Department & Institute of Pharmacology, Taipei Veterans General Hospital, Taipei, Taiwan.
J Cell Mol Med. 2011 Mar;15(3):612-24. doi: 10.1111/j.1582-4934.2010.01034.x.
MafA is a pancreatic transcriptional factor that controls β-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 β-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.
MafA 是一种胰腺转录因子，可控制胰岛素基因的β细胞特异性转录。然而，MafA 在人干细胞中胰腺转分化和重编程的调节中的作用尚不清楚。在这项研究中，我们研究了在胎盘多能干细胞（PDMSCs）中 MafA 的作用，这些细胞持续表达 Oct-4 和 Nanog。使用慢病毒载体将 MafA 转染到 PDMSCs 中。我们的结果表明，MafA 在 PDMSCs 中的过表达显著上调了胰腺发育相关基因（Sox17、Foxa2、Pdx1 和 Ngn3）的表达。微阵列分析表明，MafA 过表达的 PDMSCs 的基因表达谱与胰腺和胰岛组织相似。MafA 增加了 NKx2.2、Glut2、胰岛素、胰高血糖素和生长抑素 mRNA 的表达水平，并进一步促进了 PDMSCs 向胰岛素（+）细胞的分化。MafA 过表达的 PDMSCs 对胰岛素和 C 肽的葡萄糖刺激反应以及 C 肽的产生明显高于载体对照的 PDMSCs。我们的结果表明，与携带载体对照的 PDMSCs 相比，MafA 过表达的 PDMSCs 对氧化损伤和氧化损伤诱导的细胞凋亡具有更强的抵抗力。重要的是，PDMSCs 中 MafA 的表达在免疫缺陷小鼠异种移植后改善了对胰岛素水平的恢复，使移植细胞在免疫缺陷糖尿病小鼠中 STZ 诱导的糖尿病中的存活时间大大延长。总之，这些数据表明，MafA 在将干细胞重编程为胰腺β 前体细胞中发挥新的作用，促进 PDMSCs 的胰岛样特征，并在功能上增强胰岛素的产生，以恢复移植移植物中血糖水平的调节。
