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

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.

Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress

“…The reduction in ERS by melatonin through activation of ERAD has been reported in several studies [ 24 – 26 ]. Consistent with this, the ERAD markers Hrd1, Vcp , and Os9 increased remarkably after treatment of cADMSCs with melatonin for 12h, while Hrd1 was inhibited by luzindole ( Fig.…”

A noncanonical role of NOD-like receptor NLRP14 in PGCLC differentiation and spermatogenesis

“…Secondly, the C18-4 cells used in our study were an immortalized SSC line ( 29 ) which were characterized with typical SSC marker expression ( SI Appendix , Fig. S7 A and B ) ( 58 ) and had been extensively used for investigating self-renewal regulation of SSCs ( 59 – 61 ) and in vitro germline toxicity assessment ( 62 ); however, their competence for continued spermatogenesis was not proven. While other germline stem cells, such as mouse GS cells ( 63 ), would be a closer mimic of primary SSCs, the transgene delivery method (mainly through electroporation) and its relatively low efficiency limited large-scale biochemical analysis of them ( 64 – 66 ).…”

Melatonin appears to protect against steroidogenic collapse in both mice fed with high‐fat diet and H 2 O 2 ‐treated TM3 cells

“…MT has been shown to prevent environmental and drug-induced testicular damage due to its antioxidant properties (Galano, Castaneda-Arriaga, Perez-Gonzalez, Tan, & Reiter, 2016;Li et al, 2016;Mukherjee, Haldar, & Vishwas, 2015;Reiter et al, 2017). Moreover, MT may reduce the damage dealt with diabetic Leydig cells (Du, et al, 2018). Moreover, MT may reduce the damage dealt with diabetic Leydig cells (Du, et al, 2018).…”

“…Our previous study (Zhang, Lv, Jia, & Huang, 2012) showed that MT could also effectively protect testicular tissues against the structural and functional damage caused by an HFD. Moreover, MT may reduce the damage dealt with diabetic Leydig cells (Du, et al, 2018). As testosterone replacement therapy has a number of side effects and risks (Cao & Kaufman, 2014), a more natural, safe treatment for infertility in obese males would be beneficial.…”