Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors.
During pancreas development, transcription factors play critical roles in exocrine and endocrine differentiation. Transcriptional regulation in eukaryotes occurs within chromatin and is influenced by posttranslational histone modifications (e.g., acetylation) involving histone deacetylases (HDACs). Here, we show that HDAC expression and activity are developmentally regulated in the embryonic rat pancreas. We discovered that pancreatic treatment with different HDAC inhibitors (HDACi) modified the timing and determination of pancreatic cell fate. HDACi modified the exocrine lineage via abolition and enhancement of acinar and ductal differentiation, respectively. Importantly, HDACi treatment promoted the NGN3 proendocrine lineage, leading to an increased pool of endocrine progenitors and modified endocrine subtype lineage choices. Interestingly, treatments with trichostatin A and sodium butyrate, two inhibitors of both class I and class II HDACs, enhanced the pool of beta cells. These results highlight the roles of HDACs at key points in exocrine and endocrine differentiation. They show the powerful use of HDACi to switch pancreatic cell determination and amplify specific cellular subtypes, with potential applications in cell replacement therapies in diabetes.
Haumaitre
Cécile
C
INSERM U845, Centre de Recherche Croissance et Signalisation, Université Paris Descartes, Faculté de Médecine, Hôpital Necker, Paris, France. cecile.haumaitre-sarron@inserm.fr
Lenoir
Olivia
O
Scharfmann
Raphaël
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010179:Pancreas / Q000166:cytology / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology*; D046790:Pancreas, Exocrine / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010183:Pancreatic Ducts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D050418:Pancreatic Polypeptide-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology
D051792:Basic Helix-Loop-Helix Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009419:Nerve Tissue Proteins; D014635:Valproic Acid; C498696:Neurog3 protein, rat; C012589:trichostatin A