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<p>Non-alcoholic fatty liver disease (NAFLD), a common metabolic disorder, is increasingly linked to impaired male reproductive health. This study investigates the therapeutic potential of adipose-derived mesenchymal stem cells (AD-MSCs) and their exosomes (AD-MSCs-Exo) in ameliorating NAFLD-induced testicular dysfunction in a murine model. Male C57BL/6 mice were divided into four groups: [<i>n</i> = 8 per group: control, high-fat diet (HFD), HFD + AD-MSCs, and HFD + AD-MSCs-Exo]. Sperm parameters according to the WHO Laboratory Manual, hormonal profiles via ELISA, and expression of genes involved in autophagy and spermatogenesis were assessed using qRT-PCR. HFD-induced NAFLD significantly reduced sperm count (<i>P</i> = 0.036), motility (<i>P</i> &lt; 0.0001), viability (<i>P</i> = 0.023), and normal morphology (<i>P</i> = 0.015) while increasing DNA fragmentation (<i>P</i> = 0.004). Moreover, in the HFD group, LH and total testosterone levels decreased significantly (<i>P</i> = 0.0002 and <i>P</i> &lt; 0.0001), whereas estradiol levels increased significantly (<i>P</i> = 0.0001) compared with controls. Expression of <i>STAR</i> was significantly downregulated (<i>P</i> = 0.0001); conversely, the relative fold changes of <i>BECN1</i> (<i>P</i> = 0.0003), <i>MAP-LC3b-a</i> (<i>P</i> = 0.0002), and <i>SQSTM-1/p62</i> (<i>P</i> = 0.005) were significantly enhanced in the HFD group compared to the controls. Treatment with AD-MSCs or AD-MSCs-Exo improved sperm quantity and quality and balanced hormonal levels. AD-MSCs showed slightly greater modulation of key autophagy genes (<i>BECN1</i>, <i>MAP-LC3b-a</i>, and <i>SQSTM1/p62</i>), whereas exosomes were more effective in hormonal restoration (especially testosterone) and in enhancing genes related to steroidogenesis (especially <i>INHBB</i>). AD-MSCs and their exosomes improve sperm-related abnormalities, hormonal imbalance, and testicular autophagy dysregulation in the NAFLD model. These findings support their potential as therapeutic agents for NAFLD-induced male infertility, highlighting translational relevance while noting the need for further clinical validation.</p>

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Adipose-Derived Mesenchymal Stem Cells and Their Exosomes Ameliorate Sperm-related Abnormalities, Hormonal Imbalance, and Disrupted Testicular Autophagy in A Diet-Induced Murine Model for Non-Alcoholic Fatty Liver Disease

  • 期刊论文

  • 发表日期：

    2026年7月21日

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  • Maryam Mirani,
  • Zahra Moayedfard,
  • Sedigheh Bahmyari,
  • Fatemeh Masjedi,
  • Ali Akbar Nekooeian,
  • Soghra Bahmanpour,
  • Ronak Heidarian,
  • Mahintaj Dara,
  • Farhad Koohpeyma,
  • Negar Azarpira

摘要

Non-alcoholic fatty liver disease (NAFLD), a common metabolic disorder, is increasingly linked to impaired male reproductive health. This study investigates the therapeutic potential of adipose-derived mesenchymal stem cells (AD-MSCs) and their exosomes (AD-MSCs-Exo) in ameliorating NAFLD-induced testicular dysfunction in a murine model. Male C57BL/6 mice were divided into four groups: [n = 8 per group: control, high-fat diet (HFD), HFD + AD-MSCs, and HFD + AD-MSCs-Exo]. Sperm parameters according to the WHO Laboratory Manual, hormonal profiles via ELISA, and expression of genes involved in autophagy and spermatogenesis were assessed using qRT-PCR. HFD-induced NAFLD significantly reduced sperm count (P = 0.036), motility (P < 0.0001), viability (P = 0.023), and normal morphology (P = 0.015) while increasing DNA fragmentation (P = 0.004). Moreover, in the HFD group, LH and total testosterone levels decreased significantly (P = 0.0002 and P < 0.0001), whereas estradiol levels increased significantly (P = 0.0001) compared with controls. Expression of STAR was significantly downregulated (P = 0.0001); conversely, the relative fold changes of BECN1 (P = 0.0003), MAP-LC3b-a (P = 0.0002), and SQSTM-1/p62 (P = 0.005) were significantly enhanced in the HFD group compared to the controls. Treatment with AD-MSCs or AD-MSCs-Exo improved sperm quantity and quality and balanced hormonal levels. AD-MSCs showed slightly greater modulation of key autophagy genes (BECN1, MAP-LC3b-a, and SQSTM1/p62), whereas exosomes were more effective in hormonal restoration (especially testosterone) and in enhancing genes related to steroidogenesis (especially INHBB). AD-MSCs and their exosomes improve sperm-related abnormalities, hormonal imbalance, and testicular autophagy dysregulation in the NAFLD model. These findings support their potential as therapeutic agents for NAFLD-induced male infertility, highlighting translational relevance while noting the need for further clinical validation.