Induction of Sertoli-like cells from human fibroblasts by NR5A1 and GATA4

Abstract

Sertoli cells are essential nurse cells in the testis that regulate the process of spermatogenesis and establish the immune-privileged environment of the blood-testis-barrier (BTB). Here, we report the in vitro reprogramming of fibroblasts to human induced Sertoli-like cells (hiSCs). Initially, five transcriptional factors and a gene reporter carrying the AMH promoter were utilized to obtain the hiSCs. We further reduce the number of reprogramming factors to two, NR5A1 and GATA4, and show that these hiSCs have transcriptome profiles and cellular properties that are similar to those of primary human Sertoli cells. Moreover, hiSCs can sustain the viability of spermatogonia cells harvested from mouse seminiferous tubules. hiSCs suppress the proliferation of human T lymphocytes and protect xenotransplanted human cells in mice with normal immune systems. hiSCs also allow us to determine a gene associated with Sertoli cell only syndrome (SCO), CX43, is indeed important in regulating the maturation of Sertoli cells.

Selenium attenuates diclofenac‐induced testicular and epididymal toxicity in rats

“…The fundamental endocrine factors regulating testicular functions are LH, testosterone and FSH in mammals (Ramaswamy & Weinbauer, 2014). Spermatogenesis is initiated when LH from the pituitary activates the Leydig cell to produce testosterone which then acts in conjunction with FSH (O'Shaughnessy, 2014) to stimulate the Sertoli cell relevant in all aspect of spermatogenesis (Jones, 2014) and facilitates germ cells progression to spermatozoa and in the nourishment of developing sperm cells (Griswold, 1998, 2018; Liang et al., 2019). Testicular activities of LDH, ALP and ACP are important in the maintenance of normal germ cell growth and phosphorylative role in glucose usage by germ cells during spermatogenesis (Akhigbe & Ajayi, 2020; Motawi, Sadik, & Refaat, 2010; Rizk, Zaki, & Mina, 2014), while G6PD is essential for providing reducing equivalent necessary for steroidogenesis (Aly & Khafagy, 2014).…”

Coordination of Multiple Cellular Processes by NR5A1/Nr5a1

“…Notably, Nr5a1 is required for all three steps. By applying a similar experimental design, Liang et al [ 34 ] revealed that two genes, NR5A1 and GATA4 , are sufficient for the direct reprograming of human fibroblasts to Sertoli cells. Moreover, under the same concept, Yang et al [ 35 ] successfully reprogramed mouse fibroblasts directly to Leydig cells using Nr5a1 , Gata4 , and Dmrt1 .…”

An In Vitro Differentiation Protocol for Human Embryonic Bipotential Gonad and Testis Cell Development

“…Some have overexpressed transcription factors to directly reprogram mouse or human fibroblasts into Sertoli and Leydig-like cells ( Buganim et al., 2012 ; Jadhav and Jameson 2011 ; Yang et al., 2015 , 2017 ; Yazawa et al., 2006 ). The ectopic expression of the transcription factors GATA4 and NR5A1 appears to be sufficient to reprogram human fibroblasts into Sertoli-like cells ( Liang et al., 2019 ). Other protocols have used co-cultures of human and mouse cells ( Rodríguez Gutiérrez et al., 2018 ; Shlush et al., 2017 ; Yamashiro et al., 2018 ) or co-cultures of human iPSCs with NT2D1 cells to differentiate Sertoli-like cells ( Rodríguez Gutiérrez et al., 2018 ).…”