SLE incidence is believed to be related to genetic causes, hormonal factors, certain medications, infections, and other factors. Similar to other autoimmune diseases, the body continues to produce IgG class autoantibodies to self-antigens, forming a large number of circulating immune complexes deposited in the glomeruli capillaries and other tissues to cause glomerulonephritis and whole body multiple systemic disease. The mechanism is similar to type III hypersensitivity. Currently, nonspecific immunosuppression is used in clinical treatment, and hematopoietic stem cell transplantation is used to treat a small number of refractory cases. However, SLE prognosis remains to be improved to prevent infection, recurrence, kidney failure, and heart and brain damage, and for other reasons. We hope that the establishment of the tree shrew SLE model and infusion of UC-MSCs in this new therapeutic animal study will help to improve treatment efficacy and explore a therapeutic mechanism.

Under certain conditions, MSCs can differentiate into a variety of tissue cells, such as osteoblasts, chondrocytes, tendon cells, and adipocytes. However, they can also differentiate across the mesoderm to the endoderm and neural ectoderm (such as the liver, bile duct epithelium, lung, intestine, skin epithelium, and neuronal and glial cells) [11]. Pan et al. [12] have reported using BM-MSC transplantation to treat diabetic nephropathy in tree shrews. However, UC-MSCs are readily available and not rejected after replantation; these cells show a strong ability to self-replicate, are easily separated and amplified in vitro, and should be widely used in tissue engineering, cell transplantation, and gene therapy. UC-MSCs are therefore an ideal seed cell. UC-MSCs have immunosuppressive effects. Application of UC-MSC treatment for SLE involves allogeneic cell transplantation. By restoring the balance of autoreactive T cells in SLE patients, UC-MSCs exert immunosuppressive effects by reaching immune homeostasis again and achieve a therapeutic effect.

The role of CD4+CD25+ T cells is not fully understood [13]. The possible mechanisms are secretion of TGF-β and/or IL-10 or induction of other cells to secrete other inhibitory cytokines. With high cell surface expression of TGF-β, CD4+CD25+ T cells bind the TGF-β receptor and inhibit the autoreactive T cells and B cells. CD4+CD25+ T cells in the body account for 10 % of total CD4+ T cells. The number and activity of CD4+CD25+ T cells meet the need to inhibit autoreactive T-lymphocyte and B-lymphocyte activation, as well as the proliferation and maintenance of autoimmune balance. In individuals susceptible to SLE, environmental factors, genetic abnormalities, and other factors affect the production of CD4+CD25+ T cells in the thymus, which can lead to SLE [14]. Previous studies showed that the level of CD4+CD25+ T cells was significantly lower in SLE patients than in healthy controls, irrespective of the status (active or inactive) [15]. Because the numbers of CD4+CD25+ T cells were reduced, which results in immune suppression, the activation of T-helper cells was enhanced, the expression of B-cell activating factor increased, and B-lymphocyte hyperthyroidism was induced to produce a variety of autoantibodies, which led to a series of immune system interaction disorders that resulted in multiple organ damage. We used quantitative PCR to detect the Foxp3 gene because its change indirectly represents the change in CD4+CD25+ T cells in peripheral blood. Our results showed in that in the model tree shrew, the expression of the Foxp3 gene decreased. The relative expression of the Foxp3 gene was less than 0.5 of that in the normal control group (P < 0.01). The decrease in Foxp3 gene expression is enough to have biological impact on CD4+CD25+ T cells. This result indirectly shows that in the SLE model CD4+CD25+ T cells are significantly lower than in healthy controls. According to the literature, CD4+CD25+ T cells are a subset of regulatory T cells that mainly originate from the thymus. Their main function is related to the inhibition of the immune response of autoreactive T cells, the inhibition of conventional T-cell activation, and the promotion of the secretion of some suppression cytokines. The cells play an important role in the maintenance of a stable internal environment and tumor immune surveillance, and induce transplantation tolerance and autoimmune diseases. SLE patients with increased Th17 cells in the peripheral blood show a decreased population of CD4+CD25+ T cells, which increases peripheral IL-17 gene expression and decreases Foxp3 gene expression.

The literature indicates the use of LPS [1618] and pristane [1921] by intraperitoneal injection to induce SLE in mouse studies, but the tree shrew SLE model has not been studied. We therefore used 80 tree shrews, divided into four groups of 20. Studies have shown that pristane and LPS injection in tree shrews induces SLE-related changes, including an increase in the peripheral IL-17 gene [22], reduction in the Foxp3 gene, elevated serum IgG and C3, multiorgan lesions, and immune complex deposition in kidney sections. We divided 10 model tree shrews into five model control groups and five treatment groups, and the model success criterion was defined as an ELISA OD value of standard model tree shrews >2.8, more than twice the mean OD value (1.4) of the normal control group. Quantitative PCR showed that the relative expression of the IL-17 gene was more than twice that of the normal control group, while that of the Foxp3 gene was less than 0.5 that of the normal control group. DiR-labeled cells (1 × 106 cells) were transplanted into each tree shrew in the treatment and the normal control groups; 2 weeks later, three groups of tree shrews were used to detect serum antiphospholipid and antinuclear antibodies simultaneously with an inflammatory cytokine antibody microarray. From three groups of tree shrews, morning urine was analyzed for urine protein concentration, and the heart, liver, spleen, lungs, and kidneys were imaged. The imaging results showed that labeled cells were distributed in the lung, liver, and spleen of tree shrews in the treatment group, and fluorescence intensity values of the normal and model control groups of all organs were lower than in the treatment group. Labeled UC-MSCs from tree shrews mainly were located in the damaged organs. Because organ damage was absent in the normal control group, the detected fluorescence intensity values were lower than those in the treatment group, and most values were lower by an order of magnitude. Labeled cells did not transplant in the model control group; thus, the detected fluorescence intensity values were lower than in the treatment group, and most values were lower by an order of magnitude. Serum antiphospholipid and antinuclear antibodies results showed that in the model group antiphospholipid and antinuclear antibodies increased significantly. In the treatment group, antiphospholipid and antinuclear antibodies decreased significantly. This result indicates that UC-MSC therapy is effective in the SLE model. Urine protein quantitation results also showed that UC-MSC therapy can effectively decrease urine protein concentrations in the SLE model.

In summary, we reviewed a large body of domestic and foreign literature and established a tree shrew SLE model. The pathological and serological results and genomics showed that the SLE tree shrew model was established successfully. After initial UC-MSC therapy, we found labeled cells in the heart, liver, spleen, lung, and kidney of tree shrews in the treatment group. The region of interest (ROI) fluorescence values were higher than in the control tree shrews, and most of these ROI values were larger by one order of magnitude. These findings provide a theoretical and experimental basis for using UC-MSCs to treat SLE.