Direct Reprogramming of Fibroblasts into Embryonic Sertoli-like Cells by Defined Factors

• Published in: Cell stem cell 2012-09, Vol.11 (3), p.373-386
• Main Authors: Buganim, Yosef, Itskovich, Elena, Hu, Yueh-Chiang, Cheng, Albert W., Ganz, Kibibi, Sarkar, Sovan, Fu, Dongdong, Welstead, G. Grant, Page, David C., Jaenisch, Rudolf
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Aggregation - genetics; Cell Differentiation - genetics; Cell differentiation, maturation, development, hematopoiesis; Cell Movement - genetics; Cell physiology; Cell Proliferation; Cell Survival - genetics; Cellular Reprogramming - genetics; Embryo, Mammalian - cytology; Embryo, Mammalian - metabolism; Endothelial Cells - cytology; Endothelial Cells - metabolism; Epithelial Cells - cytology; Epithelial Cells - metabolism; Epithelial-Mesenchymal Transition - genetics; Fibroblasts - cytology; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; GATA4 Transcription Factor - metabolism; Gene Expression Profiling; Karyotyping; Male; Mice; Molecular and cellular biology; Neovascularization, Physiologic - genetics; Neurons - cytology; Neurons - metabolism; Proto-Oncogene Proteins c-met - metabolism; Sertoli Cells - cytology; Sertoli Cells - metabolism; SOX9 Transcription Factor - metabolism; Steroidogenic Factor 1 - metabolism; Testis - cytology; Testis - embryology; Transcription Factors - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2012.07.019

Sertoli cells are considered the “supporting cells” of the testis that play an essential role in sex determination during embryogenesis and in spermatogenesis during adulthood. Their essential roles in male fertility along with their immunosuppressive and neurotrophic properties make them an attractive cell type for therapeutic applications. Here we demonstrate the generation of induced embryonic Sertoli-like cells (ieSCs) by ectopic expression of five transcription factors. We characterize the role of specific transcription factor combinations in the transition from fibroblasts to ieSCs and identify key steps in the process. Initially, transduced fibroblasts underwent a mesenchymal to epithelial transition and then acquired the ability to aggregate, formed tubular-like structures, and expressed embryonic Sertoli-specific markers. These Sertoli-like cells facilitated neuronal differentiation and self-renewal of neural progenitor cells (NPCs), supported the survival of germ cells in culture, and cooperated with endogenous embryonic Sertoli and primordial germ cells in the generation of testicular cords in the fetal gonad. [Display omitted] ► Nr5a1, Wt1, and Dmrt1 induce proliferation and mesenchymal to epithelial transition ► Nr5a1, Wt1, and Sox9 promote cell aggregation in various cell types ► Nr5a1, Wt1, Dmrt1, Gata4, Sox9 convert fibroblasts to embryonic Sertoli-like cells ► Induced cells contribute to fetal cord formation and to germ cell and NPC survival Transcription-factor-mediated conversion of fibroblasts yields Sertoli-like cells with appropriate functional properties in vitro and after transplantation. Sertoli cells have a variety of potential applications for the treatment of fertility and neurological disorders.