Research progress in inducing stem cells to differentiate toward the β-like cells of pancreatic islet

19 5 2007 10 Chinese Bulletin of Life Sciences Vol. 19, No. 5 Oct., 2007 1004-0374(2007)05-0526-05 β ( 510632) β 1 β Q813 R587.1 Research progress in inducing stem cells to differentiate toward the β-like cells of pancreatic islet JING Xudong, WANG Yuechun, ZHANG Huan* (Institute of Hematology, Medical College, Jinan University, Guangzhou 510632, China) Abstract: Cell replacement therapy is the only method that can cure Type 1 diabetes, but the critical shortage of available donor tissue impedes this therapeutics in clinic application. So the study of regulating differentiation of stem cells toward mature, functional islets cells becomes the hotspot recently. This article reviewed related advances in this field, and focused on the gene regulation of islet cell development and differentiation and also the actions of some bioactive molecules on the induction of stem cells to differentiate toward the β-like cells of pancreatic islet and their action mechanisms. Key words: stem cells; β-like cells of pancreatic islet; bioactive molecules; differentiation 1 (1) (2) β (3) 1 1.1 Shh TGF-β activin β-b ( β-b) FGF2 Shh Shh Pdx1 [1] Shh (Cyclopamine Shh ) Pdx1 2007-01-17 2007-04-26 (2005) (2005) (1970 ) (1948 ) * E-mail: tzyuan@jnu.edu.cn

5 β 527 [2] activin β-b FGF2 Cyclopamine Shh hlxb9 Isl-1 hnf3-β pdx1 Shh 1.2 HB9 Isl-1 Pdx1 ngn3 Pdx1 ngn3 Ngn3 [3] HNF1-α HNF3-β HNF6 ngn3 Hes-1 ngn3 [4] ngn3 bhlh Ngn3 Ngn3 ngn3 Ngn3 β α δ PP ngn3 TGF-β TGFβ BMP7 TGF-β notch TGF-β notch Shh Hes Shh Hes ngn3 (hlx-b9 Isl-1 hnf3- β ) 1.3 Ngn3 β2/neurod Ngn3 Nkx2.2 Nkx6.1 Pdx4 Pdx6 α β δ PP β2 Nkx2.2 α β PP Nkx2.2 β β Nkx2.2 β Nkx6.1 β Pdx4 β δ α [5] Pdx6 1 1 β 2 β 2.1 2.1.1 PI3K β ATP/ADP ATP K L Ca 2+ β β β e3 5 25% EGF [6] (25 5mmol/L) ESC

528 β ESC β β 2.1.2 β β MHC β IL1 β [7] IL12 TNFα ADP (PARP) PARP ( DNA ) ESC [8] DNA [9] 2.1.3 [10] 2.2 β [11] 2.3 Shh Cyclopamine Smoothened (Shh ) Shh Shh Shh FGF-2 β-b Pdx1 Pdx1 (e9.5 10d) e18d Pdx1 β β GLUT-2 Pdx1 MODY4 Shh Smoothened Conophylline Cyclopamine Shh Pdx1 [12] ESCs 2.4 (Activin) Activin, Activin A p38 ngn3 [13] α β δ PP Activin 2.5 Betacellulin (BTC) Betacellulin (EGF) erbb-1 erbb-4 β β Yamamoto [14] β β β Li [15] BTC β β β ICCs BTC BTC BTC Li [16] Pdx1 HepG 2 mrna 100 BTC BTC

5 β 529 Pax4 Pax4 / [17] Rescan [18] 1 nmol/ L BTC Ki67 (MEK) ( ERK) MEK/ ERK BTC 2.6 Ly294002 Wortmannin( ) Ly294002 Worfmannin PI3K PI3K 3 PKB β PI3K ATP PI3K Ly294002 Wortmannin PI3K mrna Ly294002 Wortmannin ESCs ESCs LIF PI3K ESCs PI3K ERK Ly294002 Wortmannin ESCs ERK [19] PI3K β ( ) [20] β Wnt GSK-3 [19] Papadopoulou Edlund [21] Wnt 2.7 GLP Exendin4 PKA Pdx1 PI3K PKA Pdx1 GLP β α (TGF-α) β (IGF) β [22] 2 2 3 Shh β -B FGF2 Cyclopamine Ly294002 Wortmannin PI3K ESCs ERK A ngn3 GLP Exendin4 Betacellulin β β

530 [1] Wilson M E, Scheel D, German M S. Gene expression cascades in pancreatic development. Mec Dev, 2003, 120: 65-80 [2] Jonsson J, Cartsson I, Ediund T, et al. Insulin-promotor factor 1 is required for pancreas development in mice. Nature, 1994, 371(6498): 606-609 [3] Apeiqvist A, Li H, Sommer L, et al. Notch signaling controls pancreatic cell differentiation. Nature,1999, 400(6747): 877-881 [4] Lee J C, Smith S B, Watada H, et al. Regulation of the pancreatic pro-endocrine gene neurogenin3. Diabetes, 2001, 50 (5): 928-936 [5] Sosa-Pineda B, Chowdhury K, Torres M, et al. The Pax4 gene is essential for differentiation of insulinproducing β cells in the mammalian pancreas. Nature,1997, 386(6623): 399-402 [6] Horie N, Moriya T, Mitome M, et al. Lowered glucose suppressed the proliferation and increased the differentiation of murine neural stem cells in vitro. FEBS Lett, 2004, 571: 237 [7] Kawasaki E, Abiru N, Eguchi K. Prevention of type 1 diabetes: from the view point of β cell damage. Diabetes Res Clin Pract, 2004, 66(Suppl. 1): S27-S32 [8] Miyazaki S, Yamato E, Miyazaki J I. Regulated expression of pdx-1 promotes in vitro differentiation of insulin-producing cells from embryonic stem cells. Diabetes, 2004, 53 (4): 1030-1037 [9] Leon-Quinto T, Jones J, Skoudy A, et al. In vitro directed differentiation of mouse embryonic stem cells into insulinproducing cells. Diabetologia, 2004, 47: 1442-1451 [10] Lefebvre P, Martin P J, Flajollet S, et al. Transcriptional activities of retinoic acid receptors. Vitam Horm, 2005, 70: 199-264 [11] Monneret C. Histone deacetylase inhibitors. Eur J Med Chem, 2005, 40: 1-13 [12] Ogata T, Li L, Yamada S, et al. Promotion of β-cell differentiation by conophylline in fetal and neonatal rat pancreas. Diabetes, 2004, 53: 2596-2602 [13] Kim S K, Hebrok M. Intercellular signals regulating pancreas development and function. Genes Dev, 2001, 15: 111-127 [14] Yamamoto K, Miyagawa J, Waguri M, et al. Recombinant human β-cellulin promotes the neogenesis of β-cells and ameliorates glucose intolerame in mice with diabetes induced by selective alloxan perfusion. Diabetes, 2000, 49(12): 2021-2027 [15] Li L, Yi Z H, Seno M, et al. Activin A and betacellulin: effect on regeneration of pancreatic β-cells in neonatal streptozotocintreated rats. Diabetes, 2004, 53 (3): 608-615 [16] Li W C, Horb M E, Tosh D, et al. In vitro transdifferentiation of hepatoma cells into functional pancreatic cells. Mech Dev, 2005, 122: 835-847 [17] Brun T, Franklin I, St-Onge L, et al. The diabetes-linked transcription factor PAX4 promotes {β}-cell proliferation and survival in rat and human islets. J Cell Biol, 2004, 20: 1123-1135 [18] Rescan C, Le Bras S, Lefebvre V H, et al. EGF-induced proliferation of adult human pancreatic duct cells is mediated by the MEK/ ERK cascade. Lab Invest, 2005, 85: 65-74 [19] Paling N R, Wheadon H, Bone H K, et al. Regulation of embryonic stem cell self-renewal by phosphoinositide 3- kinase-dependent signaling. J Biol Chem, 2004, 279: 48063-48070 [20] Craddock B L, Hobbs J, Edmead C E, et al. Phosphoinositide 3-kinase-dependent regulation of interleukin-3-induced proliferation: involvement of mitogen-activated protein kinases, SHP2 and Gab2. J Biol Chem, 2001, 276: 24274-24283 [21] Papadopoulou S, Edlund H. Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function. Diabetes, 2005, 54 (10): 2844-2851 [22] Zhang Y Q, Sarvetnick N. Development of cell markers for the identification and expansion of islet progenitor cells. Diabetes Metab Res Rev, 2003, 19: 363-374 2008,, 1974 1999 SCIE CA ISI, 2005 ( SCI )0.215 ISSN 1000-3282 CN 11-2161/Q, 2-816 ( 20 ), (210 mm 297 mm), 120 48.00 ( 576.00 ) 15 : 100101 (010)64888459; (010)64889892 E-mail prog@sun5.ibp.ac.cn http://www.pibb.ac.cn