Reversal of Diabetes in Rats Using GLP-1-Expressing Adult Pancreatic Duct-Like Precursor Cells Transformed From Acinar to Ductal Cells

Abstract

Pancreatic injury induces replacement of exocrine acinar cells with ductal cells. These ductal cells have the potential to regenerate the pancreas, but their origin still remains unknown. It has been reported that adult pancreatic acinar cells have the potential to transdifferentiate to ductal progenitor cells. In this regards, we established novel adult pancreatic duct-like progenitor cell lines YGIC4 and YGIC5 and assessed the usefulness of these ductal progenitors in the cell therapy of diabetic rats. Acinar cells were cultured from pancreata of male Sprague Dawley rats and gradually attained ductal cell characteristics, such as expression of CK19 and CFTR with a concomitant down-regulation of amylase expression over time, suggesting transdifferentiation from acinar to ductal cells. During cell culture, the expression of Pdx-1, c-Kit, and vimentin peaked and then decreased, suggesting that transdifferentiation recapitulated embryogenesis. Overexpression of pancreas development regulatory genes and CK19, as well as the ability to differentiate into insulin-producing cells, suggests that the YGIC5 cells had characteristics of pancreatic progenitor cells. Finally, YGIC5 cells coexpressing Green fluorescent protein (GFP) and glucagon-like peptide (GLP)-1 under the activation of a zinc-inducible metallothionein promoter were intravenously infused to STZ-induced diabetic rats. Hyperglycemia was ameliorated with elevation of plasma insulin, and GFP-positive donor cells were colocalized in the acinar and islet areas of recipient pancreata following zinc treatment. In conclusion, after establishing pancreatic progenitor cell lines YGIC4 and YGIC5 under the concept of acinar to ductal transdifferentiation in vitro, we demonstrate how these adult pancreatic stem/progenitor cells can be used to regulate adult pancreatic differentiation toward developing therapy for pancreatic disease such as diabetes mellitus.

Gastrointestinal hormones and the regulation of β‐cell mass

“…Two studies have challenged this model by transplanting duct‐rich cell populations into diabetic rodents. Intravenous treatment with GLP‐1 overexpressing primary duct cells of rats made diabetic with streptozotocin treatment restored glucose homeostasis via graft cell infiltration into the exocrine and endocrine pancreas 80 . Second, transplantation of low‐purity human islet preparations into streptozotocin‐induced diabetic NOD‐Scid mice (NOD mice without a competent immune system) improved glycemia, increased graft insulin content, and increased insulin‐positive graft cells during gastrin and GLP‐1 combination therapy 81 .…”

Roles of the co-culture of human umbilical cord Wharton’s jelly-derived mesenchymal stem cells with rat pancreatic cells in the treatment of rats with diabetes mellitus

“…Thus far, selecting appropriate methods to transplant stem cells is one study foci. In animal experiments, the common stem cell transplantation methods include orthotopic transplantation ( 12 ), renal subcapsular transplantation ( 13 ), subcutaneous transplantation ( 14 ), intravenous transplantation ( 15 ), transplantation in the portal vein ( 16 ) and transplantation in the testes ( 17 ). However, these methods will encounter a number of difficulties when applied in clinical practice.…”

Oct4 and Nanog Expression Is Associated With Early Stages of Pancreatic Carcinogenesis

“…5 Considering the presence of metaplastic ducts as a precancerous condition and the recapitulation of embryonic development, key players in embryonic development might therefore also be crucial to the process of carcinogenesis. 6 Oct4 and Nanog are transcription factors essential for maintaining stem cell phenotypes. Oct4 is a POU domainY containing transcription factor.…”