Background The incidence of dry eye is gradually increased,and researches showed that inflammation participated in the pathogenesis and development of dry eye.The current therapy for dry eye can only relieve symptom but not achieve final cure.Stem cell therapy has been used in the treatment of limbal stem cell deficiency.However,whether it is feasible for the stem cell treating dry eye is still unclear.Objective This study attempted to investigate a new approach to treat dry eye syndrom by using human umbilical cord mesenchymal stem cells (HUCMSCs).Methods The use and care of experimental animals complied with the Tsinghua University School of Medicine Laboratory Animal Care Details.HUCMSCs were cultured and cell suspension was prepared with the cell density of 5×105/ml.Twenty 24-week-old male NOD/Ltj mice were randomized into 4 groups.0.1 ml PBSHUCMSCs suspension was injected via tail vein or lacrimal respectively in the caudal vein injection group and lacrimal injection group,and 10 μ1 PBS-HUCMSCs suspension was topically administed in the eye drops group.The NOD/Ltj mice without any treatment served as the model group.Five male ICR mice were used as the normal control group.Tear secretion was quantitatively detected with phenol red cotton thread in 1,2,3 weeks after injection,and corneal epithelial defect was scored by fluorescein staining.The serum levels of interleukin (IL)-6,IL-17a,tumor necrosis factor-α (TNF-αt) and interferon-γ (IFN-γ) were assayed by ELISA.The relative expression levels of p65,Stat3,Stat5 and extracellular signal-regulated kinases (Erk)-1 in lacrimal gland were detected by Western blot.Results The tear secretion amount was significantly different among the model group,caudal vein injection group,lacrimal injection group and eye drops group in various time points (1 week:F =3.700,P =0.040;2 weeks:F =5.150,P =0.008;3 weeks:F=10.130,P＜0.001).The tear secretion amount was increased in the caudal vein injection group and lacrimal injection group compared with the model group in different time points (all at P＜0.05),and no significant difference was seen in tear secretion amount between eye drops group and model group among various time points (all at P＞0.05).The fluorescein staining score was 3.00±0.63,9.40±1.62,5.20±1.17,4.20±1.17 and 7.20±0.98 in the ICR mouse control group,model group,caudal vein injection group,lacrimal injection group and eye drops group 1 week after injection respectively,and the scores were significantly lower in the caudal vein injection group,lacrimal injection group and eye drops group than those in the model group (P =0.001,0.000,0.033).The serum levels of IL-6,IL-17a and TNF-α in the caudal vein injection group were evidently lower than those in the model group (t =4.70,3.46,11.0,all at P＜0.01),but no significant difference was displayed in the serum IFN-γ level among the five groups (F=1.740,P=0.170).The expressions of STAT5 were significantly decreased in the mice treated with tail vein injection and lacrimal injection compared with mice without treatment (both at P＜0.05).Conclusions Administration of HUCMSCs via intravenous and lacrimal injection can alleviate the inflammatory response during progression of dry eye syndrome by down-regulating the serum level and expression of inflammation-related factors in NOD/Ltj mice.The topical administration of HUCMSCs eye drops can attenuate the symptom of dry eyes by lubricating the cornea and suppling nutrition.