Dynamic expression of microRNAs during the differentiation of human embryonic stem cells into insulin-producing cells.
Human embryonic stem (hES) cells with the capacity of self-renewal and multilineage differentiation are promising sources for generation of pancreatic islet cells for cell replacement therapy in diabetes. Here we induced hES cells into insulin-producing cells (IPCs) in a stepwise process which recapitulated islet organogenesis by directing cells through the stages resembling definitive endoderm, gut-tube endoderm, pancreatic precursor and cells that expressed pancreatic endocrine hormones. The dynamic expression of microRNAs (miRNAs) during the differentiation was analyzed and was compared with that in the development of human pancreatic islets. We found that the dynamic expression patterns of miR-375 and miR-7 were similar to those seen in the development of human fetal pancreas, whereas the dynamic expression of miR-146a and miR-34a showed specific patterns during the differentiation. Furthermore, the expression of Hnf1β and Pax6, the predicted target genes of miR-375 and miR-7, was reciprocal to that of miR-375 and miR-7. Over-expression of miR-375 down-regulated the expression of gut-endoderm/pancreatic progenitor specific markers Hnf1β and Sox9. Therefore, the miRNAs may directly or indirectly regulate the expression of pancreatic islet organogenesis-specific transcription factors to control the differentiation and maturation of pancreatic islet cells.
Department of Endocrinology and Metabolism, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China.
Rui
R
Wei
Jin
J
Yang
Guo-Qiang
GQ
Liu
Mei-Juan
MJ
Gao
Wen-Fang
WF
Hou
Lin
L
Zhang
Hong-Wei
HW
Gao
Ye
Y
Liu
Gui-An
GA
Chen
Tian-Pei
TP
Hong
D002454:Cell Differentiation / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D051539:Hepatocyte Nuclear Factor 1-beta / Q000096:biosynthesis / Q000235:genetics; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000096:biosynthesis; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D055758:SOX9 Transcription Factor / Q000096:biosynthesis / Q000235:genetics
D005136:Eye Proteins; D051539:Hepatocyte Nuclear Factor 1-beta; D018398:Homeodomain Proteins; D007328:Insulin; D035683:MicroRNAs; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D055758:SOX9 Transcription Factor; C496495:HNF1B protein, human; C542542:MIRN146 microRNA, human; C522425:MIRN34 microRNA, human; C540933:MIRN375 microRNA, human; C549242:MIRN7-1 microRNA, human; C000605730:PAX6 protein, human; C527932:SOX9 protein, human