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Generation of pancreatic islet cells from human embryonic stem cells

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Abstract

Efficiently obtaining functional pancreatic islet cells derived from human embryonic stem (hES) cells not only provides great potential to solve the shortage of islets sources for type I diabetes cell therapy, but also benefits the study of the development of the human pancreas and diabetes pathology. In 2001, hES cells were reported to have the capacity to generate insulin-producing cells by spontaneous differentiation in vitro. Since then, many strategies (such as overexpression of key transcription factors, delivery of key proteins for pancreatic development, co-transplantation of differentiated hES cells along with fetal pancreas, stepwise differentiation by mimicking in vivo pancreatic development) have been employed in order to induce the differentiation of pancreatic islet cells from hES cells. Moreover, patient-specific induced pluripotent stem (iPS) cells can be generated by reprogramming somatic cells. iPS cells have characteristics similar to those of ES cells and offer a new cell source for type I diabetes cell therapy that reduces the risk of immunologic rejection. In this review, we summarize the recent progress made in the differentiation of hES and iPS cells into functional pancreatic islet cells and discuss the challenges for their future study.

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References

  1. Hussain M A, Theise N D. Stem-cell therapy for diabetes mellitus. Lancet, 2004, 364: 203–205, 15246735, 10.1016/S0140-6736(04)16635-X

    Article  PubMed  Google Scholar 

  2. 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: 230–238, 10911004, 10.1056/NEJM200007273430401, 1:CAS:528:DC%2BD3cXlvVSmt7k%3D

    Article  PubMed  CAS  Google Scholar 

  3. Thomson J A, Itskovitz-Eldor J, Shapiro S S, et al. Embryonic stem cell lines derived from human blastocysts. Science, 1998, 282: 1145–1147, 9804556, 10.1126/science.282.5391.1145, 1:CAS:528:DyaK1cXntleisLg%3D

    Article  PubMed  CAS  Google Scholar 

  4. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 2007, 131: 861–872, 18035408, 10.1016/j.cell.2007.11.019, 1:CAS:528:DC%2BD2sXhsVCntbbK

    Article  PubMed  CAS  Google Scholar 

  5. Yu J, Vodyanik M A, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science, 2007, 318: 1917–1920, 18029452, 10.1126/science.1151526, 1:CAS:528:DC%2BD2sXhsVGjsLbN

    Article  PubMed  CAS  Google Scholar 

  6. Schuldiner M, Yanuka O, Itskovitz-Eldor J, et al. Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. Proc Natl Acad Sci USA, 2000, 97: 11307–11312, 11027332, 10.1073/pnas.97.21.11307, 1:CAS:528:DC%2BD3cXnsF2ruro%3D

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Assady S, Maor G, Amit M, et al. Insulin production by human embryonic stem cells. Diabetes, 2001, 50: 1691–1697, 11473026, 10.2337/diabetes.50.8.1691, 1:CAS:528:DC%2BD3MXlslKntbc%3D

    Article  PubMed  CAS  Google Scholar 

  8. Lavon N, Yanuka O, Benvenisty N. The effect of overexpression of Pdx1 and Foxa2 on the differentiation of human embryonic stem cells into pancreatic cells. Stem Cells, 2006, 24: 1923–1930, 16675598, 10.1634/stemcells.2005-0397, 1:CAS:528:DC%2BD28XhtFKiu77M

    Article  PubMed  CAS  Google Scholar 

  9. Liew C G, Shah N N, Briston S J, et al. PAX4 Enhances Beta-Cell Differentiation of Human Embryonic Stem Cells. PLoS ONE, 2008, 3: e1783, 18335054, 10.1371/journal.pone.0001783

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kwon Y D, Oh S K, Kim H S, et al. Cellular manipulation of human embryonic stem cells by TAT-PDX1 protein transduction. Mol Ther, 2005, 12: 28–32, 15963917, 10.1016/j.ymthe.2005.03.010, 1:CAS:528:DC%2BD2MXlt1Gls7w%3D

    Article  PubMed  CAS  Google Scholar 

  11. Brolén G, Heins N, Edsbagge J, et al. Signals from the embryonic mouse pancreas induce differentiation of human embryonic stem cells into insulin-producing beta-cell-like cells. Diabetes, 2005, 54: 2867–2874, 16186387, 10.2337/diabetes.54.10.2867

    Article  PubMed  Google Scholar 

  12. D’Amour K A, Bang A G, Eliazer S, et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol, 2006, 24: 1392–1401, 17053790, 10.1038/nbt1259

    Article  PubMed  Google Scholar 

  13. Jiang J, Au M, Lu K, et al. Generation of insulin-producing islet-like clusters from human embryonic stem cells. Stem Cells, 2007, 25: 1940–1953, 17510217, 10.1634/stemcells.2006-0761, 1:CAS:528:DC%2BD2sXhtVSqsbbI

    Article  PubMed  CAS  Google Scholar 

  14. Jiang W, Shi Y, Zhao D, et al. In vitro derivation of functional insulin-producing cells from human embryonic stem cells. Cell Res, 2007, 17: 333–344, 17426693, 10.1038/cr.2007.28, 1:CAS:528:DC%2BD2sXkt1Chu7k%3D

    Article  PubMed  CAS  Google Scholar 

  15. Phillips B W, Hentze H, Rust W L, et al. Directed differentiation of human embryonic stem cells into the pancreatic endocrine lineage. Stem Cells Dev, 2007, 16: 561–578, 17784830, 10.1089/scd.2007.0029, 1:CAS:528:DC%2BD2sXpvFWrsLg%3D

    Article  PubMed  CAS  Google Scholar 

  16. Shim J H, Kim S E, Woo D H, et al. Directed differentiation of human embryonic stem cells towards a pancreatic cell fate. Diabetologia, 2007, 50: 1228–1238, 17457565, 10.1007/s00125-007-0634-z, 1:STN:280:DC%2BD2s3mvVKltw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  17. Zhang D, Jiang W, Liu M, et al. Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res, 2009, 19: 429–438, 19255591, 10.1038/cr.2009.28, 1:CAS:528:DC%2BD1MXktVSlsbw%3D

    Article  PubMed  CAS  Google Scholar 

  18. Chen S, Borowiak M, Fox J L, et al. A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nat Chem Biol, 2009, 5: 258–265, 19287398, 10.1038/nchembio.154, 1:CAS:528:DC%2BD1MXjtFCisrw%3D

    Article  PubMed  CAS  Google Scholar 

  19. Yasunaga M, Tada S, Torikai-Nishikawa S, et al. Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat Biotechnol, 2005, 23: 1542–1550, 16311587, 10.1038/nbt1167, 1:CAS:528:DC%2BD2MXht1yisrnP

    Article  PubMed  CAS  Google Scholar 

  20. D’Amour K A, Agulnick A D, Eliazer S, et al. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol, 2005, 23: 1534–1541, 16258519, 10.1038/nbt1163

    Article  PubMed  Google Scholar 

  21. Sulzbacher S, Schroeder I S, Truong T T, et al. Activin a-Induced differentiation of embryonic stem cells into endoderm and pancreatic progenitors-the influence of differentiation factors and culture conditions. Stem Cell Rev, 2009 (in press)

  22. McLean A B, D’Amour K A, Jones K L, et al. Activin A efficiently specifies definitive endoderm from human embryonic stem cells only when phosphatidylinositol 3-kinase signaling is suppressed. Stem Cells, 2007, 25: 29–38, 17204604, 10.1634/stemcells.2006-0219, 1:CAS:528:DC%2BD2sXhvVGjsb0%3D

    Article  PubMed  CAS  Google Scholar 

  23. Era T, Izumi N, Hayashi M, et al. Multiple mesoderm subsets give rise to endothelial cells, whereas hematopoietic cells are differentiated only from a restricted subset in embryonic stem cell differentiation culture. Stem Cells, 2008, 26: 401–411, 17991917, 10.1634/stemcells.2006-0809, 1:CAS:528:DC%2BD1cXjt1Wlsr8%3D

    Article  PubMed  CAS  Google Scholar 

  24. Oliver-Krasinski J M, Stoffers D A. On the origin of the beta cell. Genes Dev, 2008, 22: 1998–2021, 18676806, 10.1101/gad.1670808, 1:CAS:528:DC%2BD1cXpslKqsLc%3D

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Murtaugh L C. Pancreas and beta-cell development: From the actual to the possible. Development, 2007, 134: 427–438, 17185316, 10.1242/dev.02770, 1:CAS:528:DC%2BD2sXjtlWgs74%3D

    Article  PubMed  CAS  Google Scholar 

  26. Maden M. Role and distribution of retinoic acid during CNS development. Int Rev Cytol. 2001, 209: 1–77, 11580199, 10.1016/S0074-7696(01)09010-6, 1:CAS:528:DC%2BD38XhvVelur0%3D

    Article  PubMed  CAS  Google Scholar 

  27. Stafford D, Prince V E. Retinoic acid signaling is required for a critical early step in zebrafish pancreatic development. Curr Biol, 2002, 12: 1215–1220, 12176331, 10.1016/S0960-9822(02)00929-6, 1:CAS:528:DC%2BD38XmtlKgsb8%3D

    Article  PubMed  CAS  Google Scholar 

  28. Shi Y, Hou L, Tang F, et al. Inducing embryonic stem cells to differentiate into pancreatic β cells by a novel three-step approach with activin A and all-trans retinoic acid. Stem Cells, 2005, 23: 656–662, 15849173, 10.1634/stemcells.2004-0241, 1:CAS:528:DC%2BD2MXltVWmu7s%3D

    Article  PubMed  CAS  Google Scholar 

  29. Jiang W, Bai Z, Zhang D, et al. Differentiation of mouse nuclear transfer embryonic stem cells into functional pancreatic beta cells. Diabetologia, 2008, 51: 1671–1679, 18581093, 10.1007/s00125-008-1065-1, 1:CAS:528:DC%2BD1cXpsVGitLY%3D

    Article  PubMed  CAS  Google Scholar 

  30. Johannesson M, Ståhlberg A, Ameri J, et al. FGF4 and retinoic acid direct differentiation of hESCs into PDX1-expressing foregut endoderm in a time- and concentration-dependent manner. PLoS ONE, 2009, 4: e4794, 19277121, 10.1371/journal.pone.0004794

    Article  PubMed  PubMed Central  Google Scholar 

  31. Gouon-Evans V, Boussemart L, Gadue P, et al. BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nat Biotechnol, 2006, 24: 1402–1411, 17086172, 10.1038/nbt1258, 1:CAS:528:DC%2BD28XhtFyqtLzO

    Article  PubMed  CAS  Google Scholar 

  32. Cai J, Zhao Y, Liu Y, et al. Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology, 2007, 45: 1229–1239, 17464996, 10.1002/hep.21582, 1:CAS:528:DC%2BD2sXlslOju7k%3D

    Article  PubMed  CAS  Google Scholar 

  33. Offield M F, Jetton T L, Labosky P A, et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development, 1996, 122: 983–995, 8631275, 1:CAS:528:DyaK28XhvVOruro%3D

    PubMed  CAS  Google Scholar 

  34. Kroon E, Martinson L A, Kadoya K, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol, 2008, 26: 443–452, 18288110, 10.1038/nbt1393, 1:CAS:528:DC%2BD1cXktlymtb0%3D

    Article  PubMed  CAS  Google Scholar 

  35. Park I H, Arora N, Huo H, et al. Disease-specific induced pluripotent stem cells. Cell, 2008, 134: 877–886, 18691744, 10.1016/j.cell.2008.07.041, 1:CAS:528:DC%2BD1cXhtFCqs7bK

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Dimos J T, Rodolfa K T, Niakan K K, et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science, 2008, 321: 1218–1221, 18669821, 10.1126/science.1158799, 1:CAS:528:DC%2BD1cXhtVGgt7zL

    Article  PubMed  CAS  Google Scholar 

  37. Chambers S M, Fasano C A, Papapetrou E P, et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol, 2009, 27: 275–280, 19252484, 10.1038/nbt.1529, 1:CAS:528:DC%2BD1MXisVOrtrc%3D

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Zhang J, Wilson G F, Soerens A G, et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res, 2009 Feb 27, 104: e30–41, 19213953, 10.1161/CIRCRESAHA.108.192237, 1:CAS:528:DC%2BD1MXhvFejtb4%3D

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Tateishi K, He J, Taranova O, et al. Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem, 2008, 283: 31601–31607, 18782754, 10.1074/jbc.M806597200, 1:CAS:528:DC%2BD1cXhtlCjsb3O

    Article  PubMed  CAS  Google Scholar 

  40. Nakagawa M, Koyanagi M, Tanabe K, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol, 2008, 26: 101–106, 18059259, 10.1038/nbt1374, 1:CAS:528:DC%2BD1cXisFGmuw%3D%3D

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing, 100871, China

    DongHui Zhang, Wei Jiang & HongKui Deng

  2. Laboratory of Chemical Genomics, Shenzhen Graduate School of Peking University, Shenzhen, 518055, China

    DongHui Zhang, Yan Shi & HongKui Deng

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  1. DongHui Zhang
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  2. Wei Jiang
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  3. Yan Shi
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  4. HongKui Deng
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Correspondence to HongKui Deng.

Additional information

Spported by the National High Technology Research and Development Program of China (Grant No. 2006AA02A113), the Science and Technology Plan of Beijing Municipal Government (Grant No. D07050701350705), the Gongjian Project of Beijing Municipal Education Commission, the National Basic Research and Development Program of China (Grant Nos. 2007CB947900 and 2009CB941200), the National Natural Science Foundation of China (Grant No. 30830061), and the 111 Project to H Deng.

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Zhang, D., Jiang, W., Shi, Y. et al. Generation of pancreatic islet cells from human embryonic stem cells. SCI CHINA SER C 52, 615–621 (2009). https://doi.org/10.1007/s11427-009-0095-3

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  • DOI: https://doi.org/10.1007/s11427-009-0095-3

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