18 1 2006 2 Chinese Bulletin of Life Sciences Vol. 18, No. 1 Feb., 2006 1004-0374(2006)01-0075-05 510632 1 2 Q813; R587.1 A Research progress of differentiation of stem cells into islet-like cells LU Yan, ZHANG Yuan* (Insititute of Hematology, Jinan University, Guangzhou 510632, China) Abstract: The morbidity rate of diabetes mellitus is increasing at present, which is a serious disease damaging human being s health. The transplantation of pancreatic islet cells has been used to treat the diabetes type 1 and 2. However, it is necessary to search new sources of insulin-secreting cells for cell therapy of diabetes mellitus due to lacking of sufficient donor cells. With the development of cell therapy and tissue engineering in recent years, the new way of new islet cells from stem cells has be found, which can provide new islets for curing of diabetes. The progress of differentiation from stem cells into islet-like cells, problems and prospect will be discussed in the review. Key words: stem cell; diabetes mellitus; cell therapy 1 (diabetes mellitus DM) WHO 1.7 2025 3 1 2 20 90 1995 8% 2000 Shapiro [1] (Edmonton) 7 1 6000 1 30 000 [2] 2005-07-18 2005-09-16 (2005) (1978 ) (1948 ) *
76 (embryonic stem cell, ESC) (adult stem cell, ASC) 2 2.1 [3] ES Lumelsky [4] ES α β 40 1/50 (islet amyloid polypeptide) 2(glucose transporter2, GLUT2) 12 (1~2 10 7 ) ES Assady [5] ES β ( GLUT2) 60%~70% (EBs) EBs 1%~3% Hori [6] LY294002( 3 ) LY294002 3 DNA (insulin-producing cell cluster, IPCC) 10% 13% Rajagopal [7] ES β β Soria [8] /βgeo pgk-hygro ES (IB/3x-99) 16.5ng/µg( /µg ) (10 6 ) 1 4 40 2.2 (transdifferentiation) [9] 2.2.1 Zhang [10] (islet-like cell cluters, ICCs) 16 nestin (hepatocyte grow factor, HGF) A β exendin4 (nicotinamide, NIC) 1.68 0.16 µiu/µg nestin CD44 CD90 CD147 CD34 CD38 CD45 CD71 CD117 CD133 HLA-DR Zalzman [11] Pdx-1 (pancreatic and duodenal homeobox 1) ITS 15
77 GLUT2 2.2.2 Ramiya [12] (NOD ) (islet-producing stem cell, IPCCs) ( 3 ) IPCCs NOD ( ADP- ) [13] β [14] NIC (epidermal growth factor, EGF) HGF 5 10 HGF HGF β β Bonner-Weir [15] (keratinocyte growth factor, KGF) Matrigel (cultured human islet buds, CHIB) Zulewski [16] nestin nestin (nestin-positive islet-derived progenitor cell, NIPs) NIPs CK-19 Pdx-1 HGF/activin A 2.5mM NIPs GLP-1 NIPs mrna 2.2.3 Yang [17] mrna PDX-1 β Ferber [18] Pdx-1 25 3 30%~60% PDX-1 0.1%~1% 600mg/dL 200mg/dL 2.2.4 Oh [19] 1% (DMSO) 3 10% (FBS) 7 mrna 186ng/mL 80% C 10 Oh [19] Tang [20] [21~22] [17] exendin4 mrna 10%~20% 10%~20% C INS-1 IPGT 60~90min Tang [20] (1) Pdx-1 insulin β 20mM β ES 5mM
78 β (2) β exendin4 [23] bfgf HGF LY294002 β 2.2.5 (umbilical cord blood, UCB) (UCB) 1 2 [24~25] Ende [24] 2 1 [25] 3 3.1 3.1.1 3.1.2 ( Matrigel ) β 3.1.3 β Soria [8] β 3.2 ES (ASC) ES ES ES β Newport Green [26] ASC ES β Dor [27] β β β ASC ASC ES ASC ASC (1) (2) (3) (4)
79 (1) ASC ASC; (2) (3) 3.3 1 β 3.4 [1] Shapiro A M, Lakey J R, Ryan E A, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med, 2000, 343(4): 230~238 [2] Watt F M, Hogan B L. Out of eden: stem cells and their niches. Science, 2000, 287(5457): 1427~1430 [3] Reubinoff B E, Pera M F, Fong C Y, et al. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol, 2000, 18 (4): 399~404 [4] Lumelsky N, Blondel O, Laeng P, et al. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science, 2001, 292(5520): 1389~1394 [5] Assady S, Maor G, Amit M, et al. Insulin production by human embryonic stem cells. Diabetes, 2001, 50(8): 1691~1697 [6] Hori Y, Rulifson I C, Tsai B C, et al. Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc Natl Acad Sci USA, 2002, 99(25): 16105~16110 [7] Rajagopal J, Anderson W J, Kume S, et al. Insulin staining of ES cell progeny from insulin uptake. Science, 2003, 299 (5605): 363 [8] Soria B, Roche E, Bema G, et al. Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes, 2000, 49 (2): 157~162 [9] Woodlbury D, Schwarz E J, Prockop D J, et al. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res, 2000, 61 (4): 364~370 [10] Zhang L, Hong T P, Hu J, et al. Nestin-positive progenitor cells isolated from human fetal pancreas have phenotypic markers identical to mesenchymal stem cells. World J Gastroenterol, 2005, 11(19): 2906~2911 [11] Zalzman M, Gupta S, Giri R K, et al. Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells. Proc Natl Acad Sci USA, 2003, 100 (12): 7253~7258 [12] Ramiya V K, Maraist M, Arfors K E, et al. Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat Med, 2000, 6 (3): 278~282 [13] Otonkoski T, Beattie G M, Mally M I, et al. Nicotinamide is a potent inducer of endocrine differentiation in cultured human fetal pancreatic cells. J Clin Invest, 1993, 92 (3): 1459~1466 [14] Ohgawara H, Kawamura M, Honda M, et al. Reversal of glucose insensitivity of pancreatic β-cells due to prolonged exposure to high glucose in culture: effect of nicotinamide on pancreatic β-cells. Tohoku J Exp Med, 1993, 169(2): 159~166 [15] Bonner-Weir S, Taneja M, Weir G C, et al. In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA, 2000, 97(14): 7999~8004 [16] Zulewski H, Abraham E J, Gerlach M J, et al. Multipotential nestin-positive stem cell isolated from adult pancreatic islet differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes, 2001, 50 (3): 521~533 [17] Yang L J, Li S W, Hatch H, et al. In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. Proc Natl Acad Sci USA, 2002, 99 (12): 8078~8083 [18] Ferber S, Halkin A, Cohen H, et al. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med, 2000, 6(5): 568~572 [19] Oh S H, Muzzonigro T M, Bae S H, et al. Adult bone marrow-derived cells transdifferentiating into insulin-producing cells for the treatment of type 1 diabetes. Lab Invest, 2004, 84: 607~617 [20] Tang D Q, Cao L Z, Burkhardt B R, et al. In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow. Diabetes, 2004, 53(7): 1721~1732 [21] Theise N D, Nimmakayalu M, Gardner K, et al. Liver from bone marrow in humans. Hepatology, 2000, 32 (1): 11~16 [22] Vassilopoulos G, Wang P R, Russell D W. Transplanted bone marrow regenerates liver by cell fusion. Nature, 2003, 422 (6934): 901~904 [23],,,.. 2003 5(5): 393~397 [24] Ende N, Chen R F, Reddi A S. Transplantation of human umbilical cord blood cells improves glycemia and glomerular hypertrophy in type 2 diabetic mice. Biochem Biophys Res Commun, 2004, 321(1): 168~171 [25] Ende N, Chen R F, Reddi A S. Effect of human umbilical cord blood cells on glycemia and insulitis in type 1 diabetic mice. Biochem Biophys Res Commun, 2004, 325(3): 665~669 [26] Lukowiak B, Vandewalle B, Riachy R, et al. Identification and purification of functional human β-cells by a new specific zinc-fluorescent probe. J Histochem Cytochem, 2001, 49(4): 519~528 [27] Dor Y, Brown J, Martinez O I, et al. Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation. Nature, 2004, 429 (6987): 41~46