title: Differentiation of human adipose tissue-derived stem cells into aggregates of insulin-producing cells through the overexpression of pancreatic and duodenal homeobox gene-1.
abstract: The pancreatic and duodenal homeobox gene 1 (Pdx-1) plays a key role in normal pancreas development and is required for maintaining the normal function of islets. In this study, we examined whether human adipose tissue-derived stem cells (hASCs) could differentiate into insulin-producing cells by exogenously expressed Pdx-1. hASCs were infected with recombinant adenovirus encoding the mouse Pdx-1 gene and differentiated under high-glucose conditions. Insulin transcript levels and the expression of key transcription factors required for pancreatic development including FoxA2, Nkx2.2, and NeuroD were significantly increased by exogenous Pdx-1 overexpression. The expression of Nkx6.1 was found only in Pdx-1-induced hASCs. In addition to transcripts for transcription factors involved in pancreatic development, transcripts for the GLP-1 receptor, glucokinase, and glucose transporter, which are required for maintaining the function of pancreatic β-cells, were observed only in Pdx-1-induced hASCs. Pdx-1-induced hASCs exhibited insulin secretion in response to glucose challenge in vitro. When Pdx-1-induced hASCs were transplanted into streptozotocin (STZ)-induced diabetic mice, they reduced blood glucose levels, although they did not restore normoglycemia. These results demonstrate that the expression of exogenous Pdx-1 is sufficient to induce pancreatic differentiation in vitro but does not induce the fully functional, mature insulin-producing cells that are required for restoring normoglycemia in vivo.
authors.affiliation: Laboratory of Stem Cell Biology and Cell Therapy, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Lee
authors.forename: Song Cheol
authors.initials: SC
authors.lastname: Kim
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Heuiran
authors.initials: H
authors.lastname: Lee
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Jung
authors.forename: Seong Hee
authors.initials: SH
authors.lastname: Jung
authors.forename: Duck Jong
authors.initials: DJ
authors.lastname: Han
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000368:Aged; D000818:Animals; D002449:Cell Aggregation; D002454:Cell Differentiation; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000628:therapy; D005947:Glucose / Q000494:pharmacology; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009687:Nuclear Proteins; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors
chemical_list: D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D007328:Insulin; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose