Conversion of Fibroblast into Functional Leydig-like Cell Using Defined Small Molecules

• Published in: Stem cell reports Vol. 15; no. 2; pp. 408 - 423
• Main Authors: Yang, Yan, Zhou, Chenxing, Zhang, Tiantian, Li, Quan, Mei, Jiaxin, Liang, Jinlian, Li, Ziyi, Li, Hanhao, Xiang, Qi, Zhang, Qihao, Zhang, Lei, Huang, Yadong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.08.2020; Elsevier
• Subjects: fibroblasts; Leydig cells; reprogramming; small molecule; testosterone; reprogramming; small molecule; fibroblasts; testosterone; Leydig cells
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2020.07.002

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. •Direct induction of fibroblasts into Leydig-like cells (CiLCs) by chemicals•CiLCs were modulated by HPG axis and produced testosterone in a diurnal rhythm•Conversion process toward CiLCs did not pass through an intermediate state In this article, Huang and colleagues show that fibroblasts can be directly reprogrammed into Leydig-like cells by exposure to a combination of forskolin, 20α-hydroxycholesterol, luteinizing hormone, and SB431542. These induced Leydig-like cells (CiLCs) were modulated by hypothalamic-pituitary-gonadal axis and produced testosterone in a diurnal rhythm.