Banga A, Greder L V, Dutton J R, Slack J M W
Stem Cell Institute, University of Minnesota, MTRF, Minneapolis, MN, USA.
Gene Ther. 2014 Jan;21(1):19-27. doi: 10.1038/gt.2013.50. Epub 2013 Oct 3.
With the long-term aim of developing a new type of therapy for diabetes, we have investigated the reprogramming of liver cells in normal mice toward a pancreatic phenotype using the gene combination Pdx1, Ngn3, MafA. CD1 mice were rendered diabetic with streptozotocin and given a single dose of Ad-PNM, an adenoviral vector containing all three genes. Ad-PNM induced hepatocytes of the liver to produce insulin, and the blood glucose became normalized. But over several weeks, the insulin-positive cells were lost and the blood glucose rose back to diabetic levels. Simultaneous administration of a peroxisome-proliferator-activated receptor agonist, WY14643, caused remission of diabetes at a lower dose of Ad-PNM and also caused the appearance of a population of insulin-secreting ductal structures in the liver. The insulin-positive ducts were stable and were able to relieve diabetes in the long term. We show that the effect of WY14643 is associated with the promotion of cell division of the ductal cells, which may increase their susceptibility to being reprogrammed toward a beta cell fate.
为了开发一种新型糖尿病治疗方法这一长期目标，我们研究了使用基因组合Pdx1、Ngn3、MafA将正常小鼠的肝细胞重编程为胰腺表型。用链脲佐菌素使CD1小鼠患糖尿病，并给予单剂量的Ad-PNM，一种包含所有三个基因的腺病毒载体。Ad-PNM诱导肝脏中的肝细胞产生胰岛素，血糖恢复正常。但在几周内，胰岛素阳性细胞消失，血糖回升至糖尿病水平。同时给予过氧化物酶体增殖物激活受体激动剂WY14643，在较低剂量的Ad-PNM时可导致糖尿病缓解，还会使肝脏中出现一群分泌胰岛素的导管结构。胰岛素阳性导管稳定，能够长期缓解糖尿病。我们表明，WY14643的作用与促进导管细胞的细胞分裂有关，这可能会增加它们被重编程为β细胞命运的易感性。
