Stem cell approaches for diabetes: Towards beta cell replacement

Genome Medicine

Volumn 3, Issue 9, 2011, Pages

  Weir, Gordon C ^a,b   Cavelti Weder, Claudia ^a,b   Bonner Weir, Susan ^a,b  

^a JOSLIN DIABETES CENTER   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

Author keywords

Beta cell; Embryonic stem cell; Islet; Islet regeneration

Indexed keywords

MICRORNA;

BIOGENESIS; CELL DESTRUCTION; CELL DIVISION; CELL LINE; CELL REGENERATION; CYTOLOGY; EMBRYONIC STEM CELL; ENDODERM; EPIGENETICS; FETUS DEVELOPMENT; GENOMICS; HEMATOPOIETIC STEM CELL; HYPERGLYCEMIA; IMMUNE SYSTEM; INSULIN DEPENDENT DIABETES MELLITUS; MESENCHYMAL STEM CELL; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS ISLET ALPHA CELL; PANCREAS ISLET BETA CELL; PANCREAS ISLET TRANSPLANTATION; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; REVIEW; STROMA CELL;

EID: 82155173429     PISSN: None     EISSN: 1756994X     Source Type: Journal    
DOI: 10.1186/gm277     Document Type: Review

References (78)

1. Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004. Clin Transplant 2005, 19:433-455. 10.1111/j.1399-0012.2005.00378.x, 16008587.
2. Alejandro R, Barton FB, Hering BJ, Wease S, . Collaborative Islet Transplant Registry I 2008 Update from the Collaborative Islet Transplant Registry. Transplantation 2008, 86:1783-1788. 10.1097/TP.0b013e3181913f6a, 19104422, Collaborative Islet Transplant Registry I.
3. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003, 52:102-110. 10.2337/diabetes.52.1.102, 12502499.
4. Nath DS, Gruessner AC, Kandaswamy R, Gruessner RW, Sutherland DE, Humar A. Outcomes of pancreas transplants for patients with type 2 diabetes mellitus. Clin Transplant 2005, 19:792-797. 10.1111/j.1399-0012.2005.00423.x, 16313327.
5. Nathan DM, Zinman B, Cleary PA, Backlund JY, Genuth S, Miller R, Orchard TJ. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group Modern-day clinical course of type 1 diabetes mellitus after 30 years' duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983-2005). Arch Intern Med 2009, 169:1307-1316. 2866072, 19636033, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group.
6. Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH. Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes 2008, 57:1759-1767. 10.2337/db08-0180, 2453631, 18586907.
7. Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R, Leibel RL, Melton DA. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci USA 2009, 106:15768-15773. 10.1073/pnas.0906894106, 2735559, 19720998.
8. Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 2010, 464:1293-1300. 10.1038/nature08933, 20432533.
9. Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, Yu L, Wegmann DR, Hutton JC, Elliott JF, Eisenbarth GS. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 2005, 435:220-223. 10.1038/nature03523, 1364531, 15889095.
10. Hakonarson H, Grant SF. GWAS and its impact on elucidating the etiology of diabetes. Diabetes Metab Res Rev 2011,
11. Weir GC, Marselli L, Marchetti P, Katsuta H, Jung MH, Bonner-Weir S. Towards better understanding of the contributions of overwork and glucotoxicity to the beta-cell inadequacy of type 2 diabetes. Diabetes Obes Metab 2009, 11(Suppl 4):82-90.
12. Meigs JB, Shrader P, Sullivan LM, McAteer JB, Fox CS, Dupuis J, Manning AK, Florez JC, Wilson PW, D'Agostino RB, Cupples LA. Genotype score in addition to common risk factors for prediction of type 2 diabetes. N Engl J Med 2008, 359:2208-2219. 10.1056/NEJMoa0804742, 2746946, 19020323.
13. Rubio-Cabezas O, Klupa T, Malecki MT, . CEED3 Consortium Permanent neonatal diabetes mellitus - the importance of diabetes differential diagnosis in neonates and infants. Eur J Clin Invest 2011, 41:323-333. 10.1111/j.1365-2362.2010.02409.x, 21054355, CEED3 Consortium.
14. Glaser B. Genetic analysis of complex disease - a roadmap to understanding or a colossal waste of money. Pediatr Endocrinol Rev 2010, 7:258-265.
15. Halban PA, German MS, Kahn SE, Weir GC. Current status of islet cell replacement and regeneration therapy. J Clin Endocrinol Metab 2010, 95:1034-1043. 10.1210/jc.2009-1819, 2841538, 20061422.
16. Pan FC, Wright C. Pancreas organogenesis: from bud to plexus to gland. Dev Dyn 2011, 240:530-565. 10.1002/dvdy.22584, 21337462.
17. Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 1994, 371:606-609. 10.1038/371606a0, 7935793.
18. Oliver-Krasinski JM, Kasner MT, Yang J, Crutchlow MF, Rustgi AK, Kaestner KH, Stoffers DA. The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in mice. J Clin Invest 2009, 119:1888-1898. 10.1172/JCI37028, 2701861, 19487809.
19. Smith SB, Qu HQ, Taleb N, Kishimoto NY, Scheel DW, Lu Y, Patch AM, Grabs R, Wang J, Lynn FC, Miyatsuka T, Mitchell J, Seerke R, Désir J, Eijnden SV, Abramowicz M, Kacet N, Weill J, Renard ME, Gentile M, Hansen I, Dewar K, Hattersley AT, Wang R, Wilson ME, Johnson JD, Polychronakos C, German MS. Rfx6 directs islet formation and insulin production in mice and humans. Nature 2010, 463:775-780. 10.1038/nature08748, 2896718, 20148032.
20. Nishimura W, Kondo T, Salameh T, El Khattabi I, Dodge R, Bonner-Weir S, Sharma A. A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. Dev Biol 2006, 293:526-539. 10.1016/j.ydbio.2006.02.028, 2390934, 16580660.
21. Mutskov V, Felsenfeld G. The human insulin gene is part of a large open chromatin domain specific for human islets. Proc Natl Acad Sci USA 2009, 106:17419-17424. 10.1073/pnas.0909288106, 2765094, 19805079.
22. Dhawan S, Georgia S, Tschen SI, Fan G, Bhushan A. Pancreatic beta cell identity is maintained by DNA methylation-mediated repression of Arx. Dev Cell 2011, 20:419-429. 10.1016/j.devcel.2011.03.012, 21497756.
23. Bhandare R, Schug J, Le Lay J, Fox A, Smirnova O, Liu C, Naji A, Kaestner KH. Genome-wide analysis of histone modifications in human pancreatic islets. Genome Res 2010, 20:428-433. 10.1101/gr.102038.109, 2847745, 20181961.
24. Fernandez-Valverde SL, Taft RJ, Mattick JS. MicroRNAs in beta-cell biology, insulin resistance, diabetes and its complications. Diabetes 2011, 60:1825-1831. 10.2337/db11-0171, 21709277.
25. Poy MN, Hausser J, Trajkovski M, Braun M, Collins S, Rorsman P, Zavolan M, Stoffel M. miR-375 maintains normal pancreatic alpha- and beta-cell mass. Proc Natl Acad Sci USA 2009, 106:5813-5818. 10.1073/pnas.0810550106, 2656556, 19289822.
26. Melkman-Zehavi T, Oren R, Kredo-Russo S, Shapira T, Mandelbaum AD, Rivkin N, Nir T, Lennox KA, Behlke MA, Dor Y, Hornstein E. miRNAs control insulin content in pancreatic beta-cells via downregulation of transcriptional repressors. EMBO J 2011, 30:835-845. 10.1038/emboj.2010.361, 21285947.
27. Weir GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes 2004, 53(Suppl 3):S16-21.
28. Scharp DW, Lacy PE, Santiago JV, McCullough CS, Weide LG, Bayle PJ, Falqui L, Marchetti P, Ricordi C, Gingerich RL. Results of our first nine intra portal islet allografts in type 1, insulin dependent diabetic patients. Transplantation 1991, 51:76-85. 10.1097/00007890-199101000-00012, 1987709.
29. King AJ, Fernandes JR, Hollister-Lock J, Nienaber CE, Bonner-Weir S, Weir GC. Normal relationship of beta- and non-beta-cells not needed for successful islet transplantation. Diabetes 2007, 56:2312-2318. 10.2337/db07-0191, 17563059.
30. Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, Young H, Richardson M, Smart NG, Cunningham J, Agulnick AD, D'Amour KA, Carpenter MK, Baetge EE. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 2008, 26:443-452. 10.1038/nbt1393, 18288110.
31. Lee SH, Hao E, Savinov AY, Geron I, Strongin AY, Itkin-Ansari P. Human beta-cell precursors mature into functional insulin-producing cells in an immunoisolation device: implications for diabetes cell therapies. Transplantation 2009, 87:983-991. 10.1097/TP.0b013e31819c86ea, 2715156, 19352116.
32. Borowiak M, Maehr R, Chen S, Chen AE, Tang W, Fox JL, Schreiber SL, Melton DA. Small molecules efficiently direct endodermal differentiation of mouse and human embryonic stem cells. Cell Stem Cell 2009, 4:348-358. 10.1016/j.stem.2009.01.014, 19341624.
33. Alipio Z, Liao W, Roemer EJ, Waner M, Fink LM, Ward DC, Ma Y. Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc Natl Acad Sci USA 2010, 107:13426-13431. 10.1073/pnas.1007884107, 2922145, 20616080.
34. Bock C, Kiskinis E, Verstappen G, Gu H, Boulting G, Smith ZD, Ziller M, Croft GF, Amoroso MW, Oakley DH, Gnirke A, Eggan K, Meissner A. Reference Maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 2011, 144:439-452. 10.1016/j.cell.2010.12.032, 21295703.
35. Pastor WA, Pape UJ, Huang Y, Henderson HR, Lister R, Ko M, McLoughlin EM, Brudno Y, Mahapatra S, Kapranov P, Tahiliani M, Daley GQ, Liu XS, Ecker JR, Milos PM, Agarwal S, Rao A. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 2011, 473:394-397. 10.1038/nature10102, 3124347, 21552279.
36. Li Z, Yang CS, Nakashima K, Rana TM. Small RNA-mediated regulation of iPS cell generation. EMBO J 2011, 30:823-834. 10.1038/emboj.2011.2, 3049216, 21285944.
37. Billings LK, Florez JC. The genetics of type 2 diabetes: what have we learned from GWAS?. Ann N Y Acad Sci 2010, 1212:59-77. 10.1111/j.1749-6632.2010.05838.x, 21091714.
38. Bonner-Weir S, Li WC, Ouziel-Yahalom L, Guo L, Weir GC, Sharma A. Beta-cell growth and regeneration: replication is only part of the story. Diabetes 2010, 59:2340-2348. 10.2337/db10-0084, 20876724.
39. Bruning JC, Winnay J, Bonner-Weir S, Taylor SI, Accili D, Kahn CR. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 1997, 88:561-572. 10.1016/S0092-8674(00)81896-6, 9038347, 9038347.
40. Nir T, Melton DA, Dor Y. Recovery from diabetes in mice by beta cell regeneration. J Clin Invest 2007, 117:2553-2561. 10.1172/JCI32959, 1957545, 17786244.
41. Porat S, Weinberg-Corem N, Tornovsky-Babaey S, Schyr-Ben-Haroush R, Hija A, Stolovich-Rain M, Dadon D, Granot Z, Ben-Hur V, White P, Girard CA, Karni R, Kaestner KH, Ashcroft FM, Magnuson MA, Saada A, Grimsby J, Glaser B, Dor Y. Control of pancreatic beta cell regeneration by glucose metabolism. Cell Metab 2011, 13:440-449. 10.1016/j.cmet.2011.02.012, 21459328.
42. Rankin MM, Kushner JA. Adaptive beta-cell proliferation is severely restricted with advanced age. Diabetes 2009, 58:1365-1372. 10.2337/db08-1198, 2682671, 19265026.
43. Meier JJ, Butler AE, Saisho Y, Monchamp T, Galasso R, Bhushan A, Rizza RA, Butler PC. Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes 2008, 57:1584-1594. 10.2337/db07-1369, 18334605.
44. In't Veld P, De Munck N, Van Belle K, Buelens N, Ling Z, Weets I, Haentjens P, Pipeleers-Marichal M, Gorus F, Pipeleers D. Beta-cell replication is increased in donor organs from young patients after prolonged life support. Diabetes 2010, 59:1702-1708. 10.2337/db09-1698, 2889770, 20413508.
45. Perl S, Kushner JA, Buchholz BA, Meeker AK, Stein GM, Hsieh M, Kirby M, Pechhold S, Liu EH, Harlan DM, Tisdale JF. Significant human beta-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating. J Clin Endocrinol Metab 2010, 95:E234-239. 10.1210/jc.2010-0932, 20660050.
46. Reers C, Erbel S, Esposito I, Schmied B, Buchler MW, Nawroth PP, Ritzel RA. Impaired islet turnover in human donor pancreata with aging. Eur J Endocrinol 2009, 160:185-191.
47. Nielsen JH. Growth and function of the pancreatic b cell in vitro: effects of glucose, hormones and serum factors on mouse, rat and human pancreatic iselts in organ culture. Acta Endocrinol(Kbh) 1985, 108(Suppl 266):1.
48. Fiaschi-Taesch N, Bigatel TA, Sicari B, Takane KK, Salim F, Velazquez-Garcia S, Harb G, Selk K, Cozar-Castellano I, Stewart AF. Survey of the human pancreatic beta-cell G1/S proteome reveals a potential therapeutic role for cdk-6 and cyclin D1 in enhancing human beta-cell replication and function in vivo. Diabetes 2009, 58:882-893. 10.2337/db08-0631, 2661601, 19136653.
49. Thorel F, Nepote V, Avril I, Kohno K, Desgraz R, Chera S, Herrera PL. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 2010, 464:1149-1154. 10.1038/nature08894, 2877635, 20364121.
50. Collombat P, Xu X, Ravassard P, Sosa-Pineda B, Dussaud S, Billestrup N, Madsen OD, Serup P, Heimberg H, Mansouri A. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell 2009, 138:449-462. 10.1016/j.cell.2009.05.035, 2792203, 19665969.
51. Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, Sharma A, O'Neil JJ. In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA 2000, 97:7999-8004. 10.1073/pnas.97.14.7999, 16659, 10884429.
52. Yatoh S, Dodge R, Akashi T, Omer A, Sharma A, Weir GC, Bonner-Weir S. Differentiation of affinity-purified human pancreatic duct cells to beta-cells. Diabetes 2007, 56:1802-1809. 10.2337/db06-1670, 17473224.
53. Inada A, Nienaber C, Katsuta H, Fujitani Y, Levine J, Morita R, Sharma A, Bonner-Weir S. Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci USA 2008, 105:19915-19919. 10.1073/pnas.0805803105, 2604974, 19052237.
54. Kopp JL, Dubois CL, Schaffer AE, Hao E, Shih HP, Seymour PA, Ma J, Sander M. Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development 2011, 138:653-665. 10.1242/dev.056499, 21266405.
55. Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, Hosokawa S, Elbahrawy A, Soeda T, Koizumi M, Masui T, Kawaguchi M, Takaori K, Doi R, Nishi E, Kakinoki R, Deng JM, Behringer RR, Nakamura T, Uemoto S. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 2011, 43:34-41. 10.1038/ng.722, 21113154.
56. Xu X, D'Hoker J, Stange G, Bonne 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. 10.1016/j.cell.2007.12.015, 18243096.
57. Solar M, Cardalda C, Houbracken I, Martin M, Maestro MA, De Medts N, Xu X, Grau V, Heimberg H, Bouwens L, Ferrer J. Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Dev Cell 2009, 17:849-860. 10.1016/j.devcel.2009.11.003, 20059954.
58. Criscimanna A, Speicher JA, Houshmand G, Shiota C, Prasadan K, Ji B, Logsdon CD, Gittes GK, Esni F. Duct cells contribute to regeneration of endocrine and acinar cells following pancreatic damage in adult mice. Gastroenterology
59. Nakamura K, Minami K, Tamura K, Iemoto K, Miki T, Seino S. Pancreatic beta-cells are generated by neogenesis from non-beta-cells after birth. Biomed Res 2011, 32:167-174. 10.2220/biomedres.32.167, 21551953.
60. Butler AE, Cao-Minh L, Galasso R, Rizza RA, Corradin A, Cobelli C, Butler PC. Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia 2010, 53:2167-2176. 10.1007/s00125-010-1809-6, 2931643, 20523966.
61. Smukler SR, Arntfield ME, Razavi R, Bikopoulos G, Karpowicz P, Seaberg R, Dai F, Lee S, Ahrens R, Fraser PE, Wheeler MB, van der Kooy D. The adult mouse and human pancreas contain rare multipotent stem cells that express insulin. Cell Stem Cell 2011, 8:281-293. 10.1016/j.stem.2011.01.015, 21362568.
62. Ratajczak MZ, Liu R, Ratajczak J, Kucia M, Shin DM. The role of pluripotent embryonic-like stem cells residing in adult tissues in regeneration and longevity. Differentiation 2011, 81:153-161. 10.1016/j.diff.2011.01.006, 21339038.
63. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002, 418:41-49. 10.1038/nature00870, 12077603.
64. De Coppi P, Bartsch G, Siddiqui MM, Xu T, Santos CC, Perin L, Mostoslavsky G, Serre AC, Snyder EY, Yoo JJ, Furth ME, Soker S, Atala A. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol 2007, 25:100-106. 10.1038/nbt1274, 17206138.
65. Akashi T, Shigematsu H, Hamamoto Y, Iwasaki H, Yatoh S, Bonner-Weir S, Akashi K, Weir GC. Bone marrow or foetal liver cells fail to induce islet regeneration in diabetic Akita mice. Diabetes Metab Res Rev 2008, 24:585-590. 10.1002/dmrr.884, 18727153.
66. Hamamoto Y, Akashi T, Inada A, Bonner-Weir S, Weir GC. Lack of evidence for recipient precursor cells replenishing beta-cells in transplanted islets. Cell Transplant 2010, 19:1563-1572. 10.3727/096368910X515881, 20719077.
67. Yechoor V, Liu V, Paul A, Lee J, Buras E, Ozer K, Samson S, Chan L. Gene therapy with neurogenin 3 and betacellulin reverses major metabolic problems in insulin-deficient diabetic mice. Endocrinology 2009, 150:4863-4873. 10.1210/en.2009-0527, 2775983, 19819964.
68. Aviv V, Meivar-Levy I, Rachmut IH, Rubinek T, Mor E, Ferber S. Exendin-4 promotes liver cell proliferation and enhances the PDX-1-induced liver to pancreas transdifferentiation process. J Biol Chem 2009, 284:33509-33520. 10.1074/jbc.M109.017608, 2785195, 19755420.
69. Nagaya M, Katsuta H, Kaneto H, Bonner-Weir S, Weir GC. Adult mouse intrahepatic biliary epithelial cells induced in vitro to become insulin-producing cells. J Endocrinol 2009, 201:37-47. 10.1677/JOE-08-0482, 19168505.
70. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 2008, 455:627-632. 10.1038/nature07314, 18754011.
71. Hess D, Li L, Martin M, Sakano S, Hill D, Strutt B, Thyssen S, Gray DA, Bhatia M. Bone marrow-derived stem cells initiate pancreatic regeneration. Nat Biotechnol 2003, 21:763-770. 10.1038/nbt841, 12819790.
72. Lee RH, Seo MJ, Reger RL, Spees JL, Pulin AA, Olson SD, Prockop DJ. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci USA 2006, 103:17438-17443. 10.1073/pnas.0608249103, 1634835, 17088535.
73. Jurewicz M, Yang S, Augello A, Godwin JG, Moore RF, Azzi J, Fiorina P, Atkinson M, Sayegh MH, Abdi R. Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes. Diabetes 2010, 59:3139-3147. 10.2337/db10-0542, 20841611.
74. Fiorina P, Jurewicz M, Vergani A, Petrelli A, Carvello M, D'Addio F, Godwin JG, Law K, Wu E, Tian Z, Thoma G, Kovarik J, La Rosa S, Capella C, Rodig S, Zerwes HG, Sayegh MH, Abdi R. Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via programmed death ligand 1. J Immunol 2011, 186:121-131. 10.4049/jimmunol.1000799, 21131428.
75. Couri CE, Oliveira MC, Stracieri AB, Moraes DA, Pieroni F, Barros GM, Madeira MI, Malmegrim KC, Foss-Freitas MC, Simões BP, Martinez EZ, Foss MC, Burt RK, Voltarelli JC. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2009, 301:1573-1579. 10.1001/jama.2009.470, 19366777.
76. Tseng YH, Cypess AM, Kahn CR. Cellular bioenergetics as a target for obesity therapy. Nat Rev Drug Discov 2010, 9:465-482. 10.1038/nrd3138, 2880836, 20514071.
77. ClinicalTrials.gov. , http://clinicaltrials.gov/
78. ISSCR (International Society for Stem Cell Research). , http://www.isscr.org/