title: Thyroid hormones promote endocrine differentiation at expenses of exocrine tissue.
abstract: Diabetes is caused by loss or dysfunction of pancreatic beta cells. Generation of beta cells in vitro is a promising strategy to develop a full-scale cell therapy against diabetes, and the development of methods without gene transfer may provide safer protocols for human therapy. Here we show that thyroid hormone receptors are expressed in embryonic murine pancreas. Addition of the thyroid hormone T3 in an ex vivo culture model of embryonic (E12.5) dorsal pancreas, mimicking embryonic pancreatic development, promoted an increase of ductal cell number at expenses of the acinar compartment. Double labeled cells expressing specific markers for ductal and acinar cells were observed, suggesting cell reprogramming. Increased mRNA levels of the pro-endocrine gene Ngn3 and an increased number of beta cells were detected in cultures treated previously with T3 suggesting that ductal cells promoted by T3 can subsequently differentiate into endocrine cells. So, indirectly, T3 induced endocrine differentiation. Moreover, T3 induced the expression of the pro-endocrine gene Ngn3 in the acinar 266-6 cell line. The pro-endocrine effect of T3 in the pancreatic explants and in the acinar cell line, was abrogated by the Akt inhibitor Ly294002 indicating the involvement of Akt signaling in this process. Altogether we show numerous evidences that define T3 as a promising candidate to generate endocrine cells from exocrine tissue, using ectopically gene expression free protocols, for cell therapy against diabetes.
authors: Inserm U845, Research Center Growth and Signaling, Faculté de Médecine, Université Paris Descartes, Sorbone Paris Cité, Necker Hospital, Paris, France.
authors: Virginie
authors: V
authors: Aïello
authors: Diabetes and Obesity Research Laboratory, Institut d׳Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors: Alba
authors: A
authors: Moreno-Asso
authors: Diabetes and Obesity Research Laboratory, Institut d׳Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors: Joan-Marc
authors: JM
authors: Servitja
authors: Inserm U845, Research Center Growth and Signaling, Faculté de Médecine, Université Paris Descartes, Sorbone Paris Cité, Necker Hospital, Paris, France; Diabetes and Obesity Research Laboratory, Institut d׳Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Electronic address: merce.martin.p@gmail.com.
authors: Mercè
authors: M
authors: Martín
mesh_terms: D061354:Acinar Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007124:Immunoenzyme Techniques; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009924:Organ Culture Techniques; D010179:Pancreas / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014284:Triiodothyronine / Q000494:pharmacology*
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt signaling pathway; Beta cell; Cell differentiation; Cell reprogramming; Diabetes; Pancreas; Thyroid hormone