MafA promotes the reprogramming of placenta-derived multipotent stem cells into pancreatic islets-like and insulin+ cells

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.

[1]  E. Oetjen,et al.  Inhibition of MafA transcriptional activity and human insulin gene transcription by interleukin-1β and mitogen-activated protein kinase kinase kinase in pancreatic islet beta cells , 2007, Diabetologia.

[2]  R. Stein,et al.  Islet-1 is Required for the Maturation, Proliferation, and Survival of the Endocrine Pancreas , 2009, Diabetes.

[3]  W. Holzgreve,et al.  Placental mesenchymal stem cells as potential autologous graft for pre- and perinatal neuroregeneration. , 2005, American journal of obstetrics and gynecology.

[4]  E. Montanya,et al.  Interleukin-1beta and inducible form of nitric oxide synthase expression in early syngeneic islet transplantation. , 2007, The Journal of endocrinology.

[5]  T. Pieler,et al.  Combined ectopic expression of Pdx1 and Ptf1a/p48 results in the stable conversion of posterior endoderm into endocrine and exocrine pancreatic tissue. , 2006, Genes & development.

[6]  Xuefeng Yu,et al.  Transcription factors involved in glucose-stimulated insulin secretion of pancreatic beta cells. , 2009, Biochemical and biophysical research communications.

[7]  C. Wright,et al.  The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors , 2002, Nature Genetics.

[8]  D. Accili,et al.  Regulation of pancreatic β‐cell function by the forkhead protein FoxO1 , 2007 .

[9]  H. Kaneto,et al.  Role of MafA in pancreatic beta-cells. , 2009, Advanced drug delivery reviews.

[10]  M. Yen,et al.  Isolation of Multipotent Cells from Human Term Placenta , 2005, Stem cells.

[11]  S. Mohr,et al.  Hyperglycemia-Induced Reactive Oxygen Species Toxicity to Endothelial Cells Is Dependent on Paracrine Mediators , 2008, Diabetes.

[12]  T. Ichisaka,et al.  Generation of germline-competent induced pluripotent stem cells , 2007, Nature.

[13]  N. Ilić,et al.  Manufacturing of human placenta‐derived mesenchymal stem cells for clinical trials , 2009, British journal of haematology.

[14]  S. Chiou,et al.  Placenta-derived multipotent stem cells induced to differentiate into insulin-positive cells. , 2007, Biochemical and biophysical research communications.

[15]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[16]  K. Kataoka,et al.  MAFA controls genes implicated in insulin biosynthesis and secretion , 2007, Diabetologia.

[17]  K. Le Blanc.  Immunomodulatory effects of fetal and adult mesenchymal stem cells. , 2003, Cytotherapy.

[18]  A. Shapiro,et al.  Successful islet transplantation: continued insulin reserve provides long-term glycemic control. , 2002, Diabetes.

[19]  P. Knoepfler.  Deconstructing Stem Cell Tumorigenicity: A Roadmap to Safe Regenerative Medicine , 2009, Stem cells.

[20]  B. Corkey,et al.  Fatty acid metabolism and insulin secretion in pancreatic beta cells , 2003, Diabetologia.

[21]  Jukka Partanen,et al.  Functional Network Reconstruction Reveals Somatic Stemness Genetic Maps and Dedifferentiation‐Like Transcriptome Reprogramming Induced by GATA2 , 2008, Stem cells.

[22]  Hideyuki Okano,et al.  Variation in the safety of induced pluripotent stem cell lines , 2009, Nature Biotechnology.

[23]  Douglas A. Melton,et al.  In vivo reprogramming of adult pancreatic exocrine cells to β-cells , 2008, Nature.

[24]  Yi-Wei Chen,et al.  Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. , 2009, Biochemical and biophysical research communications.

[25]  R. Robertson,et al.  Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. , 2003, Diabetes.

[26]  T. Matsuoka,et al.  The MafA transcription factor appears to be responsible for tissue-specific expression of insulin. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. D. Engel,et al.  MafA Is a Key Regulator of Glucose-Stimulated Insulin Secretion , 2005, Molecular and Cellular Biology.

[28]  E. Montanya,et al.  Adenoviral overproduction of interleukin-1 receptor antagonist increases beta cell replication and mass in syngeneically transplanted islets, and improves metabolic outcome , 2007, Diabetologia.

[29]  Hsin-Yang Li,et al.  Resveratrol promotes osteogenic differentiation and protects against dexamethasone damage in murine induced pluripotent stem cells. , 2010, Stem cells and development.

[30]  R. Robertson.  Islet transplantation as a treatment for diabetes - a work in progress. , 2004, The New England journal of medicine.

[31]  D. Accili,et al.  Regulation of pancreatic beta-cell function by the forkhead protein FoxO1. , 2007, Diabetes, obesity & metabolism.

[32]  T. Lai,et al.  In Vitro Differentiation of Human Placenta‐Derived Multipotent Cells into Hepatocyte‐Like Cells , 2006, Stem cells.

[33]  S. Bonner-Weir,et al.  A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. , 2006, Developmental biology.