Differentiation of Human Adipose Tissue-Derived Stem Cells into Aggregates of Insulin-Producing Cells through the Overexpression of Pancreatic and Duodenal Homeobox Gene-1

• Published in: Cell transplantation Vol. 22; no. 6; pp. 1053 - 1060
• Main Authors: Lee, Jiyeon, Kim, Song Cheol, Kim, Sung Jin, Lee, Heuiran, Jung, Eun Jung, Jung, Seong Hee, Han, Duck Jong
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.01.2013; SAGE Publishing
• Subjects: Adipose Tissue - cytology; Aged; Animals; Cell Aggregation; Cell Differentiation; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - therapy; Glucose - pharmacology; Homeodomain Proteins - genetics; Humans; Immunohistochemistry; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Male; Mice; Middle Aged; Stem Cell Transplantation; Stem Cells - cytology; Trans-Activators - genetics; Differentiation; Insulin-producing cells; Pancreatic and duodenal homeobox gene (Pdx-1); Human adipose tissue-derived stem cells (hASCs)
• ISSN: 0963-6897; 1555-3892
• DOI: 10.3727/096368912X657215

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.