去势组中，p- smad2阳性细胞的百分比在没有BM的前列腺上皮结构破坏周围的基质中明显更高。我们的研究结果表明，去势诱导的基质重塑破坏了重建的人前列腺样上皮结构，诱导tnc阳性成纤维细胞的出现，并伴有tgf - β信号的激活。前列腺基质结构的改变可能是导致基底细胞和上皮细胞极性丧失的原因。
The authors investigated the effects of castration-induced stromal remodeling and subsequent aberrant activation of epithelial-stromal interactions on reconstituted human prostate-like epithelium. They demonstrate that castration-induced stromal remodeling disrupted the reconstituted epithelial structure and induced the appearance of tenascin-C-positive fibroblasts, accompanied by activation of TGF-beta signaling. The alteration of prostate stromal structure may be responsible for loss of the basement membrane and epithelial cell polarity.The normal prostate epithelial structure is maintained by homeostatic interactions with smooth muscle cells. However, structural alterations of the stroma are commonly observed in prostatic proliferative diseases, leading to the abnormalities of prostate epithelial structure. A decrease in the androgen level experimentally induces stromal remodeling, i.e., replacement of smooth muscle cells with fibroblasts or myofibroblasts. In this study, we investigated the effects of castration-induced stromal remodeling and subsequent aberrant activation of epithelial-stromal interactions on the reconstituted human prostate-like epithelial structure. We performed in vivo experiments using the human prostate epithelial cell line BPH-1 and fetal rat urogenital sinus mesenchyme to generate heterotypic tissue recombinants that form human prostate-like epithelial structure (i.e., solid- and canalized-epithelial cords). Host mice were castrated at 12 weeks post transplantation (castration) and implanted with a dihydrotestosterone pellet at 14 days post castration (androgen replacement treatment; ART). In the castration group, the percentages of fibrotic area and disrupted prostate epithelial structure without the basement membrane (BM) increased proportionally in a time-dependent manner, but were suppressed by ART. In the castration group, tenascin-C (TNC)-positive fibroblasts were abundant in the stroma surrounding disrupted prostate epithelial structure without the BM. TGF-beta 1 secretion from BPH-1 cells was increased by co-culturing with human primary cultured prostate fibroblasts. TNC mRNA expression was increased in fibroblasts co-culturing with BPH-1 cells and was suppressed by treatment with a TGF-beta RI kinase inhibitor. Moreover, in the castration group, the percentage of p-Smad2-positive cells was significantly higher in the stroma surrounding disrupted prostate epithelial structure without the BM. Our results demonstrate that castration-induced stromal remodeling disrupted the reconstituted human prostate-like epithelial structure and induced the appearance of TNC-positive fibroblasts accompanied by activation of TGF-beta signaling. The alteration of prostate stromal structure may be responsible for loss of the BM and epithelial cell polarity.