An immortalized cell line derived from renal erythropoietin-producing (REP) cells demonstrates their potential to transform into myofibroblasts.,Scientific Reports

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An immortalized cell line derived from renal erythropoietin-producing (REP) cells demonstrates their potential to transform into myofibroblasts.
Scientific Reports ( IF 3.8 ) Pub Date : 2019-08-02 , DOI: 10.1038/s41598-019-47766-5
Koji Sato _{1,

2} , Ikuo Hirano _{1,

3} , Hiroki Sekine _{1,

4} , Kenichiro Miyauchi _{1,

2} , Taku Nakai ₁ , Koichiro Kato ₁ , Sadayoshi Ito ₂ , Masayuki Yamamoto ₅ , Norio Suzuki ₁

Affiliation

The erythroid growth factor erythropoietin (Epo) is produced by renal interstitial fibroblasts, called REP (renal Epo-producing) cells, in a hypoxia-inducible manner. In chronic kidney disease (CKD), REP cells lose their Epo-production ability, leading to renal anaemia. Concurrently, REP cells are suggested to be transformed into myofibroblasts, which are the major player of renal fibrosis. Although establishment of cultured cell lines derived from REP cells has been a long-term challenge, we here successfully established a REP-cell-derived immortalized and cultivable cell line (Replic cells) by using a genetically modified mouse line. Replic cells exhibited myofibroblastic phenotypes and lost their Epo-production ability, reflecting the situation in renal fibrosis. Additionally, we found that cell-autonomous TGFβ signalling contributes to maintenance of the myofibroblastic features of Replic cells. Furthermore, the promoters of genes for Epo and HIF2α, a major activator of Epo gene expression, were highly methylated in Replic cells. Thus, these results strongly support our contention that REP cells are the origin of myofibroblasts in fibrotic kidneys and demonstrate that cell-autonomous TGFβ signalling and epigenetic silencing are involved in renal fibrosis and renal anaemia, respectively, in CKD. The Replic cell line is a useful tool to further investigate the molecular mechanisms underlying renal fibrosis.

中文翻译：

源自肾促红细胞生成素（REP）细胞的永生细胞系显示出它们转化为成肌纤维细胞的潜力。

红血球生长因子促红细胞生成素（Epo）是由肾间质成纤维细胞（称为REP（产生肾Epo的）细胞）以缺氧诱导的方式产生的。在慢性肾脏疾病（CKD）中，REP细胞失去Epo产生能力，从而导致肾性贫血。同时，建议将REP细胞转化为成纤维细胞，成纤维细胞是肾纤维化的主要参与者。尽管建立从REP细胞衍生的培养细胞系一直是一个长期的挑战，但我们在这里通过使用基因修饰的小鼠品系成功地建立了REP细胞衍生的永生化和可培养细胞系（Replic细胞）。复制细胞表现出肌纤维母细胞表型并失去其Epo-生产能力，反映了肾纤维化的情况。此外，我们发现，细胞自主的TGFβ信号传导有助于维持Replic细胞的肌成纤维细胞特征。此外，Epo和EIF基因表达的主要激活因子HIF2α的基因启动子在Replic细胞中高度甲基化。因此，这些结果有力地支持了我们的观点，即REP细胞是纤维化肾脏中成纤维细胞的起源，并证明了CKD中细胞自主性TGFβ信号传导和表观遗传沉默分别涉及肾脏纤维化和肾性贫血。Replic细胞系是进一步研究肾纤维化的分子机制的有用工具。这些结果有力地支持了我们的观点，即REP细胞是纤维化肾脏中成纤维细胞的起源，并证明了CKD中细胞自主性TGFβ信号传导和表观遗传沉默分别与肾脏纤维化和肾性贫血有关。Replic细胞系是进一步研究肾纤维化的分子机制的有用工具。这些结果有力地支持了我们的观点，即REP细胞是纤维化肾脏中成纤维细胞的起源，并证明了CKD中细胞自主性TGFβ信号传导和表观遗传沉默分别与肾脏纤维化和肾性贫血有关。Replic细胞系是进一步研究肾纤维化的分子机制的有用工具。

更新日期：2019-08-02

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