MafA promotes the reprogramming of placenta-derived multipotent stem cells into pancreatic islets-like and insulin plus cells
MafA promotes the reprogramming of placenta-derived multipotent stem cells into pancreatic islets-like and insulin plus cells
复制标题
DOI：
10.1111/j.1582-4934.2010.01034.x
复制
发表时间：
2011-03-01
影响因子：
5.3
通讯作者：
Ku, Hung-Hai
中科院分区：
文献类型：
--
作者：
Chiou, Shih-Hwa;Chen, Shih-Jen;Ku, Hung-Hai
MafA是控制胰岛素基因的β细胞特异性转录的胰腺转录因子。然而，MafA在人类干细胞中调节胰腺转分化和重编程的作用仍不清楚。在这项研究中，我们研究了MafA在组成型表达Oct-4和Nanog的胎盘源性多能干细胞（PDMSC）中的作用。分离PDMSC并使用慢病毒载体用MafA转染。我们的研究结果表明，MafA在PDMSC中的过表达显著上调胰腺发育相关基因（Sox 17，Foxa 2，Pdx 1和Ngn 3）的表达。基因芯片分析表明，MafA过表达PDMSC的基因表达谱与胰腺和胰岛组织相似。MafA可增加NKx2.2、Glut 2、胰岛素、胰高血糖素和生长抑素mRNA的表达水平，进一步促进PDMSC向胰岛素+细胞分化。在MafA过表达的PDMSC中，葡萄糖刺激对胰岛素和c肽产生的反应显著高于载体对照的PDMSC。我们的研究结果表明，MafA过表达的PDMSC比携带载体对照的PDMSC更能抵抗氧化损伤和氧化损伤诱导的凋亡。重要的是，MafA在异种移植到免疫功能低下小鼠的PDMSC中的表达改善了血液胰岛素水平恢复到对照值，并大大延长了STZ诱导的糖尿病免疫功能低下小鼠中移植细胞的存活时间。总之，这些数据表明MafA在干细胞重编程为胰腺β祖细胞中起着新的作用，促进PDMSC的胰岛样特征，以及功能性地增强胰岛素产生以恢复移植移植物中血糖水平的调节。
MafA is a pancreatic transcriptional factor that controls beta-cell-specific transcription of the insulin gene. However, the role of MafA in the regulation of pancreatic transdifferentiation and reprogramming in human stem cells is still unclear. In this study, we investigate the role of MafA in placenta-derived multipotent stem cells (PDMSCs) that constitutively expressed Oct-4 and Nanog. PDMSCs were isolated and transfected with MafA using a lentivector. Our results showed that overexpression of MafA in PDMSCs significantly up-regulated the expression of pancreatic development-related genes (Sox17, Foxa2, Pdx1 and Ngn3). Microarray analysis suggested that the gene expression profile of MafA-overexpressing PDMSCs was similar to that of pancreas and islet tissues. MafA increased the expression levels of the mRNAs of NKx2.2, Glut2, insulin, glucagons and somatostatin, and further facilitated the differentiation of PDMSCs into insulin+ cells. The glucose-stimulated responses to insulin and c-peptide production in MafA-overexpressing PDMSCs were significantly higher than in PDMSCs with vector control. Our results indicated that MafA-overexpressing PDMSCs were more resistant to oxidative damage and oxidative damage-induced apoptosis than PDMSCs carrying the vector control were. Importantly, the expression of MafA in PDMSCs xenotransplanted into immunocompromised mice improved the restoration of blood insulin levels to control values and greatly prolonged the survival of graft cells in immunocompromised mice with STZ-induced diabetes. In summary, these data suggest that MafA plays a novel role in the reprogramming of stem cells into pancreatic beta-progenitors, promotes the islet-like characteristics of PDMSCs, as well as functionally enhances insulin production to restore the regulation of blood glucose levels in transplanted grafts.