Reversal of diabetes in rats using GLP-1-expressing adult pancreatic duct-like precursor cells transformed from acinar to ductal cells.
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.
Lee
Jieun
J
Department of Internal Medicine, Institute of Gastroenterology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 124-710, Korea.
Wen
Jing
J
Park
Jeong Youp
JY
Kim
Sun-A
SA
Lee
Eun Jig
EJ
Song
Si Young
SY
D000681:Amylases; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000628:therapy*; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000096:biosynthesis*; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006943:Hyperglycemia / Q000097:blood / Q000628:therapy; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation*; D007328:Insulin / Q000097:blood; D008297:Male; D046790:Pancreas, Exocrine / Q000166:cytology* / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation; D015534:Trans-Activators / Q000096:biosynthesis
D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D052216:Glucagon-Like Peptide 1; D019009:Proto-Oncogene Proteins c-kit; D000681:Amylases