Background  With the increase of morbidity, non-alcoholic fatty liver disease (NAFLD) has become a major metabolic disease that poses a great threat to human health, and its available clinical therapies are very limited. Mesenchymal stem cell (MSCs) is widely used in the treatment of metabolic diseases because of its powerful immunomodulatory effect, showing a good clinical application prospect.

  Objective  To observe the protective effect of umbilical cord-derived mesenchymal stem cells (UC-MSCs) on NAFLD in type 2 diabetic (T2DM) mice model, and explore the possible mechanism.

  Methods  The diabetic NAFLD mouse model was induced by a combination of high-fat diet and streptozocin (STZ). The mice were randomly divided into the model group (NAFLD group, n=6) and the MSCs treatment group (UC-MSCs group, n=6). Mice fed with a normal diet were served as control group (n=6). Mice in the UC-MSCs group were infused with UC-MSCs intravenously once a week for 4 weeks. On the 7th day after treatment, intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (IPITT) were performed on mice. Serum levels of alanine transaminase, aspartate transaminase, triglyceride, cholesterol (TC) and low-density lipoprotein were measured after treatment. The liver tissue was extracted, stained with haematoxylin and eosin (H&E), and the expressions of genes encoding inflammatory molecules and macrophage phenotype in liver tissue were detected by qRT-PCR.

  Results  Compared with the control group, the serum levels of blood glucose, alanine transaminase, aspartate transaminase, triglyceride, TC and low-density lipoprotein in the NAFLD group increased significantly (all P < 0.05). After UC-MSCs infusion, the glucose metabolism improved significantly when compared with NAFLD group (P<0.05), while the ALT, AST, triglyceride, TC and low-density lipoprotein significantly decreased (all P<0.05). H&E staining showed normal hepatocyte in control group, diffuse steatosis and inflammatory cell infiltration in NAFLD group, while these pathological changes in UC-MSCs group were significantly reduced. The NAS score of UC-MSCs group was significantly lower than that of NAFLD group (2.82 ± 0.13 vs 5.85 ± 0.41, P=0.001). Inflammatory factor test results showed that the proinflammatory factors TNF-α, IL-1β and IL-6 expression increased significantly, while the anti-inflammation suppression factors IL-4 and IL-10 expression decreased significantly (P<0.05, respectively). After UC-MSCs treatment, the increased proinflammatory factors were down-regulated, while the anti-inflammation suppression factors were up-regulated. Furthermore, the infusion of UC-MSCs led to higher expression of M2 type macrophages while lower expression of M1 type macrophages (P<0.05, respectively).

  Conclusion  UC-MSCs can significantly mitigate the fatty liver of T2DM mice, which may be related to regulating the phenotype of macrophages in liver tissue and alleviating chronic inflammation of liver.