| Background and purpose:Diabetic retinopathy(DR) is a retinal microvascular disease of diabetes and a major cause of blindness in diabetic patients. The incidence rate is positively correlated with diabetes progression. At present, the therapeutic measure for diabetic retinopathy is very limited, especially lack of treatment for early microvascular injury and visual impairment. Mesenchymal stem cells(MSCs) are the adult stem cells that have differentiation potential and low immunogenicity. They also possess injury repair, immune suppression, anti-inflammatory and neurotrophic functions. Currently, MSCs have been used in treatment of diabetes and its complications. However, the application of MSCs in treatment of DR has not been reported. Therefore, this study aimed to preliminarily investigate the safety and efficacy of that intravenous infusion of autologous bone marrow mesenchymal stem cells(ABMSCs) was used for DR treatment, so that to develop an effective treatment method for DR patients.Methods:1. A total of 17 patients with DR were enrolled in this study. The cases contained 19 severe non-proliferative diabetic retinopathy(severe NPDR) eyes and 15 mild proliferative diabetic retinopathy(mild PDR) eyes. The informed consents were signed by patients and the clinical trial of autologous bone marrow MSCS treatment of DR was approved by the First Affiliated Hospital Ethics Committee of Third Military Medical University. The approval document number was 2013 Research No.3.2. The patients’ medical history was collected. Systemic and ocular inspection were carried out and analized. The test items included liver and kidney function, hemoglobin(HbA1c), best corrected visual acuity(BCVA), fundus fluorescein angiography(FFA), optical coherence tomography(OCT), visual electrophysiology, etc.3. The autologous bone marrow was obtained by bone marrow puncture from patients. After isolation, expansion and identification of MSCs in vitro, a single intravenous infusion of MSCs at 3 × 106cells/Kg was performed.4. The safety and efficacy of ABMSCs treatment were strictly evaluated by measuring liver and kidney function, myocardial enzymes, inflammatory cytokines, glycated hemoglobin, BCVA, OCT, FFA, visual electrophysiology of patients at pre-treatment and 1 month, 3 month and 6 month of post-treatment.Results1. The ABMSC from 17 cases were successfully isolated and expanded in vitro.2. There was no any adverse event occurred for all the patients in ABMSCs therapy during the follow-up period of 6 months.Only one case had CK value increased significantly during follow-up, but no conscious adverse reactions and other abnormalities occurred.3. ABMSC infusion significantly reduced the concentrations of fasting blood glucose and Hb A1 c. Before treatment, the fasting blood glucose level was 8.30 ± 2.12 mmol / L, at the 1,3, and 6 months of post-treatment were 7.01 ± 2.51 mmol / L(p <0.05), 6.51 ± 2.35 mmol / L(p <0.01) and 6.97 ± 2.10 mmol / L(p <0.05), respectively. Compared to pre-treatment, the HbA1 c values were significantly lower at 3 and 6 months post-treatment(p<0.05 for all).4. ABMSC treatment significantly elevated the IL-6 levels in peripheral blood of patients, compared with pre-treatment(p <0.05). hs-CRP was no significant change before and after ABMSCs transplantation(p> 0.05).5. ABMSC treatment obviously improved visual acuity. At the first month after treatment, the BCVA 8 eyes were increased(8 / 34,23.53%), 19 eyes were stable(19 / 34,55.88%) and 7 eyes were decreased(7/34, 20.59%); At the third month, 15 eyes were increased(15/34, 44.12%), 14 eyes were stable(14 / 34,41.18%), 5 eyes were decreased(5/34, 14.71%); At the sixth month, 11 eyes were increased(11/28, 39.29%), 12 eyes were stable(12 / 28,42.86%), 5 eyes were decreased(5/28, 17.86%). Although there were no statistically differences between them, the trend of improving BCVA was observed. The effect of ABMSCs treatment on BCVA improvement in NPDR group was superior to PDR group, though there was no statistically significant(p> 0.05).6. FERG Ops amplitudes and dark adaptation 3.0 b / a values were in upward trend after treatment, but there was not statistically significant. OPs amplitude values in NPDR group were significantly higher than those in PDR group before and after treatment(p<0.05). No significant changes of FVEP P2 amplitude value, peak time and amplitude / peak time ratio after ABMSC treatment were observed(P> 0.05). However, PVEP P100 amplitude and A/P value were significantly decreased and the peak time was significantly delayed at the 6th month after treatment compared with pre-treatment(P<0.05 for all).7. The average thickness and the foveal thickness of macular area were not significantly changed by the treatment(P>0.05). The foveal thickness in NPDR group was significantly lower than the PDR group before and after treatment(p<0.05).8. There was no significant difference in number of Retinal capillary hemangioma pre- or post-ABMSC treatment in NPDR(p> 0.05). The retinal neovascularization was observed after ABMSC treatment. The neovascularization were occurred in 3 eyes of 19 eyes(3/19,15.79%) at the 3rd month and 9 eyes of 14 eyes(9/14,64.29%) at the 6th month.Conclution1. This is the first study using ABMSC intravenous infusion for the treatment of patients with DR. The safety of the treatment was proved by observation of a number of indicators up to six months.2. Our data demonstrates that ABMSC treatment significantly lowered blood glucose and regulated inflammatory response. It also improves visual function and alleviated macular edema to a certain extent. But this work is only a preliminary clinical study. The small sample size and the large individual differences in some indicators resulted in effectiveness of some indicators. However, the trend but not the statistically significant conclusions are gained. |
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