Cancer treatments, including cytotoxic therapy, often result in male infertility, necessitating the development of safe and effective strategies to preserve male reproductive potential during chemotherapy. Notably, our study uncovers the potential of repurposing riluzole, an FDA-approved drug for amyotrophic lateral sclerosis (ALS), in enhancing spermatogenesis. Hence, this research aims to explore the feasibility of utilizing riluzole to alleviate male infertility induced by busulfan (BSF), a commonly used chemotherapy drug. We established a BSF-induced oligospermia model in 4-week-old male mice and found that riluzole could effectively counter the detrimental effects of BSF on sperm production in mice with oligospermia. By restoring blood-testis barrier (BTB) functionality, riluzole improves sperm quality and reduces testicular atrophy. Through transcriptomic and molecular docking analyses, we identify transient receptor potential canonical subfamily member 5 (TRPC5) as a potential target for riluzole-mediated regulation of blood-testis barrier function. These findings propose riluzole as a promising therapeutic option for chemotherapy-induced male infertility, thereby addressing the fertility challenges associated with cancer treatments. Moreover, repurposing riluzole could streamline the drug development process, providing a cost-effective approach with reduced risk compared to developing entirely new drugs.
Abstract Self‐renewal and differentiation of spermatogonial stem cell (SSC) are critical for male fertility and reproduction, both of which are highly regulated by testicular microenvironment. Exosomal miRNAs have emerged as new components in intercellular communication. However, their roles in the differentiation of SSC remain unclear. Here, we observed miR‐486‐5p enriched in Sertoli cell and Sertoli cell‐derived exosomes. The exosomes mediate the transfer of miR‐486‐5p from Sertoli cells to SSCs. Exosomes release miR‐486‐5p, thus up‐regulate expression of Stra8 (stimulated by retinoic acid 8) and promote differentiation of SSC. And PTEN was identified as a target of miR‐486‐5p. Overexpression of miR‐486‐5p in SSCs down‐regulates PTEN expression, which up‐regulates the expression of STRA8 and SYCP3, promotes SSCs differentiation. In addition, blocking the exosome‐mediated transfer of miR‐486‐5p inhibits differentiation of SSC. Our findings demonstrate that miR‐486‐5p acts as a communication molecule between Sertoli cells and SSCs in modulating differentiation of SSCs. This provides a new insight on molecular mechanisms that regulates SSC differentiation and a basis for the diagnosis, treatment, and prevention of male infertility.
In the mammalian testis, two distinct populations of Sertoli cells (SCs), the immature SCs (ISCs) and adult SCs (ASCs), play significant roles in regulating the development and function of Leydig cells. However, the effect of different SC types on the function of Leydig cells is poorly understood. Here, our study showed that miR-145-5p expression was significantly different in SCs at different stages, with the highest expression observed in ISCs. Exosomes mediate the transfer of miR-145-5p from ISCs to Leydig cells. Overexpression of miR-145-5p in Leydig cells significantly downregulated steroidogenic gene expression and inhibited testosterone synthesis. Additionally, miR-145-5p functioned by directly targeted steroidogenic factor-1 (Sf-1) and downregulated the expression of SF-1, which further downregulated the expression of steroidogenic genes, induced accumulation of lipid droplets, and eventually suppressed testosterone production. These findings demonstrate that SC-derived miR-145-5p plays a significant role in regulating the functions of Leydig cells and may therefore serve as a diagnostic biomarker for male hypogonadism developmental abnormalities during puberty.
Increasing rates of male infertility require more experimental models to understand the mechanisms underlying male infertility.In vitroorganoids hold unprecedented promise for this purpose; however, the development of organoids with tissue architecture similar to that of the testisin vivoremains a challenge. Here, we generated testicular organoids derived from testicular cells by combining a hanging drop culture and a rotation culture system. Our results indicated that testicular cells could self-assemble into spheroid organoids with tubule-like structures in hanging drop culture. The organoids can subsequently be cultured and maintained in a rotation culture system. These established organoids have gene expression profiles similar to those of adult testis tissue, produce testosterone with preserved gonadotropin responsiveness, and exhibit sensitivity to reproductive toxicants. More importantly, each testicular organoid can be generated from only 2000 cells, and they maintain their proliferative ability after freezing and thawing. These features make it possible to obtain fresh primary testis cells from testicular biopsies taken from patients or endangered wild species, and to build individual-specific biobanks. These findings will help enable the exploration of self-organization process of testicular cells and provide an experimental model for reproductive biology research, pharmacotoxicology testing, and regenerative medicine.
The epidermal barrier is vital for protecting the skin from environmental stressors and ultraviolet (UV) radiation. Filaggrin-2 (FLG2), a critical protein in the stratum corneum, plays a significant role in maintaining skin barrier homeostasis. However, the precise role of FLG2 in mitigating the adverse effects of UV-induced barrier disruption and photoaging remains poorly understood. In this study, we revealed that UVB exposure resulted in a decreased expression of FLG2 in HaCaT keratinocytes, which correlated with a compromised barrier function. The administration of recombinant filaggrin-2 (rFLG2) enhanced keratinocyte differentiation, bolstered barrier integrity, and offered protection against apoptosis and oxidative stress induced by UVB irradiation. Furthermore, in a UV-induced photodamage murine model, the dermal injection of rFLG2 facilitated the enhanced restoration of the epidermal barrier, decreased oxidative stress and inflammation, and mitigated the collagen degradation that is typical of photoaging. Collectively, our findings suggested that targeting FLG2 could be a strategic approach to prevent and treat skin barrier dysfunction and combat the aging effects associated with photoaging. rFLG2 emerges as a potentially viable therapy for maintaining skin health and preventing skin aging processes amplified by photodamage.
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.
The ovary is a highly susceptible organ to senescence, and granulosa cells (GCs) have a crucial role in oocyte development promotion and overall ovarian function maintenance. As age advances, GCs apoptosis and dysfunction escalate, leading to ovarian aging. However, the molecular mechanisms underpinning ovarian aging remain poorly understood. In this study, we observed a correlation between the age-related decline of fertility and elevated expression levels of miR-143-3p in female mice. Moreover, miR-143-3p was highly expressed in senescent ovarian GCs. The overexpression of miR-143-3p in GCs not only hindered their proliferation and induced senescence-associated secretory phenotype (SASP) but also impeded steroid hormone synthesis by targeting ubiquitin-conjugating enzyme E2 E3 (Ube2e3) and luteinizing hormone and human chorionic gonadotropin receptor (Lhcgr). These findings suggest that miR-143-3p plays a substantial role in senescence and steroid hormone synthesis in GCs, indicating its potential as a therapeutic target for interventions in the ovarian aging process.
Chronic wound repair is a clinical treatment challenge. The development of multifunctional hydrogels is of great significance in the key aspects of treating chronic wounds, including reducing oxidative stress, promoting angiogenesis, and improving the natural remodeling of extracellular matrix and immune regulation. In this study, we prepared a composite hydrogel, sodium alginate (SA)@MnO2/recombinant humanized collagen III (RHC)/mesenchymal stem cells (MSCs), composed of SA, MnO2 nanoparticles, RHC, and MSCs. The hydrogel has high mechanical properties and good biocompatibility. In vitro, SA@MnO2/RHC/MSCs hydrogel effectively enhanced the formation of intricate tubular structures and angiogenesis and showed synergistic effects on cell proliferation and migration. In vivo, the SA@MnO2/RHC/MSCs hydrogel enhanced diabetes wound healing, rapid re-epithelization, favorable collagen deposition, and abundant wound angiogenesis. These findings demonstrated that the combined effects of SA, MnO2, RHC, and MSCs synergistically accelerate healing, resulting in a reduced healing time. These observed healing effects demonstrated the potential of this multifunctional hydrogel to transform chronic wound care and improve patient outcomes.
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