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.
Chiou
Shih-Hwa
SH
Department & Institute of Pharmacology, Taipei Veterans General Hospital, Taipei, Taiwan. shchiou@vghtpe.gov.tw
Chen
Shih-Jen
SJ
Chang
Yuh-Lih
YL
Chen
Yu-Chih
YC
Li
Hsin-Yang
HY
Chen
Dow-Tien
DT
Wang
Hsin-Hui
HH
Chang
Chia-Ming
CM
Chen
Yi-Jen
YJ
Ku
Hung-Hai
HH
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000473:pathology / Q000601:surgery; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D010920:Placenta / Q000166:cytology; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation; D014157:Transcription Factors; D014162:Transfection; D014183:Transplantation, Heterologous
D001786:Blood Glucose; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C485159:MAFA protein, human; D051473:Maf Transcription Factors, Large; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins