Induction of pancreatic stem/progenitor cells into insulin-producing cells by adenoviral-mediated gene transfer technology.
beta-Cell replacement therapy via islet transplantation is a promising possibility for the optimal treatment of type 1 diabetes; however, such an approach is severely limited by the shortage of donor organs. This problem could be overcome if it were possible to generate transplantable islets from stem cells. We showed previously that adult beta-cells might originate from duct or duct-associated cells. Ductal progenitor cells in the pancreas would become particularly useful for therapies that target beta-cell replacement in diabetic patients, because duct cell types are abundantly available in the pancreas of these patients and in donor organs. In this study, we examined which embryonic transcription factors in adult mouse and human duct cells could efficiently induce their differentiation into insulin-expressing cells. Infection with the adenovirus expressing PDX-1, Ngn3, NeuroD, or Pax4 induced the insulin gene expression. NeuroD was the most effective inducer of insulin expression in primary duct cells. Surprisingly, adenovirus Pax4 strongly induced Ngn3 expression, while Pax4 is considered the downstream target of Ngn3. These data suggest that the overexpression of transcription factors, especially NeuroD, facilitates pancreatic stem/progenitor cell differentiation into insulin-producing cells.
Noguchi
Hirofumi
H
Diabetes Research Institute Japan, Toyoake, Aichi 470-1192, Japan. noguchih@med.nagoya-u.ac.jp
Xu
Gang
G
Matsumoto
Shinichi
S
Kaneto
Hideaki
H
Kobayashi
Naoya
N
Bonner-Weir
Susan
S
Hayashi
Shuji
S
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014162:Transfection / Q000379:methods
D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein