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褪黑素通过维持莱迪希细胞来减轻糖尿病对小鼠精原干细胞龛的不利影响。

Melatonin attenuates detrimental effects of diabetes on the niche of mouse spermatogonial stem cells by maintaining Leydig cells.

机构信息

College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, 712100, Shaanxi, China.

Centre for Healthy Brain Ageing, UNSW Medicine, Randwick, NSW, 2031, Australia.

出版信息

Cell Death Dis. 2018 Sep 20;9(10):968. doi: 10.1038/s41419-018-0956-4.

Abstract

Diabetes mellitus affects a large number of men of reproductive age and it usually leads to serious reproductive disorders. However, the underlying mechanisms and specific therapies still remain largely unknown. We observed Leydig cell loss in the testes of diabetic mice. Continuous high glycemic status of testes stimulated expression of Caspase12, Grp78, and Chop, the three ERS response factors; this might induce cell cycle arrest and apoptosis of Leydig cells in response to ERS. In these diabetic mouse models, melatonin alleviated apoptosis of testicular stromal cell induced by ERS, and promoted SSCs self-renewal by recovering Leydig cells secretion of CSF1 after 8 weeks of treatment. To explore the relationship between CSF-1 and ERS in Leydig cells, we treated Leydig tumor cell line with an activator Tuniamycin and an inhibitor 4-Phenylbutyrate of ERS. Our data showed that the CSF-1 expression in mouse Leydig cell lines decreased six-fold while reversely increasing five-fold in the 4-Phenylbutyrate-treated group. Thus, melatonin likely alleviates the loss of Leydig cells in diabetic testes and provides a healthier niche for SSCs to self-renew and continually provide healthy sperm for male fertility.

摘要

糖尿病影响了大量处于生育年龄的男性,通常会导致严重的生殖障碍。然而,其潜在的机制和具体的治疗方法仍知之甚少。我们观察到糖尿病小鼠的睾丸间质细胞丢失。睾丸内持续的高血糖状态刺激了 Caspase12、Grp78 和 Chop 的表达,这三种 ERS 反应因子;这可能会诱导细胞周期停滞和细胞凋亡。在这些糖尿病小鼠模型中,褪黑素通过恢复 ERS 诱导的睾丸基质细胞凋亡,促进 SSCs 的自我更新,在治疗 8 周后恢复了 Leydig 细胞分泌 CSF1。为了探讨 ERS 与 Leydig 细胞中 CSF-1 的关系,我们用 ERS 的激活剂 Tuniamycin 和抑制剂 4-苯基丁酸处理 Leydig 肿瘤细胞系。我们的数据显示,在小鼠 Leydig 细胞系中,CSF-1 的表达降低了六倍,而在 4-苯基丁酸处理组中则增加了五倍。因此,褪黑素可能减轻了糖尿病睾丸中 Leydig 细胞的丢失,并为 SSCs 的自我更新提供了更健康的小生境,为男性生育能力持续提供健康的精子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/93c9/6148071/f445f4f4bec7/41419_2018_956_Fig1_HTML.jpg

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