9 ans d’intéractions avec l’AFD: Ou en est on?

1. 9 ans d’intéractions avec l’AFD: Ou en est on? Raphael Scharfmann Directeur de Recherche INSERM Faculté Necker, Paris

2. DIABETES: Diminution de la masse fonctionnelle de cellules bêta (cellules qui produisent l’insuline)

3. Guillaume Charpentier

4. DIABETES: Diminution de la masse fonctionnelle de cellules bêta (cellules qui produisent l’insuline) ETAT DES LIEUX: On sait SOIGNER, mais on ne sait pas GUERIR les patients diabétiques. OBJECTIF en 1999: Définir les bases de nouvelles approches thérapeutiques des diabètes (augmenter la masse de cellules bêta fonctionnelles) - Thérapie cellulaire - Approches régénératives

5. STRATEGIE en 1999 Embryonic stem cells ES Mesoderm Endoderm Ectoderm Lung precursors Pancreatic precursors Thyroid precursors Endocrine Acinar Ducts Glucagon Insulin

6. Embryonic stem cells ES Mesoderm Endoderm Ectoderm Lung precursors Pancreatic precursors Thyroid precursors Endocrine Acinar Ducts Glucagon Insulin -1- Il faut comprendre -2- Il faut appliquer

7. -1- Il faut comprendre -2- Il faut appliquer Durant ces années: - Nous avons beaucoup compris

8. -1- Castaing, M, Peault, B, Basmaciogullari, A, Casal, I, Czernichow, P, Scharfmann, R. Blood glucose normalization upon transplantation of human embryonic pancreas into beta cell deficient SCID mice. Diabetologia 2001, 44: 2066- -2- Elghazi, L, Cras-Méneur, C, Czernichow, P, Scharfmann, R. Role for FGFR2IIIb-mediated signals in controlling pancreatic endocrine progenitor cell proliferation. Proc Natl Acad Sci USA 2002, 99: 3884- -3- Cras-Méneur, C, Scharfmann, R. FGFR1-IIIb is a putative marker of pancreatic progenitor cells. Mech Dev 2002, 116: 205-208. -4- Assouline B, Nguyen V, Mahé S, Bourrat F, Scharfmann R. Development of the pancreas in medaka. Mech Dev 2002, 117: 299- -5- Scharfmann R. Alternative sources of beta cells for cell therapy of diabetes. Eur J. Clin Invest 2003, 33:595-600 -6- Duvillie B, Attali M, Aiello V, Quemeneur E, Scharfmann R. Label-Retaining Cells in the Rat Pancreas: Location and Differentiation Potential In Vitro. Diabetes 2003, 52: 2035- -7- Ye F, Duvillie B, Scharfmann R. Fibroblast growth factors 7 and 10 are expressed in the human embryonic pancreatic mesenchyme and promote the proliferation of embryonic pancreatic epithelial cells. Diabetologia. 2005, 48:277- -8- Castaing M, Guerci A, Mallet J, Czernichow P, Ravassard P, Scharfmann R. Efficient restricted gene expression in beta cells by lentivirus-mediated gene transfer into pancreatic stem/progenitor cells. Diabetologia. 2005, 48:709 -9- Castaing M, Duvillie B, Quemeneur E, Basmaciogullari A, Scharfmann R. Ex vivo analysis of acinar and endocrine cell development in the human embryonic pancreas. Dev Dyn. 2005, 234:339-345 -10- Duvillié B, Attali M, Bounacer A, Ravassard P, Bamaciogullari A, Scharfmann R. The Mesenchyme Controls the Timing of Pancreatic Beta Cell Differentiation. Diabetes, 2006, 55:582- Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006, 355:456- -11- Cauchi S, Meyre D, Dina C, Choquet H, Samson C, Gallina S, Balkau B, Charpentier G, Pattou F, Stetsyuk V, Scharfmann R, Staels B, Fruhbeck G, Froguel P. Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes. Diabetes. 2006, 55:2903-.

9. -12- Zertal-Zidani S, Bounacer A, Scharfmann R. Regulation of pancreas development by sulphated proteoglycans. Diabetologia. 2007, 50:585-595. -13- Attali M, Stetsyuk V, Basmaciogullari A, Aiello V, Zanta-Boussif MA, Duvillie B, Scharfmann R. Control of Beta-Cell Differentiation by the Pancreatic Mesenchyme. Diabetes 2007, 56:1248-1258 -14- Stetsyuk V, Peers B, Mavropoulos A, Verbruggen V. Thisse B, Thisse C, Motte P, Duvillié B, Scharfmann R. Calsenilin is Required for Endocrine Pancreas Development in Zebrafish. Dev Dyn 2007236:1517-1525 -15- Guillemain G, Filhoulaud G, Da Silva-Xavier G, Rutter GA, Scharfmann R Glucose is necessary for embryonic pancreatic endocrine cell differentiation J Biol Chem 2007, 282:15228-37 -16- Vaxillaire M, Dechaume A, Busiah K, Cavé H, Pereira S, Scharfmann R, Perez de Nanclares G, Castano L, Froguel P, Polak M, and the SUR1-NDM Study Group New ABCC8 mutations in Relapsing Neonatal Diabetes and Clinical Features. Diabetes, 2007, 56 :1737-1741 -17- Baroukh N, Ravier MA, Loder MK, Hill EV, Bounacer A, Scharfmann R, Rutter GA, Van Obberghen E. MicroRNA-124a regulates Foxa2 expression and intracellular signaling in pancreatic beta-cells lines. J Biol Chem. 2007, 282:19575-88 -18- Flechtner I, Vaxillaire M, Cave H, Scharfmann R, Froguel P, Polak M. Diabetes in very young children and mutations in the insulin-secreting cell potassium channel genes: therapeutic consequences. Endocr Dev. 2007;12:86-98. -19- Scharfmann R. Pancreatic development as a basis for the definition of new therapies for diabetes. Endocr Dev. 2007;12:1-11. -20- Xu X, D'Hoker J, Stangé G, Bonné S, De Leu N, Xiao X, Van De Casteele M, Mellitzer G, Ling Z, Pipeleers D, Bouwens L, Scharfmann R, Gradwohl G, Heimberg H. Beta Cells Can Be Generated from Endogenous Progenitors in Injured Adult Mouse Pancreas. Cell. 2008;132:197-207. -21- Polak M, Dechaume A, Cavé H, Nimri R, Crosnier H, Sulmont V, de Kerdanet M, Scharfmann R, Lebenthal Y, Froguel P, Vaxillaire M. Heterozygous Missense Mutations in the Insulin Gene are linked to Permanent Diabetes appearing in the Neonatal Period or in Early-Infancy: A report from the French ND Study Group. Diabetes. 2008;57:1115-1119 -22- Flechtner I, Vaxillaire M, Cavé H, Scharfmann R, Froguel P, Polak M. Neonatal hyperglycaemia and abnormal development of the pancreas. Best Pract Res Clin Endocrinol Metab. 2008;22:17-40. -23- Scharfmann R. Expanding human beta cells. Diabetologia. 2008;51:692-693. -24- Duvillié B, Stetsyuk V, Filhoulaud G, Guillemain G, Scharfmann R. Control of pancreatic development by intercellular signals. Biochem Soc Trans. 2008;36:276-9.

10. -25- Haumaitre C, Lenoir O, Scharfmann R. Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Mol Cell Biol. 2008;28:6373-6383. -26- Scharfmann R, Xiao X, Heimberg H, Mallet J, Ravassard P. Beta cells within single human islets originate from multiple progenitors. Plos One. 2008; (in press). -27- Fontaniere S, Duvillie B, Scharfmann R, Carreira C, Wang ZQ, Zhang C.Tumour suppressor MENIN is essential for development ofthe pancreatic endocrine cells. J Endocrinol. 2008; (in press) -28- Scharfmann R, Duvillie B, Stetsyuk V, Attali M, Filhoulaud G, Guillemain G. Beta-cell development: the role of intercellular signals. Diabetes Obes Metab. 2008; Suppl 4:195-200.

11. Embryonic stem cells ES Mesoderm Endoderm Ectoderm Lung precursors Pancreatic precursors Thyroid precursors Endocrine Acinar Ducts Glucagon Insulin -1- Il faut comprendre -2- Il faut appliquer

12. Guillaume Charpentier Entrée dans des consortiums europeens à objectifs thérapeutiques MERCI A L’AFD