Li Jinming, Goodyer Cynthia G, Fellows Fraser, Wang Rennian
Department of Physiology & Pharmacology, University of Western Ontario, London, Canada.
Int J Biochem Cell Biol. 2006;38(5-6):961-72. doi: 10.1016/j.biocel.2005.08.014. Epub 2005 Sep 15.
Stem cell factor (SCF), a progenitor cell growth factor, binds to and activates the c-Kit receptor tyrosine kinase, which is critical for early stem cell differentiation in haematopoiesis and gametogenesis. Nothing is known regarding these interactions during islet development in the human fetal pancreas. The present study was to investigate whether an increase in c-Kit receptor activity in isolated human fetal islet-epithelial clusters, by giving exogenous SCF, would promote beta-cell development. In the intact fetal pancreas, SCF and c-Kit were observed co-localizing with cytokeratin 19 in both ductal and newly forming islet cells. Islet cells isolated from 14 to 16 weeks fetal pancreata were cultured with SCF (50 ng/ml) or vehicle for 48 h. We observed an increase in the number of c-Kit-, pancreatic and duodenal homeobox gene 1- (PDX-1-), insulin- and glucagon-expressing cells in the SCF-treated group (PDX-1 and insulin, p < 0.05). PDX-1 and c-Kit mRNA levels were also up-regulated in the SCF group (PDX-1, p < 0.05), with no change in preproinsulin or proglucagon gene expression. Co-localization of insulin with PDX-1 or c-Kit was observed frequently in SCF-treated cultures. A significantly (p < 0.05) greater proliferative capacity of islet-epithelial clusters was found in the SCF group in parallel with increased (p < 0.02) phosphorylation of Akt in a phosphatidylinositol-3 kinase (PI3K)-dependent manner. Our results demonstrate that SCF/c-Kit interactions are likely to be involved in mediating islet cell differentiation and proliferation during human fetal pancreatic development, and that phosphorylated Akt may have a role downstream of SCF/c-Kit signaling.
干细胞因子（SCF）是一种祖细胞生长因子，它能与c-Kit受体酪氨酸激酶结合并激活该激酶，这对于造血和配子发生过程中的早期干细胞分化至关重要。关于这些相互作用在人类胎儿胰腺胰岛发育过程中的情况，目前尚不清楚。本研究旨在探讨通过给予外源性SCF来增加分离出的人类胎儿胰岛上皮细胞团中c-Kit受体活性是否会促进β细胞发育。在完整的胎儿胰腺中，观察到SCF和c-Kit与细胞角蛋白19在导管细胞和新形成的胰岛细胞中共同定位。从14至16周龄胎儿胰腺分离出的胰岛细胞用SCF（50 ng/ml）或溶剂培养48小时。我们观察到，在SCF处理组中，表达c-Kit、胰腺和十二指肠同源盒基因1（PDX-1）、胰岛素和胰高血糖素的细胞数量增加（PDX-1和胰岛素，p<0.05）。SCF组中PDX-1和c-Kit mRNA水平也上调（PDX-1，p<0.05），而胰岛素原或胰高血糖素原基因表达无变化。在SCF处理的培养物中经常观察到胰岛素与PDX-1或c-Kit的共同定位。SCF组中胰岛上皮细胞团的增殖能力显著增强（p<0.05），同时以磷脂酰肌醇-3激酶（PI3K）依赖的方式，Akt的磷酸化增加（p<0.02）。我们的结果表明，SCF/c-Kit相互作用可能参与介导人类胎儿胰腺发育过程中的胰岛细胞分化和增殖，并且磷酸化的Akt可能在SCF/c-Kit信号传导的下游发挥作用。
