Recent studies have demonstrated that fibroblasts can be directly converted into functional Leydig cells by transcription factors. However, the transgenic approach used in these studies raises safety concerns for its future application. Here, we report that fibroblasts can be directly reprogrammed into Leydig-like cells by exposure to a combination of forskolin, 20α-hydroxycholesterol, luteinizing hormone, and SB431542. These chemical compound-induced Leydig-like cells (CiLCs) express steroidogenic genes and have a global gene expression profile similar to that of progenitor Leydig cells, although not identical. In addition, these cells can survive in testis and produce testosterone in a circadian rhythm. This induction strategy is applicable to reprogramming human periodontal ligament fibroblasts toward Leydig-like cells. These findings demonstrated fibroblasts can be directly converted into Leydig-like cells by pure chemical compounds. This strategy overcomes the limitations of conventional transgenic-based reprogramming and provides a simple, effective approach for Leydig cell-based therapy while simultaneously preserving the hypothalamic-pituitary-gonadal axis.

最近的研究表明，成纤维细胞可以通过转录因子直接转化为功能性Leydig细胞。然而，这些研究中使用的转基因方法引起了对其未来应用的安全性担忧。在这里，我们报道成纤维细胞可以通过暴露于福司可林，20α-羟基胆固醇，黄体生成素和SB431542的组合而直接重编程为Leydig样细胞。这些化合物诱导的类Leydig样细胞（CiLC）表达类固醇生成基因，并且具有类似于祖细胞Leydig的全局基因表达谱，尽管并不完全相同。此外，这些细胞可以在睾丸中存活并以昼夜节律产生睾丸激素。该诱导策略适用于将人牙周膜成纤维细胞重编程为Leydig样细胞。这些发现表明，成纤维细胞可以通过纯化合物直接转化为Leydig样细胞。该策略克服了常规基于转基因的重编程的局限性，并为基于Leydig细胞的治疗提供了一种简单有效的方法，同时保留了下丘脑-垂体-性腺轴。