Direct reprogramming of fibroblasts into renal tubular epithelial cells by defined transcription factors
Direct reprogramming of fibroblasts into renal tubular epithelial cells by defined transcription factors
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DOI：
10.1038/ncb3437
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发表时间：
2016-12-01
影响因子：
21.3
通讯作者：
Lienkamp, Soeren S.
中科院分区：
文献类型：
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作者：
Kaminski, Michael M.;Tosic, Jelena;Lienkamp, Soeren S.
通过强迫表达转录因子的直接重编程可以将一种细胞类型转化为另一种细胞类型。因此，可以绕过多能性产生所需的细胞类型。然而，直接对肾细胞进行重编程仍然是一个未解决的挑战。本研究基于组织特异性和进化保守性表达鉴定肾细胞命运诱导因子，并证实Emx2、Hnf1b、Hnf4a和Pax8联合表达可将小鼠和人成纤维细胞转化为诱导肾小管上皮细胞（iRECs）。iRECs具有上皮性特征，具有与天然细胞相似的全局基因表达谱，具有分化肾小管细胞的功能特性以及对肾毒性物质的敏感性。此外，iRECs可以整合到肾类器官中，并在去细胞化的肾脏中形成小管。我们的方法表明，重编程因子可以通过针对性的硅分析来识别。通过强制表达转录因子在体外产生的肾小管上皮细胞可能有助于疾病建模、药物和肾毒性测试以及再生方法。
Direct reprogramming by forced expression of transcription factors can convert one cell type into another. Thus, desired cell types can be generated bypassing pluripotency. However, direct reprogramming towards renal cells remains an unmet challenge. Here, we identify renal cell fate-inducing factors on the basis of their tissue specificity and evolutionarily conserved expression, and demonstrate that combined expression of Emx2, Hnf1b, Hnf4a and Pax8 converts mouse and human fibroblasts into induced renal tubular epithelial cells (iRECs). iRECs exhibit epithelial features, a global gene expression profile resembling their native counterparts, functional properties of differentiated renal tubule cells and sensitivity to nephrotoxic substances. Furthermore, iRECs integrate into kidney organoids and form tubules in decellularized kidneys. Our approach demonstrates that reprogramming factors can be identified by targeted in silico analysis. Renal tubular epithelial cells generated ex vivo by forced expression of transcription factors may facilitate disease modelling, drug and nephrotoxicity testing, and regenerative approaches.