The evidences of β cell dedifferentiation in type 2 diabetes mellitus and relevant transcription factors_West China Medical Journal

Authors：

LIU Yuqi ,  TONG Nanwei

Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

TONG Nanwei, Email: tongnw@scu.edu.cn

Keywords：

Diabetes mellitus; Islet beta cells; Dedifferentiation

DOI：

10.7507/1002-0179.201803163

Video：

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Diabetes is characterised by hyperglycaemia resulted as the relative or absolute insulin deficiency which is closely related to islet beta cell failure. Apoptosis is the core mechanism of beta cell failure according to the studies on human islet. However, apoptosis can’t fully explain the loss of beta cell mass in the process of type 2 diabetes or the protective effect of early intervention. Recently, some other possible mechanisms of beta cell dysfunction have been proposed and dedifferentiation of beta cell draws extensive attention. Evidences of beta cell dedifferentiation in type 2 diabetes patients and animal models outlined and the transcription factors which determine beta cells of identity during this procedure are discussed in this review.

Citation： LIU Yuqi, TONG Nanwei. The evidences of β cell dedifferentiation in type 2 diabetes mellitus and relevant transcription factors. West China Medical Journal, 2018, 33(5): 598-604. doi: 10.7507/1002-0179.201803163 Copy

1.	Klöppel G, Löhr M, Habich K, et al. Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Pathol Res, 1985, 4(2): 110-125.
2.	Butler AE, Janson J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes, 2003, 52(1): 102-110.
3.	Meier JJ, Bonadonna RC. Role of reduced β-cell mass versus impaired β-cell function in the pathogenesis of type 2 diabetes. Diabetes Care, 2013, 36(Suppl 2): S113-S119.
4.	White MG, Marshall HL, Rigby R, et al. Expression of mesenchymal and α-cell phenotypic markers in islet β-cells in recently diagnosed diabetes. Diabetes Care, 2013, 36(11): 3818-3820.
5.	Spijker HS, Song H, Ellenbroek JH, et al. Loss of β-cell identity occurs in type 2 diabetes and is associated with islet amyloid deposits. Diabetes, 2015, 64(8): 2928-2938.
6.	Cinti F, Bouchi R, Kim-Muller JY, et al. Evidence of β-cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab, 2016, 101(3): 1044-1054.
7.	Guo S, Dai C, Guo M, et al. Inactivation of specific β cell transcription factors in type 2 diabetes. J Clin Invest, 2013, 123(8): 3305-3316.
8.	Segerstolpe Å, Palasantza A, Eliasson P, et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab, 2016, 24(4): 593-607.
9.	Xin Y, Kim J, Okamoto H, et al. RNA sequencing of single human islet cells reveals type 2 diabetes genes. Cell Metab, 2016, 24(4): 608-615.
10.	Dahan T, Ziv O, Horwitz E, et al. Pancreatic β-cells express the fetal islet hormone gastrin in rodent and human diabetes. Diabetes, 2017, 66(2): 426-436.
11.	Talchai C, Xuan SH, Lin HV, et al. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell, 2012, 150(6): 1223-1234.
12.	Brereton MF, Iberl M, Shimomura K, et al. Reversible changes in pancreatic islet structure and function produced by elevated blood glucose. Nat Commun, 2014, 5: 4639.
13.	Wang Z, York NW, Nichols CG, et al. Pancreatic β cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab, 2014, 19(5): 872-882.
14.	Zhang C, Moriguchi T, Kajihara M, et al. MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol, 2005, 25(12): 4969-4976.
15.	Kaneto H, Matsuoka TA, Kawashima S, et al. Role of MafA in pancreatic beta-cells. Adv Drug Deliv Rev, 2009, 61(7/8): 489-496.
16.	He KH, Juhl K, Karadimos M, et al. Differentiation of pancreatic endocrine progenitors reversibly blocked by premature induction of MafA. Dev Biol, 2014, 385(1): 2-12.
17.	Nishimura W, Takahashi S, Yasuda K. MafA is critical for maintenance of the mature beta cell phenotype in mice. Diabetologia, 2015, 58(3): 566-574.
18.	Fu Z, Gilbert ER, Liu D. Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev, 2013, 9(1): 25-53.
19.	Jonsson J, Carlsson L, Edlund T, et al. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature, 1994, 371(6498): 606-609.
20.	Kim SK, Hebrok M. Intercellular signals regulating pancreas development and function. Genes Dev, 2001, 15(2): 111-127.
21.	Bernardo AS, Hay CW, Docherty K. Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic beta cell. Mol Cell Endocrinol, 2008, 294(1/2): 1-9.
22.	Fujimoto K, Polonsky KS. Pdx1 and other factors that regulate pancreatic beta-cell survival. Diabetes Obes Metab, 2009, 11(Suppl 4): 30-37.
23.	Gao T, Mckenna B, Li C, et al. Pdx1 maintains β cell identity and function by repressing an α cell program. Cell Metab, 2014, 19(2): 259-271.
24.	Wang R, Li J, Yashpal N. Phenotypic analysis of c-Kit expression in epithelial monolayers derived from postnatal rat pancreatic islets. J Endocrinol, 2004, 182(1): 113-122.
25.	Yang YP, Thorel F, Boyer DF, et al. Context-specific alpha-to-beta-cell reprogramming by forced Pdx1 expression. Genes Dev, 2011, 25(16): 1680-1685.
26.	Spijker HS, Ravelli RB, Mommaas-Kienhuis AM, et al. Conversion of mature human β-cells into glucagon-producing α-cells. Diabetes, 2013, 62(7): 2471-2480.
27.	Gradwohl G, Dierich A, Lemeur M, et al. Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA, 2000, 97(4): 1607-1611.
28.	Schwitzgebel VM, Scheel DW, Conners JR, et al. Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development, 2000, 127(16): 3533-3542.
29.	Rukstalis JM, Habener JF. Neurogenin3: a master regulator of pancreatic islet differentiation and regeneration. Islets, 2009, 1(3): 177-184.
30.	Ishida E, Kim-Muller JY, Accili D. Pair feeding, but not insulin, phloridzin, or rosiglitazone treatment, curtails markers of beta-cell dedifferentiation in db/db mice. Diabetes, 2017, 66(8): 2092-2101.
31.	Neelankal John A, Morahan G, Jiang FX. Incomplete re-expression of neuroendocrine progenitor/stem cell markers is a key feature of β-cell dedifferentiation. J Neuroendocrinol, 2017, 29(1). Doi:10.1111/jne.12450.
32.	Marcato P, Dean CA, Giacomantonio CA, et al. Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform. Cell Cycle, 2011, 10(9): 1378-1384.
33.	Kim-Muller JY, Zhao S, Srivastava S, et al. Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice. Cell Metab, 2014, 20(4): 593-602.
34.	Wang J, Cortina G, Wu SV, et al. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med, 2006, 355(3): 270-280.
35.	Suzuki T, Kadoya Y, Sato Y, et al. The expression of pancreatic endocrine markers in centroacinar cells of the normal and regenerating rat pancreas: their possible transformation to endocrine cells. Arch Histol Cytol, 2003, 66(4): 347-358.
36.	Li J, Feng ZC, Yeung FS, et al. Aldehyde dehydrogenase 1 activity in the developing human pancreas modulates retinoic acid signalling in mediating islet differentiation and survival. Diabetologia, 2014, 57(4): 754-764.
37.	Kim-Muller JY, Fan J, Kim YJ, et al. Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice. Nat Commun, 2016, 7: 12631.
38.	Burke SJ, Batdorf HM, Burk DH, et al. db/db mice exhibit features of human type 2 diabetes that are not present in weight-matched C57BL/6J mice fed a western diet. J Diabetes Res, 2017, 2017: 8503754.
39.	Feng AL, Xiang YY, Gui L, et al. Paracrine GABA and insulin regulate pancreatic alpha cell proliferation in a mouse model of type 1 diabetes. Diabetologia, 2017, 60(6): 1033-1042.
40.	Accili D, Talchai SC, Kim-Muller JY, et al. When β-cells fail: lessons from dedifferentiation. Diabetes Obes Metab, 2016, 18(Suppl 1): 117-122.
41.	Daitoku H, Sakamaki J, Fukamizu A. Regulation of FoxO transcription factors by acetylation and protein-protein interactions. Biochim Biophys Acta, 2011, 1813(11): 1954-1960.
42.	Kitamura T, Nakae J, Kitamura Y, et al. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest, 2002, 110(12): 1839-1847.
43.	Nakae J, Kitamura T, Kitamura Y, et al. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev Cell, 2003, 4(1): 119-129.
44.	Kitamura YI, Kitamura T, Kruse JP, et al. FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metab, 2005, 2(3): 153-163.
45.	Kawamori D, Kaneto H, Nakatani Y, et al. The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation. J Biol Chem, 2006, 281(2): 1091-1098.
46.	Kobayashi M, Kikuchi O, Sasaki T, et al. FoxO1 as a double-edged sword in the pancreas: analysis of pancreas- and β-cell-specific FoxO1 knockout mice. Am J Physiol Endocrinol Metab, 2012, 302(5): E603-E613.
47.	Naya FJ, Huang HP, Qiu Y, et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev, 1997, 11(18): 2323-2334.
48.	Malecki MT, Jhala US, Antonellis A, et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet, 1999, 23(3): 323-328.
49.	German MS, Wang J. The insulin gene contains multiple transcriptional elements that respond to glucose. Mol Cell Biol, 1994, 14(6): 4067-4075.
50.	Sharma A, Stein R. Glucose-induced transcription of the insulin gene is mediated by factors required for beta-cell-type-specific expression. Mol Cell Biol, 1994, 14(2): 871-879.
51.	Chae JH, Stein GH, Lee JE. NeuroD: the predicted and the surprising. Mol Cells, 2004, 18(3): 271-288.
52.	Binot AC, Manfroid I, Flasse L, et al. Nkx6.1 and nkx6.2 regulate alpha- and beta-cell formation in zebrafish by acting on pancreatic endocrine progenitor cells. Dev Biol, 2010, 340(2): 397-407.
53.	Schaffer AE, Taylor BL, Benthuysen JR, et al. Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity. PLoS Genet, 2013, 9(1): e1003274.
54.	Schaffer AE, Freude KK, Nelson SB, et al. Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. Dev Cell, 2010, 18(6): 1022-1029.
55.	Nelson SB, Janiesch C, Sander M. Expression of Nkx6 genes in the hindbrain and gut of the developing mouse. J Histochem Cytochem, 2005, 53(6): 787-790.
56.	Saunders A, Faiola F, Wang J. Concise review: pursuing self-renewal and pluripotency with the stem cell factor Nanog. Stem Cells, 2013, 31(7): 1227-1236.
57.	Gj P, Chang ZY, Scholer HR, et al. Stem cell pluripotency and transcription factor Oct4. Cell Res, 2002, 12(Z2): 321-329.
58.	Kallas A, Pook M, Trei A, et al. SOX2 is regulated differently from NANOG and OCT4 in human embryonic stem cells during early differentiation initiated with Sodium butyrate. Stem Cells Int, 2014: 298163.
59.	Niwa H. Molecular mechanism to maintain stem cell renewal of ES cells. Cell Struct Funct, 2001, 26(3): 137-148.
60.	Segev H, Fishman B, Schulman R, et al. The expression of the class 1 glucose transporter isoforms in human embryonic stem cells, and the potential use of GLUT2 as a marker for pancreatic progenitor enrichment. Stem Cells Dev, 2012, 21(10): 1653-1661.

1. Klöppel G, Löhr M, Habich K, et al. Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Pathol Res, 1985, 4(2): 110-125.
2. Butler AE, Janson J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes, 2003, 52(1): 102-110.
3. Meier JJ, Bonadonna RC. Role of reduced β-cell mass versus impaired β-cell function in the pathogenesis of type 2 diabetes. Diabetes Care, 2013, 36(Suppl 2): S113-S119.
4. White MG, Marshall HL, Rigby R, et al. Expression of mesenchymal and α-cell phenotypic markers in islet β-cells in recently diagnosed diabetes. Diabetes Care, 2013, 36(11): 3818-3820.
5. Spijker HS, Song H, Ellenbroek JH, et al. Loss of β-cell identity occurs in type 2 diabetes and is associated with islet amyloid deposits. Diabetes, 2015, 64(8): 2928-2938.
6. Cinti F, Bouchi R, Kim-Muller JY, et al. Evidence of β-cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab, 2016, 101(3): 1044-1054.
7. Guo S, Dai C, Guo M, et al. Inactivation of specific β cell transcription factors in type 2 diabetes. J Clin Invest, 2013, 123(8): 3305-3316.
8. Segerstolpe Å, Palasantza A, Eliasson P, et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab, 2016, 24(4): 593-607.
9. Xin Y, Kim J, Okamoto H, et al. RNA sequencing of single human islet cells reveals type 2 diabetes genes. Cell Metab, 2016, 24(4): 608-615.
10. Dahan T, Ziv O, Horwitz E, et al. Pancreatic β-cells express the fetal islet hormone gastrin in rodent and human diabetes. Diabetes, 2017, 66(2): 426-436.
11. Talchai C, Xuan SH, Lin HV, et al. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell, 2012, 150(6): 1223-1234.
12. Brereton MF, Iberl M, Shimomura K, et al. Reversible changes in pancreatic islet structure and function produced by elevated blood glucose. Nat Commun, 2014, 5: 4639.
13. Wang Z, York NW, Nichols CG, et al. Pancreatic β cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab, 2014, 19(5): 872-882.
14. Zhang C, Moriguchi T, Kajihara M, et al. MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol, 2005, 25(12): 4969-4976.
15. Kaneto H, Matsuoka TA, Kawashima S, et al. Role of MafA in pancreatic beta-cells. Adv Drug Deliv Rev, 2009, 61(7/8): 489-496.
16. He KH, Juhl K, Karadimos M, et al. Differentiation of pancreatic endocrine progenitors reversibly blocked by premature induction of MafA. Dev Biol, 2014, 385(1): 2-12.
17. Nishimura W, Takahashi S, Yasuda K. MafA is critical for maintenance of the mature beta cell phenotype in mice. Diabetologia, 2015, 58(3): 566-574.
18. Fu Z, Gilbert ER, Liu D. Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev, 2013, 9(1): 25-53.
19. Jonsson J, Carlsson L, Edlund T, et al. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature, 1994, 371(6498): 606-609.
20. Kim SK, Hebrok M. Intercellular signals regulating pancreas development and function. Genes Dev, 2001, 15(2): 111-127.
21. Bernardo AS, Hay CW, Docherty K. Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic beta cell. Mol Cell Endocrinol, 2008, 294(1/2): 1-9.
22. Fujimoto K, Polonsky KS. Pdx1 and other factors that regulate pancreatic beta-cell survival. Diabetes Obes Metab, 2009, 11(Suppl 4): 30-37.
23. Gao T, Mckenna B, Li C, et al. Pdx1 maintains β cell identity and function by repressing an α cell program. Cell Metab, 2014, 19(2): 259-271.
24. Wang R, Li J, Yashpal N. Phenotypic analysis of c-Kit expression in epithelial monolayers derived from postnatal rat pancreatic islets. J Endocrinol, 2004, 182(1): 113-122.
25. Yang YP, Thorel F, Boyer DF, et al. Context-specific alpha-to-beta-cell reprogramming by forced Pdx1 expression. Genes Dev, 2011, 25(16): 1680-1685.
26. Spijker HS, Ravelli RB, Mommaas-Kienhuis AM, et al. Conversion of mature human β-cells into glucagon-producing α-cells. Diabetes, 2013, 62(7): 2471-2480.
27. Gradwohl G, Dierich A, Lemeur M, et al. Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA, 2000, 97(4): 1607-1611.
28. Schwitzgebel VM, Scheel DW, Conners JR, et al. Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development, 2000, 127(16): 3533-3542.
29. Rukstalis JM, Habener JF. Neurogenin3: a master regulator of pancreatic islet differentiation and regeneration. Islets, 2009, 1(3): 177-184.
30. Ishida E, Kim-Muller JY, Accili D. Pair feeding, but not insulin, phloridzin, or rosiglitazone treatment, curtails markers of beta-cell dedifferentiation in db/db mice. Diabetes, 2017, 66(8): 2092-2101.
31. Neelankal John A, Morahan G, Jiang FX. Incomplete re-expression of neuroendocrine progenitor/stem cell markers is a key feature of β-cell dedifferentiation. J Neuroendocrinol, 2017, 29(1). Doi:10.1111/jne.12450.
32. Marcato P, Dean CA, Giacomantonio CA, et al. Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform. Cell Cycle, 2011, 10(9): 1378-1384.
33. Kim-Muller JY, Zhao S, Srivastava S, et al. Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice. Cell Metab, 2014, 20(4): 593-602.
34. Wang J, Cortina G, Wu SV, et al. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med, 2006, 355(3): 270-280.
35. Suzuki T, Kadoya Y, Sato Y, et al. The expression of pancreatic endocrine markers in centroacinar cells of the normal and regenerating rat pancreas: their possible transformation to endocrine cells. Arch Histol Cytol, 2003, 66(4): 347-358.
36. Li J, Feng ZC, Yeung FS, et al. Aldehyde dehydrogenase 1 activity in the developing human pancreas modulates retinoic acid signalling in mediating islet differentiation and survival. Diabetologia, 2014, 57(4): 754-764.
37. Kim-Muller JY, Fan J, Kim YJ, et al. Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice. Nat Commun, 2016, 7: 12631.
38. Burke SJ, Batdorf HM, Burk DH, et al. db/db mice exhibit features of human type 2 diabetes that are not present in weight-matched C57BL/6J mice fed a western diet. J Diabetes Res, 2017, 2017: 8503754.
39. Feng AL, Xiang YY, Gui L, et al. Paracrine GABA and insulin regulate pancreatic alpha cell proliferation in a mouse model of type 1 diabetes. Diabetologia, 2017, 60(6): 1033-1042.
40. Accili D, Talchai SC, Kim-Muller JY, et al. When β-cells fail: lessons from dedifferentiation. Diabetes Obes Metab, 2016, 18(Suppl 1): 117-122.
41. Daitoku H, Sakamaki J, Fukamizu A. Regulation of FoxO transcription factors by acetylation and protein-protein interactions. Biochim Biophys Acta, 2011, 1813(11): 1954-1960.
42. Kitamura T, Nakae J, Kitamura Y, et al. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest, 2002, 110(12): 1839-1847.
43. Nakae J, Kitamura T, Kitamura Y, et al. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev Cell, 2003, 4(1): 119-129.
44. Kitamura YI, Kitamura T, Kruse JP, et al. FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metab, 2005, 2(3): 153-163.
45. Kawamori D, Kaneto H, Nakatani Y, et al. The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation. J Biol Chem, 2006, 281(2): 1091-1098.
46. Kobayashi M, Kikuchi O, Sasaki T, et al. FoxO1 as a double-edged sword in the pancreas: analysis of pancreas- and β-cell-specific FoxO1 knockout mice. Am J Physiol Endocrinol Metab, 2012, 302(5): E603-E613.
47. Naya FJ, Huang HP, Qiu Y, et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev, 1997, 11(18): 2323-2334.
48. Malecki MT, Jhala US, Antonellis A, et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet, 1999, 23(3): 323-328.
49. German MS, Wang J. The insulin gene contains multiple transcriptional elements that respond to glucose. Mol Cell Biol, 1994, 14(6): 4067-4075.
50. Sharma A, Stein R. Glucose-induced transcription of the insulin gene is mediated by factors required for beta-cell-type-specific expression. Mol Cell Biol, 1994, 14(2): 871-879.
51. Chae JH, Stein GH, Lee JE. NeuroD: the predicted and the surprising. Mol Cells, 2004, 18(3): 271-288.
52. Binot AC, Manfroid I, Flasse L, et al. Nkx6.1 and nkx6.2 regulate alpha- and beta-cell formation in zebrafish by acting on pancreatic endocrine progenitor cells. Dev Biol, 2010, 340(2): 397-407.
53. Schaffer AE, Taylor BL, Benthuysen JR, et al. Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity. PLoS Genet, 2013, 9(1): e1003274.
54. Schaffer AE, Freude KK, Nelson SB, et al. Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. Dev Cell, 2010, 18(6): 1022-1029.
55. Nelson SB, Janiesch C, Sander M. Expression of Nkx6 genes in the hindbrain and gut of the developing mouse. J Histochem Cytochem, 2005, 53(6): 787-790.
56. Saunders A, Faiola F, Wang J. Concise review: pursuing self-renewal and pluripotency with the stem cell factor Nanog. Stem Cells, 2013, 31(7): 1227-1236.
57. Gj P, Chang ZY, Scholer HR, et al. Stem cell pluripotency and transcription factor Oct4. Cell Res, 2002, 12(Z2): 321-329.
58. Kallas A, Pook M, Trei A, et al. SOX2 is regulated differently from NANOG and OCT4 in human embryonic stem cells during early differentiation initiated with Sodium butyrate. Stem Cells Int, 2014: 298163.
59. Niwa H. Molecular mechanism to maintain stem cell renewal of ES cells. Cell Struct Funct, 2001, 26(3): 137-148.
60. Segev H, Fishman B, Schulman R, et al. The expression of the class 1 glucose transporter isoforms in human embryonic stem cells, and the potential use of GLUT2 as a marker for pancreatic progenitor enrichment. Stem Cells Dev, 2012, 21(10): 1653-1661.

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