Jiang Yongwei, Zhang Wenjian, Xu Shiqing, Lin Hua, Sui Weiguo, Liu Honglin, Peng Liang, Fang Qing, Chen Li, Lou Jinning
Department of Laboratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, China.
Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China.
J Transl Med. 2017 Jun 27;15(1):147. doi: 10.1186/s12967-017-1253-1.
Diabetic nephropathy (DN) is a severe complication of diabetes mellitus (DM). Pancreas or islet transplantation has been reported to prevent the development of DN lesions and ameliorate or reverse existing glomerular lesions in animal models. Shortage of pancreas donor is a severe problem. Islets derived from stem cells may offer a potential solution to this problem.
To evaluate the effect of stem cell-derived islet transplantation on DN in a rat model of streptozotocin-induced DM.
Pancreatic progenitor cells were isolated from aborted fetuses of 8 weeks of gestation. And islets were prepared by suspension culture after a differentiation of progenitor cells in medium containing glucagon-like peptide-1 (Glp-1) and nicotinamide. Then islets were transplanted into the liver of diabetic rats via portal vein. Blood glucose, urinary volume, 24 h urinary protein and urinary albumin were measured once biweekly for 16 weeks. Graft survival was evaluated by monitoring human C-peptide level in rat sera and by immunohistochemical staining for human mitochondrial antigen and human C-peptide in liver tissue. The effect of progenitor-derived islets on filtration membrane was examined by electron microscopy and real-time polymerase chain reaction (PCR). Immunohistochemical staining, real-time PCR and western blot were employed for detecting fibronectin, protein kinase C beta (PKCβ), protein kinase A (PKA), inducible nitric oxide synthase (iNOS) and superoxide dismutase (SOD).
Islet-like clusters derived from 8th gestational-week human fetal pancreatic progenitors survived in rat liver. And elevated serum level of human C-peptide was detected. Blood glucose, 24 h urinary protein and urinary albumin were lower in progenitor cell group than those in DN or insulin treatment group. Glomerular basement membrane thickness and fibronectin accumulation decreased significantly while podocytes improved morphologically in progenitor cell group. Furthermore, receptor of advanced glycation end products and PKCβ became down-regulated whereas PKA up-regulated by progenitor cell-derived islets. And iNOS rose while SOD declined.
DN may be reversed by transplantation of human fetal pancreatic progenitor cell-derived islets. And fetal pancreatic progenitor cells offer potential resources for cell replacement therapy.
糖尿病肾病（DN）是糖尿病（DM）的一种严重并发症。据报道，胰腺或胰岛移植可预防动物模型中DN病变的发展，并改善或逆转现有的肾小球病变。胰腺供体短缺是一个严重问题。源自干细胞的胰岛可能为解决这一问题提供潜在方案。
评估干细胞来源的胰岛移植对链脲佐菌素诱导的糖尿病大鼠模型中DN的影响。
从妊娠8周的流产胎儿中分离胰腺祖细胞。在含有胰高血糖素样肽-1（Glp-1）和烟酰胺的培养基中使祖细胞分化后，通过悬浮培养制备胰岛。然后将胰岛经门静脉移植到糖尿病大鼠的肝脏中。每两周测量一次血糖、尿量、24小时尿蛋白和尿白蛋白，持续16周。通过监测大鼠血清中的人C肽水平以及对肝组织中的人线粒体抗原和人C肽进行免疫组织化学染色来评估移植物存活情况。通过电子显微镜和实时聚合酶链反应（PCR）检测祖细胞来源的胰岛对滤过膜的影响。采用免疫组织化学染色、实时PCR和蛋白质印迹法检测纤连蛋白、蛋白激酶Cβ（PKCβ）、蛋白激酶A（PKA）、诱导型一氧化氮合酶（iNOS）和超氧化物歧化酶（SOD）。
源自妊娠第8周人胎儿胰腺祖细胞的胰岛样簇在大鼠肝脏中存活。并且检测到血清中人C肽水平升高。祖细胞组的血糖、24小时尿蛋白和尿白蛋白低于DN组或胰岛素治疗组。祖细胞组的肾小球基底膜厚度和纤连蛋白积聚显著减少，而足细胞形态得到改善。此外，晚期糖基化终产物受体和PKCβ下调，而祖细胞来源的胰岛使PKA上调。并且iNOS升高而SOD下降。
人胎儿胰腺祖细胞来源的胰岛移植可能逆转DN。胎儿胰腺祖细胞为细胞替代治疗提供了潜在资源。
