Direct Reprogramming of Mouse Fibroblasts toward Leydig-like Cells by Defined Factors.
Direct Reprogramming of Mouse Fibroblasts toward Leydig-like Cells by Defined Factors.
复制标题
通过确定的因子将小鼠成纤维细胞直接重编程为间质样细胞
DOI：
10.1016/j.stemcr.2016.11.010
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发表时间：
2017-01-10
影响因子：
5.9
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Yang Y;Li Z;Wu X;Chen H;Xu W;Xiang Q;Zhang Q;Chen J;Ge RS;Su Z;Huang Y
间质细胞（LCs）在产生睾丸激素中起着至关重要的作用，它们的功能障碍导致男性性腺功能减退。LC移植是治疗男性性腺功能减退的一种很有前途的替代疗法。然而，lc的来源限制了这一策略的临床应用。在这里，我们通过表达三种转录因子Dmrt1、Gata4和Nr5a1，成功地将小鼠成纤维细胞重编程为LCs。诱导的leydigi样细胞（iLCs）表达类固醇基因，具有与成年LCs相似的全局基因表达谱，并获得雄激素合成能力。将il - c移植到选择性去除内源性lc的大鼠或小鼠睾丸中，移植细胞可在睾丸间质中存活并发挥功能，使血清睾酮恢复正常水平。这些发现表明，成纤维细胞能够通过少数确定的因素直接转化为ilc，这可能有助于未来在再生医学中的应用。诱导的间质样细胞（iLCs）表现出成人间质细胞的特征，向iLCs的转化过程不经过有丝分裂细胞状态，iLCs的移植可以在睾丸间质中存活并发挥作用。和他的同事们表明，转录因子的混合物可以驱动小鼠成纤维细胞直接谱系重编程为具有功能的间质细胞（iLCs），这些细胞表现出成年间质细胞的特征，并获得雄激素合成能力。此外，当将il - c移植到大鼠或小鼠的睾丸中时，可以恢复睾丸激素缺乏的啮齿动物的睾丸激素水平。
Leydig cells (LCs) play crucial roles in producing testosterone, and their dysfunction leads to male hypogonadism. LC transplantation is a promising alternative therapy for male hypogonadism. However, the source of LCs limits this strategy for clinical applications. Here, we report our success in reprogramming mice fibroblasts into LCs by expressing three transcriptional factors, Dmrt1, Gata4, and Nr5a1. The induced Leydig-like cells (iLCs) expressed steroidogenic genes, had a global gene expression profile similar to that of adult LCs, and acquired androgen synthesis capabilities. When iLCs were transplanted into rats or mice testes that were selectively depleted of endogenous LCs, the transplanted cells could survive and function in the interstitium of testis, resulting in the restoration of normal levels of serum testosterone. These findings demonstrate that the fibroblasts were able to be directly converted into iLCs by few defined factors, which may facilitate future applications in regenerative medicine. Direct reprogramming of fibroblasts into Leydig cell fate by defined factors Induced Leydig-like cells (iLCs) exhibit adult Leydig cell characterizations Conversion process toward iLCs did not pass through a mitotic cell state Transplantation of iLCs could survive and function in the interstitium of testis In this article, Huang, Su, and colleagues show that a cocktail of transcriptional factors can drive direct lineage reprogramming of mouse fibroblasts into functional Leydig cells (iLCs) which exhibit adult Leydig cell characterizations and acquired androgen synthesis capabilities. Furthermore, iLCs could restore testosterone levels of testosterone-deficient rodents when transplanted into rats or mice testes.