Neurogenin 3 Expressing Cells in the Human Exocrine Pancreas Have the Capacity for Endocrine Cell Fate.
Neurogenin 3 (NGN3) is necessary and sufficient for endocrine differentiation during pancreatic development and is expressed by a population of progenitor cells that give rise exclusively to hormone-secreting cells within islets. NGN3 protein can be detected in the adult rodent pancreas only following certain types of injury, when it is transiently expressed by exocrine cells undergoing reprogramming to an endocrine cell fate. Here, NGN3 protein can be detected in 2% of acinar and duct cells in living biopsies of histologically normal adult human pancreata and 10% in cadaveric biopsies of organ donor pancreata. The percentage and total number of NGN3+ cells increase during culture without evidence of proliferation or selective cell death. Isolation of highly purified and viable NGN3+ cell populations can be achieved based on coexpression of the cell surface glycoprotein CD133. Transcriptome and targeted expression analyses of isolated CD133+ / NGN3+ cells indicate that they are distinct from surrounding exocrine tissue with respect to expression phenotype and Notch signaling activity, but retain high level mRNA expression of genes indicative of acinar and duct cell function. NGN3+ cells have an mRNA expression profile that resembles that of mouse early endocrine progenitor cells. During in vitro differentiation, NGN3+ cells express genes in a pattern characteristic of endocrine development and result in cells that resemble beta cells on the basis of coexpression of insulin C-peptide, chromogranin A and pancreatic and duodenal homeobox 1. NGN3 expression in the adult human exocrine pancreas marks a dedifferentiating cell population with the capacity to take on an endocrine cell fate. These cells represent a potential source for the treatment of diabetes either through ex vivo manipulation, or in vivo by targeting mechanisms controlling their population size and endocrine cell fate commitment.
Children's Research Institute, Department of Pediatrics, University of South Florida Morsani College of Medicine, St. Petersburg, FL, United States of America.
Danielle L
DL
Gomez
Children's Research Institute, Department of Pediatrics, University of South Florida Morsani College of Medicine, St. Petersburg, FL, United States of America.
Marci
M
O'Driscoll
Department of Gynecology and Obstetrics, John Hopkins University, Baltimore, MD, United States of America.
Timothy P
TP
Sheets
Departments of Pathology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
Ralph H
RH
Hruban
Department of Surgery, University of Illinois at Chicago, Chicago, IL, United States of America; Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, United States of America.
Jose
J
Oberholzer
Department of Surgery, University of Illinois at Chicago, Chicago, IL, United States of America.
James J
JJ
McGarrigle
Children's Research Institute, Department of Pediatrics, University of South Florida Morsani College of Medicine, St. Petersburg, FL, United States of America; Department of Gynecology and Obstetrics, John Hopkins University, Baltimore, MD, United States of America.
Michael J
MJ
Shamblott
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D002096:C-Peptide / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D055098:Endocrine Cells / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D046790:Pancreas, Exocrine / Q000378:metabolism*; D010455:Peptides / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics
D000071916:AC133 Antigen; D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D002096:C-Peptide; D006023:Glycoproteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D010455:Peptides; D012333:RNA, Messenger; D051880:Receptors, Notch; C498695:NEUROG3 protein, human; C000606023:PROM1 protein, human; C000606024:Prom1 protein, mouse