Small‐Molecule‐Driven Direct Reprogramming of Fibroblasts into Functional Sertoli‐Like Cells as a Model for Male Reproductive Toxicology

Abstract

Sertoli cells (SCs) are vital to providing morphological and nutritional support for spermatogenesis. Defects in SCs often lead to infertility. SCs transplantation is a promising potential strategy to compensate for SC dysfunction. However, isolation of SCs from testes is impractical due to obvious and ethical limitations. Here, a molecular cocktail is identified comprising of pan‐BET family inhibitor (I‐BET151), retinoic acid, and riluzole that enables the efficient conversion of fibroblasts into functional Sertoli‐like cells (CiSCs). The gene expression profiles of CiSCs resemble those of mature SCs and exhibit functional properties such as the formation of testicular seminiferous tubules, engulfment of apoptotic sperms, supporting the survival of germ cells, and suppressing proliferation of primary lymphocytes in vitro. Moreover, CiSCs are sensitive to toxic substances, making them an alternative model to study the deleterious effects of toxicants on SCs. The study provides an efficient approach to reprogram fibroblasts into functional SCs by using pure chemical compounds.

Riluzole reverses blood-testis barrier loss to rescue chemotherapy-induced male infertility by binding to TRPC

“…In our previous study, we accidentally found that riluzole, the first drug approved by the FDA for the clinical treatment of amyotrophic lateral sclerosis (ALS), had the ability to induce reprogramming of mouse embryonic fibroblastic cells (MEFs) into Sertoli-like cells (CiSCs) (Y. Yang, Li, et al, 2022). Interestingly, our study also revealed that treatment with riluzole resulted in a significant upregulation of gene expression levels of various secreted factors in SCs.…”

“…In our previous study, we found that riluzole had the ability to induce the transformation of mouse embryonic fibroblasts into Sertoli-like cells (Y. Yang, Li, et al, 2022). These Sertoli-like cells showed increased expression of key cytokines (Gdnf, Bmp4, Scf, Cxcl12, Inhibin B, and Fgf2) involved in the regulation of spermatogonial stem cell proliferation and differentiation.…”

“…Furthermore, riluzole has demonstrated therapeutic efficacy in epilepsy and certain psychiatric disorders such as bipolar depression and anxiety (Diao et al, 2013;Lapidus, Soleimani, & Murrough, 2013;Mathew et al, 2005;Park et al, 2017). It modulated the Wnt/β-catenin signaling pathway by inhibiting glycogen synthase kinase-3β (GSK-3β) opens up potential applications in cell self-renewal, embryonic development, and organogenesis (Biechele et al, 2010;Y. Yang, Li, et al, 2022).…”

“…In our previous study, we accidentally found that riluzole, the first drug approved by the FDA for the clinical treatment of amyotrophic lateral sclerosis (ALS), had the ability to induce reprogramming of mouse embryonic fibroblastic cells (MEFs) into Sertoli-like cells (CiSCs) (Y. Yang, Li, et al, 2022).…”

Integrating network pharmacology and in vitro experiment to investigate the protective effects of semen cuscutae flavonoid on sertoli cells and blood-testis barrier in male infertility under heat stress

“…Interestingly, SCs are essential for maintaining the structure and function of spermatogenic cell. SCs are adjacent to the spermatogenesis cells and are vital to providing morphological and nutritional support for spermatogenesis, it have been widely studied in recent years [4]. In addition, SCs participate in the formation of the BTB (made of tight, adherens and gap-junctions between SCs) [5], and the primary function of the BTB is to restrict the paracellular ow of water and nutrients across the SCs epithelia and at the same time to protect the developing haploid forms of male germ cells by establishing an immune-privileged environment [6].…”