Beta-cell differentiation from a human pancreatic cell line in vitro and in vivo.
Cell transplantation therapy for diabetes is limited by an inadequate supply of cells exhibiting glucose-responsive insulin secretion. To generate an unlimited supply of human beta-cells, inducibly transformed pancreatic beta-cell lines have been created by expression of dominant oncogenes. The cell lines grow indefinitely but lose differentiated function. Induction of beta-cell differentiation was achieved by stimulating the signaling pathways downstream of the transcription factor PDX-1, cell-cell contact, and the glucagon-like peptide (GLP-1) receptor. Synergistic activation of those pathways resulted in differentiation into functional beta-cells exhibiting glucose-responsive insulin secretion in vitro. Both oncogene-expressing and oncogene-deleted cells were transplanted into nude mice and found to exhibit glucose-responsive insulin secretion in vivo. The ability to grow unlimited quantities of human beta-cells is a major step toward developing a cell transplantation therapy for diabetes.
University of California San Diego Cancer Center La Jolla, California 92093-0912, USA.
D
D
de la Tour
T
T
Halvorsen
C
C
Demeterco
B
B
Tyrberg
P
P
Itkin-Ansari
M
M
Loy
S J
SJ
Yoo
E
E
Hao
S
S
Bossie
F
F
Levine
D051697:Activating Transcription Factor 1; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D017690:Cell Transplantation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins; D000067757:Glucagon-Like Peptide-1 Receptor; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D013004:Somatostatin / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D015854:Up-Regulation
D051697:Activating Transcription Factor 1; D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D002096:C-Peptide; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D000067757:Glucagon-Like Peptide-1 Receptor; D005941:Glucokinase; D018398:Homeodomain Proteins; D007328:Insulin; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D018027:Receptors, Glucagon; D012097:Repressor Proteins; D013004:Somatostatin; D015534:Trans-Activators; D014157:Transcription Factors; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C093970:NEUROD1 protein, human; C501008:Neurod1 protein, mouse; C000605730:PAX6 protein, human; C000605732:Pax6 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein