Transforming growth factor (TGF)beta, fibroblast growth factor (FGF) and retinoid signalling pathways promote pancreatic exocrine gene expression in mouse embryonic stem cells.
Extracellular signalling cues play a major role in the activation of differentiation programmes. Mouse embryonic stem (ES) cells are pluripotent and can differentiate into a wide variety of specialized cells. Recently, protocols designed to induce endocrine pancreatic differentiation in vitro have been designed but little information is currently available concerning the potential of ES cells to differentiate into acinar pancreatic cells. By using conditioned media of cultured foetal pancreatic rudiments, we demonstrate that ES cells can respond in vitro to signalling pathways involved in exocrine development and differentiation. In particular, modulation of the hedgehog, transforming growth factor beta, retinoid, and fibroblast growth factor pathways in ES cell-derived embryoid bodies (EB) resulted in increased levels of transcripts encoding pancreatic transcription factors and cytodifferentiation markers, as demonstrated by RT-PCR. In EB undergoing spontaneous differentiation, expression of the majority of the acinar genes (i.e. amylase, carboxypeptidase A and elastase) was induced after the expression of endocrine genes, as occurs in vivo during development. These data indicate that ES cells can undergo exocrine pancreatic differentiation with a kinetic pattern of expression reminiscent of pancreas development in vivo and that ES cells can be coaxed to express an acinar phenotype by activation of signalling pathways known to play a role in pancreatic development and differentiation.
Skoudy
Anouchka
A
Unitat de Biologia Cel.lular i Molecular, Institut Municipal d'Investigació Mèdica, 08003 Barcelona, Spain. askoudy@imim.es
Rovira
Meritxell
M
Savatier
Pierre
P
Martin
Franz
F
León-Quinto
Trinidad
T
Soria
Bernat
B
Real
Francisco X
FX
D028341:Activins / Q000494:pharmacology; D000681:Amylases / Q000235:genetics; D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018398:Homeodomain Proteins; D028322:Inhibin-beta Subunits / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D014704:Veratrum Alkaloids / Q000494:pharmacology
D015415:Biomarkers; D017077:Culture Media, Conditioned; C496454:Fgf7 protein, mouse; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D012176:Retinoids; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014704:Veratrum Alkaloids; C422405:activin A; C084010:pancreatic and duodenal homeobox 1 protein; D028341:Activins; D051523:Fibroblast Growth Factor 7; D014212:Tretinoin; D005346:Fibroblast Growth Factors; D028322:Inhibin-beta Subunits; D000681:Amylases; C000541:cyclopamine