Autophagy modulation influenced the spermatogenesis in rodent testicular organoids and diabetic condition

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Purpose: Here, the effect of autophagy activity was investigated in rat testicular organoids embedded within the alginate/gelatin (Alg/Gel) hydrogel. Besides, we monitored the spermatogenesis potential in diabetic mice after the administration of metformin (Met), and/or hydroxychloroquine (HCQ). Methods: Alg/Gel hydrogel was fabricated and physicochemical properties were studied. The survival rate of freshly isolated rat whole testicular tissue cells being plated on the Alg/Gel hydrogel surface was monitored after 7 days. Rat testicular organoids were embedded inside Alg/Gel hydrogel and exposed to 15 µM HCQ, and/or 5 µM Met for 7 days. Histological examination was used to monitor OCT3/4+ progenitors and maturing sperm cells. Using western blotting, the levels of Beclin-1, LC3, and P62 were assessed. Diabetic mice received 120 mg/kg body weight Met and/or 70 mg/kg bodyweight HCQ for 4 weeks followed by histological examinations and sperm analysis. Results: The fabricated Alg/Gel hydrogel exhibited suitable physicochemical properties that coincided with an increased survival rate of whole testicular tissue cells compared to the control group (p<0.05). Data indicated the promotion (Beclin-1↑, LC3-II/-I ratio↑, and P62↓), and inhibition (LC3↓) of autophagy in testicular organoids after treatment with Met, and HCQ, respectively compared to the control group (p<0.05). These changes coincided with the induction of SOD activity in Met-treated testicular organoids (p<0.05). In the presence of Met, and HCQ, OCT3/4+ progenitors were reduced in rat organoids related to non-treated control organoids (p<0.05). Administration of Met, but not HCQ, in diabetic mice, can restore some sperm parameters such as motility, and reduce abnormal morphologies compared to the matched diabetic mice (p<0.05). Conclusions: Regulation of autophagy status can influence spermatogenesis capacity in terms of seminiferous tubule progenitors, maturation, and sperm parameters. In rat testicular organoids, and diabetic mice. These features indicate that autophagy response is an interesting signaling pathway target in subfertile, or infertile males.

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