beta-cell transplantation in diabetes mellitus
https://doi.org/10.14341/2072-0351-812
Abstract
Patients with diabetes mellitus suffer either from destruction of pancreatic beta-cells or progressive deterioration of their function. Thus, transplantation of an intact beta-cell population fully capable of insulin secretion is the only means to cure this disease. Despite glycemic benefits and decrease in risks for late complications, islet transplantation or complete pancreatic grafting in humans remains a challenge due to necessity of lifetime immunosuppression and increasingly sparse donor resources. Current paper presents a review of modern endeavours to obtain a limitless source for glucose-sensitive insulin secreting cells. We discuss, in particular, complex aspects of beta-cell proliferation and/or neogenesis in vivo, issues with xenogenous pancreatic islets, and latest advances in controlled differentiation of embryonic and induced polypotent stem cells ? the most promising and relevant source of beta-cells.
About the Authors
S Pellegrini
Diabetes Research Institue, Ospidale San Raffaele, Milano; Universita degli Studi dell'Insubria, Varese, Italy
Italy
Italy
V Sordi
Diabetes Research Institue, Ospidale San Raffaele, Milano, Italy
Italy
Italy
L Piemonti
Diabetes Research Institue, Ospidale San Raffaele, Milano, Italy
Italy
Italy
References
1. Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes research and clinical practice. 2011; 94(3):311-321. doi: 10.1016/j.diabres.2011.10.029
2. Stanekzai J, Isenovic ER, Mousa SA. Treatment options for diabetes: Potential role of stem cells. Diabetes Research and Clinical Practice. 2012;98(3):361-368. DOI:http://dx.doi.org/10.1016/j.diabres.2012.09.010
3. Van Belle TL, Coppieters KT, Von Herrath MG. Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies. Physiological Reviews. 2011;91(1):79-118. DOI: http://dx.doi.org/10.1152/physrev.00003.2010
4. Saudek CD, Duckworth WC, Giobbie-Hurder A, Henderson WG, Henry RR, Kelley DE, Implantable insulin pump vs multiple-dose insulin for non-insulin-dependent diabetes mellitus: a randomized clinical trial. Department of Veterans Affairs Implantable Insulin Pump Study Group. JAMA: the journal of the American Medical Association. 1996; 276(16):1322-1327. DOI: 10.1001/jama.1996.03540160044031
5. Ichii H, Ricordi C. Current status of islet cell transplantation. Journal of Hepato-Biliary-Pancreatic Surgery. 2009;16(2):101-112. DOI: http://dx.doi.org/10.1007/s00534-008-0021-2
6. Venturini M, Angeli E, Maffi P, Fiorina P, Bertuzzi F, Salvioni M, et al. Technique, Complications, and Therapeutic Efficacy of Percutaneous Transplantation of Human Pancreatic Islet Cells in Type 1 Diabetes: The Role of US1. Radiology. 2005;234(2):617-624. DOI: 10.1148/radiol.2342031356
7. Barton FB, Rickels MR, Alejandro R, Hering BJ, Wease S, Naziruddin B, et al. Improvement in Outcomes of Clinical Islet Transplantation: 1999–2010. Diabetes Care. 2012;35(7):1436-1445. DOI: 10.2337/dc12-0063
8. Shapiro AMJ. State of the Art of Clinical Islet Transplantation and Novel Protocols of Immunosuppression. Current Diabetes Reports. 2011;11(5):345-354. DOI: 10.1007/s11892-011-0217-8
9. Bertuzzi F, Verzaro R, Provenzano V, Ricordi C. Brittle type 1 diabetes mellitus. Current medicinal chemistry. 2007;14(16):1739-1744. DOI: 10.2174/092986707781058922.
10. Teta M, Long SY, Wartschow LM, Rankin MM, Kushner JA. Very Slow Turnover of β-Cells in Aged Adult Mice. Diabetes. 2005;54(9):2557-2567. DOI: 10.2337/diabetes.54.9.2557
11. Butler PC, Meier JJ, Butler AE, Bhushan A. The replication of [beta] cells in normal physiology, in disease and for therapy. Nature clinical practice Endocrinology End metabolism. 2007;3(11):758-768. DOI: 10.1038/ncpendmet0647
12. Lipsett M, Aikin R, Castellarin M, Hanley S, Jamal A-M, Laganiere S, et al. Islet neogenesis: A potential therapeutic tool in type 1 diabetes. The International Journal of Biochemistry & Cell Biology. 2006;38(4):498-503. DOI: 10.1016/j.biocel.2005.08.022
13. Meier JJ, Butler AE, Saisho Y, Monchamp T, Galasso R, Bhushan A, et al. β-Cell Replication Is the Primary Mechanism Subserving the Postnatal Expansion of β-Cell Mass in Humans. Diabetes. 2008;57(6):1584-1594.
14. Parsons JA, Bartke A, Sorenson RL. Number and size of islets of Langerhans in pregnant, human growth hormone-expressing transgenic, and pituitary dwarf mice: effect of lactogenic hormones. Endocrinology. 1995;136(5):2013-2021.
15. Gupta RK, Gao N, Gorski RK, White P, Hardy OT, Rafiq K, et al. Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha. Genes and Development. 2007;21(7):756-769. DOI: 10.1101/gad.1535507
16. Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Evidence of increased islet cell proliferation in patients with recent-onset type 1 diabetes. Diabetologia. 2010;53(9):2020-2028. DOI: 10.1007/s00125-010-1817-6
17. Pipeleers D, Ling Z. Pancreatic beta cells in insulin-dependent diabetes. Diabetes/Metabolism Reviews. 1992;8(3):209-227. DOI: 10.1002/dmr.5610080303
18. Keenan HA, Sun JK, Levine J, Doria A, Aiello LP, Eisenbarth G, et al. Residual Insulin Production and Pancreatic β-Cell Turnover After 50 Years of Diabetes: Joslin Medalist Study. Diabetes. 2010;59(11):2846-2853. DOI: 10.2337/db10-0676.
19. Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic [beta]-cells are formed by self-duplication rather than stem-cell differentiation. Nature. 2004;429(6987):41-46. DOI: 10.1038/nature02520
20. Nir T, Melton DA, Dor Y. Recovery from diabetes in mice by beta cell regeneration. Journal of Clinical Investigation. 2007;117(9):2553-2561. DOI: 10.1172/JCI32959
21. Cozar-Castellano I, Takane KK, Bottino R, Balamurugan AN, Stewart AF. Induction of β-Cell Proliferation and Retinoblastoma Protein Phosphorylation in Rat and Human Islets Using Adenovirus-Mediated Transfer of Cyclin-Dependent Kinase-4 and Cyclin D1. Diabetes. 2004;53(1):149-159. DOI: 10.2337/diabetes.53.1.149.
22. Fiaschi-Taesch NM, Salim F, Kleinberger J, Troxell R, Cozar-Castellano I, Selk K, et al. Induction of Human β-Cell Proliferation and Engraftment Using a Single G1/S Regulatory Molecule, cdk6. Diabetes. 2010;59(8):1926-1936.
23. Nauck MA, Kleine N, Ørskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in Type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36(8):741-744. DOI: 10.1007/BF00401145
24. Parnaud G, Bosco D, Berney T, Pattou F, Kerr-Conte J, Donath MY, et al. Proliferation of sorted human and rat beta cells. Diabetologia. 2008;51(1):91-100. DOI: 10.1007/s00125-007-0855-1
25. Rachman J, Barrow BA, Levy JC, Turner RC. Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia. 1997;40(2):205-211. DOI: 10.1007/s001250050664
26. Yi P, Park J-S, Melton Douglas A. Betatrophin: A Hormone that Controls Pancreatic Cell Proliferation. Cell. 2013;153(4):747-758.
27. Gazdar AF, Chick WL, Oie HK, Sims HL, King DL, Weir GC, et al. Continuous, clonal, insulin- and somatostatin-secreting cell lines established from a transplantable rat islet cell tumor. Proceedings of the National Academy of Sciences. 1980;77(6):3519-3523. doi: 10.1073/pnas.77.6.3519
28. Hohmeier HE, Newgard CB. Cell lines derived from pancreatic islets. Molecular and Cellular Endocrinology. 2004;228(1-2):121-128. DOI: 10.1016/j.mce.2004.04.017
29. Levine F, Wang S, Beattie GM, et al. Development of a cell line from the human fetal pancreas. Transplantation proceedings. 1995;27:3410.
30. Dufayet de la Tour D, Halvorsen T, Demeterco C, Tyrberg B, Itkin-Ansari P, Loy M, et al. β-Cell Differentiation from a Human Pancreatic Cell Line in Vitro and in Vivo. Molecular Endocrinology. 2001;15(3):476-483. doi: 10.1210/me.15.3.476
31. Narushima M, Kobayashi N, Okitsu T, Tanaka Y, Li S-A, Chen Y, et al. A human [beta]-cell line for transplantation therapy to control type 1 diabetes. Nature Biotechnology. 2005;23(10):1274-1282. DOI: 10.1038/nbt1145
32. Ravassard P, Hazhouz Y, Pechberty S, Bricout-Neveu E, Armanet M, Czernichow P, et al. A genetically engineered human pancreatic beta cell line exhibiting glucose-inducible insulin secretion. Journal of Clinical Investigation. 2011;121(9):3589-3597. doi: http://dx.doi.org/10.1172/JCI58447
33. Butler AE, Cao-Minh L, Galasso R, Rizza RA, Corradin A, Cobelli C, et al. Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia. 2010;53(10):2167-2176. doi: 10.1007/s00125-010-1809-6
34. Jones PM, Courtney ML, Burns CJ, Persaud SJ. Cell-based treatments for diabetes. Drug Discovery Today. 2008;13(19-20):888-893. DOI: 10.1016/j.drudis.2008.06.014
35. Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE. A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes. 1993;42(12):1715-1720.
36. Li WC, Rukstalis JM, Nishimura W, Tchipashvili V, Habener JF, Sharma A, et al. Activation of pancreatic-duct-derived progenitor cells during pancreas regeneration in adult rats. Journal of Cell Science. 2010;123(Pt 16):2792-2802. DOI: 10.1242/jcs.065268
37. 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(10):2340-2348. DOI: 10.2337/db10-0084
38. Gianani R. Beta cell regeneration in human pancreas. Seminars in Immunopathology. 2011;33(1):23-27. DOI: 10.1007/s00281-010-0235-7
39. Collombat P, Xu X, Ravassard P, Sosa-Pineda B, Dussaud S, Billestrup N, et al. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell. 2009;138(3):449-462. DOI: 10.1016/j.cell.2009.05.035
40. Thorel F, Nepote V, Avril I, Kohno K, Desgraz R, Chera S, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature. 2010;464(7292):1149-1154. DOI: 10.1038/nature08894
41. Saisho Y, Manesso E, Butler AE et al. Ongoing beta-cell turnover in adult nonhuman primates is not adaptively increased in streptozotocin-induced diabetes. Diabetes. 2011;60(3):848-856. doi: 10.2337/db09-1368
42. Klymiuk N, Aigner B, Brem G, Wolf E. Genetic modification of pigs as organ donors for xenotransplantation. Molecular Reproduction and Development. 2010;77(3):209-221. DOI: 10.1002/mrd.21127
43. Galili U, Shohet SB, Kobrin E, Stults CL, Macher BA. Man, apes, and Old World monkeys differ from other mammals in the expression of alpha-galactosyl epitopes on nucleated cells. Journal of Biological Chemistry. 1988;263(33):17755-17762.
44. Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nature Medicine. 1997;3(3):282-286.
45. Wilson CA, Wong S, Muller J, Davidson CE, Rose TM, Burd P. Type C Retrovirus Released from Porcine Primary Peripheral Blood Mononuclear Cells Infects Human Cells. Journal of Virology. 1998;72(4):3082-3087.
46. van der Laan LJW, Lockey C, Griffeth BC, Frasier FS, Wilson CA, Onions DE, et al. Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID mice. Nature. 2000;407(6800):90-94.
47. McKenzie IFC, Koulmanda M, Mandel TE, Sandrin MS. Cutting Edge: Pig Islet Xenografts Are Susceptible to “Anti-Pig” But Not Galα(1,3)Gal Antibody Plus Complement in Gal o/o Mice. The Journal of Immunology. 1998;161(10):5116-5119.
48. van der Windt DJ, Bottino R, Casu A, Campanile N, Smetanka C, He J, et al. Long-term controlled normoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets. American Journal of Transplantation. 2009;9(12):2716-2726. DOI: 10.1111/j.1600-6143.2009.02850.x
49. Klymiuk N, van Buerck L, Bahr A, Offers M, Kessler B, Wuensch A, et al. Xenografted islet cell clusters from INSLEA29Y transgenic pigs rescue diabetes and prevent immune rejection in humanized mice. Diabetes. 2012;61(6):1527-1532. DOI: 10.2337/db11-1325
50. Ekser B, Ezzelarab M, Hara H, van der Windt DJ, Wijkstrom M, Bottino R, et al. Clinical xenotransplantation: the next medical revolution? The Lancet. 2012;379(9816):672-683.. doi: 10.1016/S0140-6736(11)61091-X
51. Hering BJ, Wijkstrom M, Graham ML, Hardstedt M, Aasheim TC, Jie T, et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nature Medicine. 2006;12(3):301-303.
52. Rayat GR, Rajotte RV, Ao Z, Korbutt GS. Microencapsulation of neonatal porcine islets: protection from human antibody/complement-mediated cytolysis in vitro and long-term reversal of diabetes in nude mice. Transplantation. 2000;69(6):1084-1090.
53. Dufrane D, Goebbels RM, Gianello P. Alginate macroencapsulation of pig islets allows correction of streptozotocin-induced diabetes in primates up to 6 months without immunosuppression. Transplantation. 2010;90(10):1054-1062. DOI: 10.1097/TP.0b013e3181f6e267
54. Elliott RB, Escobar L, Tan PL, Muzina M, Zwain S, Buchanan C. Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation. Xenotransplantation. 2007;14(2):157-161. DOI: 10.1111/j.1399-3089.2007.00384.x
55. Sun Y, Ma X, Zhou D, Vacek I, Sun AM. Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. Journal of Clinical Investigation. 1996;98(6):1417-1422. DOI: 10.1172/JCI118929
56. Takeuchi Y, Fishman J. Long life with or without PERV. Xenotransplantation. 2010;17(6):429-430. DOI: 10.1111/j.1399-3089.2010.00614.x
57. Langford GA, Galbraith D, Whittam AJ, McEwan P, Fernandez-Suarez XM, Black J, et al. In vivo analysis of porcine endogenous retrovirus expression in transgenic pigs. Transplantation. 2001;72(12):1996-2000.
58. Elliott RB, Escobar L, Garkavenko O, et al. No evidence of infection with porcine endogenous retrovirus in recipients of encapsulated porcine islet xenografts. Cell transplantation. 2000; 9(6):895–901.
59. Tacke SJ, Bodusch K, Berg A, Denner J. Sensitive and specific immunological detection methods for porcine endogenous retroviruses applicable to experimental and clinical xenotransplantation. Xenotransplantation. 2001;8(2):125-135. DOI: 10.1034/j.1399-3089.2001.00080.x-i1
60. Soria B, Roche E, Berná G, León-Quinto T, Reig JA, Martín F. Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes. 2000;49(2):157-162. DOI: 10.2337/diabetes.49.2.157
61. Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science. 2001;292(5520):1389-1394. DOI: 10.1126/science.1058866
62. D'Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nature Biotechnology. 2005;23(12):1534-1541. DOI: 10.1038/nbt1163
63. D'Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nature Biotechnology. 2006;24(11):1392-1401. DOI: 10.1038/nbt1259
64. Jiang J, Au M, Lu K, Eshpeter A, Korbutt G, Fisk G, et al. Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells. 2007;25(8):1940-1953. DOI: 10.1634/stemcells.2006-0761
65. Jiang W, Shi Y, Zhao D, Chen S, Yong J, Zhang J, et al. In vitro derivation of functional insulin-producing cells from human embryonic stem cells. Cell Research. 2007;17(4):333-344. DOI: 10.1038/cr.2007.28
66. Chen S, Borowiak M, Fox JL, Maehr R, Osafune K, Davidow L, et al. A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nature Chemical Biology. 2009;5(4):258-265. DOI: 10.1038/nchembio.154
67. Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nature Biotechnology. 2008;26(4):443-452. DOI: 10.1038/nbt1393
68. Schulz TC, Young HY, Agulnick AD, Babin MJ, Baetge EE, Bang AG, et al. A Scalable System for Production of Functional Pancreatic Progenitors from Human Embryonic Stem Cells. PloS One. 2012;7(5):e37004. DOI: 10.1371/journal.pone.0037004
69. Kelly OG, Chan MY, Martinson LA, Kadoya K, Ostertag TM, Ross KG, et al. Cell-surface markers for the isolation of pancreatic cell types derived from human embryonic stem cells. Nature Biotechnology. 2011;29(8):750-756. DOI: 10.1038/nbt.1931
70. Jiang W, Sui X, Zhang D, Liu M, Ding M, Shi Y, et al. CD24: a novel surface marker for PDX1-positive pancreatic progenitors derived from human embryonic stem cells. Stem Cells. 2011;29(4):609-617. DOI: 10.1002/stem.608
71. Ben-David U, Gan QF, Golan-Lev T, Arora P, Yanuka O, Oren YS, et al. Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen. Cell Stem Cell. 2013;12(2):167-179. DOI: 10.1016/j.stem.2012.11.015
72. Osafune K, Caron L, Borowiak M, Martinez RJ, Fitz-Gerald CS, Sato Y, et al. Marked differences in differentiation propensity among human embryonic stem cell lines. Nature Biotechnology. 2008;26(3):313-315. DOI: 10.1038/nbt1383
73. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663-676. DOI: 10.1016/j.cell.2006.07.024
74. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861-872. DOI: 10.1016/j.cell.2007.11.019
75. Stadtfeld M, Hochedlinger K. Induced pluripotency: history, mechanisms, and applications. Genes and Development. 2010;24(20):2239-2263. DOI: 10.1101/gad.1963910
76. Wu SM, Hochedlinger K. Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nature Cell Biology. 2011;13(5):497-505. DOI: 10.1038/ncb0511-497
77. Tateishi K, He J, Taranova O, Liang G, D'Alessio AC, Zhang Y. Generation of insulin-secreting islet-like clusters from human skin fibroblasts. Journal of Biological Chemistry. 2008;283(46):31601-31607. DOI: 10.1074/jbc.M806597200
78. Zhang D, Jiang W, Liu M, Sui X, Yin X, Chen S, et al. Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Research. 2009;19(4):429-438. DOI: 10.1038/cr.2009.28
79. Alipio Z, Liao W, Roemer EJ, Waner M, Fink LM, Ward DC, et al. Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(30):13426-13431. DOI: 10.1073/pnas.1007884107
80. Thatava T, Nelson TJ, Edukulla R, Sakuma T, Ohmine S, Tonne JM, et al. Indolactam V/GLP-1-mediated differentiation of human iPS cells into glucose-responsive insulin-secreting progeny. Gene Therapy. 2011;18(3):283-293. DOI: 10.1038/gt.2010.145
81. Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R, et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(37):15768-15773. DOI: 10.1073/pnas.0906894106
82. Bar-Nur O, Russ HA, Efrat S, Benvenisty N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell. 2011;9(1):17-23. DOI: 10.1016/j.stem.2011.06.007
83. Polo JM, Liu S, Figueroa ME, Kulalert W, Eminli S, Tan KY, et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nature Biotechnology. 2010;28(8):848-855. DOI: 10.1038/nbt.1667
84. Okano H, Nakamura M, Yoshida K, Okada Y, Tsuji O, Nori S, et al. Steps toward safe cell therapy using induced pluripotent stem cells. Circulation Research. 2013;112(3):523-533. DOI: 10.1161/CIRCRESAHA.111.256149
85. Ichida JK, Blanchard J, Lam K, Son EY, Chung JE, Egli D, et al. A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell. 2009;5(5):491-503.
86. Zhu S, Li W, Zhou H, Wei W, Ambasudhan R, Lin T, et al. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell. 2010;7(6):651-655.
Review
For citations:
Pellegrini S., Sordi V., Piemonti L. beta-cell transplantation in diabetes mellitus. Diabetes mellitus. 2013;16(3):11-20. (In Russ.) https://doi.org/10.14341/2072-0351-812
Views:
7216
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0).
Email this article 
