Induction of Pancreatic Stem/Progenitor Cells into Insulin-Producing Cells by Adenoviral-Mediated Gene Transfer Technology

Abstract

β-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 β-cells might originate from duct or duct-associated cells. Ductal progenitor cells in the pancreas would become particularly useful for therapies that target β-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.

Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

“…70,132 In combination with other factors, NeuroD1 can drive b-cell differentiation. 154,155 Additionally, the combination of NeuroD1, Pdx1 and MafA in non-b-cells induced insulin production. 156 Regulatory factor X 3 and 6 (Rfx3 and Rfx6) Rfx3 and Rfx6 are members of the regulatory factor X family of winged-helix transcription factors and are implicated in islet development.…”

Encapsulation technologies in beta cell replacement therapies for Type 1 diabetes

“…However, if these stem cell-derived insulin-producing cells are enclosed within protective, bioinert devices and implanted at appropriate sites, teratoma formation can be prevented and long-term maintenance of euglycemia can be achieved [190].…”

Differentiation of PDX1 gene-modified human umbilical cord mesenchymal stem cells into insulin-producing cells in vitro

“…Recent studies have demonstrated the feasibility of generating insulin-producing cells from stem cells and progenitor cells of various cellular sources (1)(2)(3)(4)(5)(6). Despite their promising potential, it has proven to be difficult to obtain enough autologous adult stem cells.…”