İndüklenmiş Pluripotent Kök Hücreler ve Uygulamaları

Abstract

Pluripotent özellik, organizmanın bütün dokularındaki hücreleri oluşturabilme özelliğidir ve sadece embriyonik kök hücre (EKH)’ler bu özelliğe sahiptir. İlk olarak 2006 yılında Takahashi ve Yamanaka isimli araştırmacıların çalışmaları ile somatik bir hücreye gen aktarılması sonucu pluripotent özellikte hücreler elde edilmiştir ve bu hücrelere indüklenmiş pluripotent kök hücre (İPKH) adı verilmiştir. İPKH’ler oluşturulurken pluripotent özelliği sağlamak amacıyla c-Myc, Sox-2, Oct ¾ ve Klf-4 genleri transfeksiyonla somatik hücrelere aktarılmaktadır. Gen aktarımı işlemi sonucunda aktif genleri içeren hücre kolonilerinin seçimi ile İPKH’ler elde edilmektedir. Pluripotent özellikteki EKH’lerde karakteristik olan; kültür ortamındaki gelişim evreleri, DNA metilasyon modeli, teratom oluşturabilme yeteneği, üç germ tabakasına ait hücrelere farklılaşabilme potansiyeli ve kimerik canlılar oluşturabilme özellikleri İPKH’lerde de bulunmaktadır. Bunun yanında, etik olarak çalışılmasında sorunlar yaşanan EKH’ler yerine kullanılabilecek tek kaynaktır. Organizmadaki bütün hücrelere farklılaşabilme özellikleri ile geri dönüşümsüz hücre hasarlarının oluştuğu bütün hastalık modellerinde hücresel tedavi amaçlı kullanılabilir. Ayrıca bu hücreler elde edildiği organizmaya otolog implante edilebilme şansına da sahiptir ve böylece implantasyonlarda yaşanan immun cevap riski ortadan kalkmaktadır. Bu nedenle, İPKH ile hücresel tedaviler, ilaç araştırmaları ve hastalık modellerinin araştırılmasına olanak sağlayabilecek en uygun kaynaktır. Bu derlemede, günümüzde yeni bir araştırma alanı olan İPKH’Lerin elde edilmesi ve kullanım alanları ile ilgili yakın zamanda yapılan araştırmalar hakkında bilgi verilmesi amaçlanmıştır.

Keywords

• Pluripotent kök hücre, Embriyonik kök hücre, Doku tedavisi,Transfeksiyon, Oktamer transkripsiyon faktörü-3, SoxB1 transkripsiyon faktörleri

References

1. 1. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663–76. doi 10.1016/j.cell.2006.07.024
2. 2. Keller GM. In vitro differentiation of embryonic stem cells. Curr. Opin. Cell Biol. 1995;7:862–9.
3. 3. Gardner RL, Brook FA. Reflections on the biology of embryonic stem cells. Int J Dev Biol 1997;41:235–43.
4. 4. Özel HB, Ozan E, Dabak DÖ. Embriyonik kök Hücreler. Review. Turkiye Klinikleri 2008, 28:333-41.
5. 5. Can A. A concise review on the classification and nomenclature of stem cells. Turk J Hematol 2008;25: 57-9.
6. 6. Kaygusuz I, Kantarcıoğlu B, Toptaş T, et al. Factors Affecting Stem Cell Mobilization in Patients Treated With Hematopoietic Peripheral Stem Cell Transplantation, Marmara Med J 2011; 24 :31-7. doi:10.5472/MMJ.2010.01763.1
7. 7. Wernig M, Meissner A, Foreman R, et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 2007 ;448:260- 2. doi:10.1038/nature05944.
8. 8. Saigal S, Bhargava A. Stem Cell - Is There Any Role in Tumorigenic Activity, Turk Patoloji Derg. Cilt/Vol. 27,2011; Sayfa/Page 93-97. doi: 10.5146/tjpath.2011.01055.

9. 9. Aoi T, Yae K, Nakagawa M, et al. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 2008;321:699–702. doi:10.1126/science.1154884
10. 10. Hanna J, Markoulaki S, Schorderet P, et al. Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 2008;133:250–64. doi 10.1016/j.cell.2008.03.028
11. 11. Stadtfeld M, Brennand K, Hochedlinger K. Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Curr Biol 2008;18:890–4. doi 10.1016/j.cub.2008.05.010
12. 12. Kim JB, Sebastiano V, Wu G, et al. Oct4-induced pluripotency in adult neural stem cells. Cell 2009;136:411–9. doi 10.1016/j.cell.2009.01.023
13. 13. Kunisato A, Wakatsuki M, Kodama Y, et al. Generation of induced pluripotent stem (iPS) cells by efficient reprogramming of adult bone marrow cells. Stem Cells Dev 2010;19:229–38. doi:10.1089/scd.2009.0149.
14. 14. Tsai S-Y, Clavel C, Kim S, et al. Oct4 and Klf4 reprogram dermal papilla cells into induced pluripotent stem cells. Stem Cells 2010;28:221–8. doi: 10.1002/stem.281
15. 15. Sancho-Bru P, Roelandt P, Narain N, et al. Directed differentiation of murine-induced pluripotent stem cells to functional hepatocyte-like cells. J Hepatol. 2011;54:98-107. doi:10.1016/j.jhep.2010.06.014
16. 16. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007;131:861–72. doi:10.1016/j.cell.2007.11.019
17. 17. Yanıkkaya Demirel G, Budak-Alpdoğan T, Aktaş S, Bayık M. Kısıtlı dilüsyon yöntemi ile CD34+ kordon kanı hücrelerinden uzun dönemli kültür-başlatan hücreler (UDK-BH) üretimi. Turk J Hematol 2010; 24: 234-41. doi: 10.5152/tjh.2010.44
18. 18. Park IH, Arora N, Huo H, et al. Disease-specific induced pluripotent stem cells. Cell 2008;134:877–86. doi:10.1016/j.cell.2008.07.041
19. 19. Li C, Zhou J, Shi G, et al. Pluripotency can be rapidly and efficiently induced in human amniotic fluid-derived cells. Hum Mol Genet 2009;18:4340–9. doi:10.1093/hmg/ddp386
20. 20. Loh YH, Agarwal S, Park IH, et al. Generation of induced pluripotent stem cells from human blood. Blood 2009;113:5476–9. doi:10.1182/blood-2009-02-204800
21. 21. Sun N, Panetta NJ, Gupta DM, et al. Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells. Proc Natl Acad Sci USA 2009;106:15720–5. doi:10.1073/pnas.0908450106
22. 22. Miyoshi K, Tsuji D, Kudoh K,et al. Generation of human induced pluripotent stem cells from oral mucosa. J Biosci Bioeng 2010;110: 345–50. doi:10.1016/j.jbiosc.2010.03.004
23. 23. Yan X, Qin H, Qu C,et al. iPS cells reprogrammed from human mesenchymal-like stem/progenitor cells of dental tissue origin. Stem Cells Dev 2010;19:469–80. doi:10.1089/scd.2009.0314.
24. 24. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007;318:1917-20. doi:10.1126/science.1151526
25. 25. Schöler HR, Hatzopoulos AK, Balling R, Suzuki N, Gruss P. A family octomer-specific prteins present during Mouse embryogenesis; evidence for germline-specific expression of an Oct factor. EMBO J 1989;8:2543-50.
26. 26. Amabile G, Meissner A. Induced pluripotent stem cells: current progress and potentials for regenerative medicine. Trends Mol Med. 2009;15:59-68. doi:10.1016/j.molmed.2008.12.003
27. 27. Rizzino A. Sox2 and Oct-3/4: A versatile pair of master regulators that orchestrate the self-renewal and pluripotency of embryonic stem cells. Wiley Interdiscip Rev Syst Biol Med. 2009;1:228-36. doi:10.1002/wsbm.12
28. 28. Zeller KI, Jegga AG, Aronow BJ, O'Donnell KA, Dang CV: An integrated database of genes responsive to the Myc oncogenic transcription factor: identification of direct genomic targets. Genome Biol. 2003;4 :Article R69. doi:10.1186/gb-2003-4-10-r69
29. 29. Dang CV. c-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism. Molecular And Cellular Bıology 1999;19:1–11.
30. 30. Köse O, Özdoğan S. Epidermal Kök Hücreler ve Klinik Kullanımları, Turkiye Klinikleri J Dermatol 2010;20:74-80
31. 31. Zhao W, Hisamuddin IF, Nandan MO, et al. Identification of Kruppellike factor 4 as a potential tumor suppressorgene in colorectal cancer: Oncogene 2004;23:395–402. doi:10.1038/sj.onc.1207067
32. 32. Chambers I, Colby D, Robertson M, et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 2003;113:643-55. doi:10.1016/S0092-8674(03)00392-1
33. 33. Nakagawa M, Koyanagi M, Tanabe K, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 2008;26:101-6. doi:10.1038/nbt1374
34. 34. Asgari S, Pournasr B, Salekdeh GH, et al. Induced pluripotent stem cells: a new era for hepatology. J Hepatol 2010;53:738-51. doi:10.1016/j.jhep.2010.05.009
35. 35. Zhou H, Wu S, Joo JY, et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell. 2000;4:581-4. doi:10.1016/j.stem.2009.04.005
36. 36. Maherali N, Sridharan R, Xie W, et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell. 2007;1:367-8. doi:10.1016/j.stem.2007.05.014
37. 37. Sullivan GJ, Hay DC, Park IH, et al. Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology 2010; 51:329–35. doi:10.1002/hep.23335
38. 38. Gallicano IG, Mishra L. Hepatocytes from induced pluripotent stem cells: a giant leap forward for hepatology. Hepatology 2010;51:20-2. doi:10.1002/hep.23474.
39. 39. Dimos JT, Rodolfa KT, Niakan KK, et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 2008;321:1169-70. doi:10.1126/science.1158799
40. 40. Wernig M, Zha JP, Pruszak J, et al. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci 2008;105:5856–61. doi:10.1073/pnas.0801677105
41. 41. Tokumoto Y, Ogawa S, Nagamune T, Miyake J. Comparison of efficiency of terminal differentiation of oligodendrocytes from induced pluripotent stem cells versus embryonic stem cells in vitro. J Biosci Bioeng 2010;109: 622–8. doi:10.1016/j.jbiosc.2009.11.013
42. 42. Sasaki N, Hirano T, Kobayashi K, et al. Chemical inhibition of sulfation accelerates neural differentiation of mouse embryonic stem cells and human induced pluripotent stem cells. Biochem Biophys Res Commun. 2010;401:480–6. doi:10.1016/j.bbrc.2010.09.085
43. 43. Onorati M, Camnasio S, Binetti M, Jung CB, Moretti A, Cattaneo E. Neuropotent self-renewing neural stem (NS) cells derived from mouse induced pluripotent stem (iPS) cells. Mol Cell Neurosci 2010;43:287-95. doi:10.1016/j.mcn.2009.12.002
44. 44. Mizuno Y, Chang H, Umeda K, et al. Generation of skeletal muscle stem/progenitor cells from murine induced pluripotent stem cells. FASEB J 2010; 24:2245-53. doi:10.1096/fj.09-137174
45. 45. Mauritz C, Schwanke K, Reppel M, et al. Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation 2008;118:472-5. doi:10.1161/circulationaha.108.778795
46. 46. Zhang J, Wilson GF, Soerens AG, et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res. 2009;104:e30-41. doi:10.1161/circresaha.108.192237
47. 47. Lei F, Haque R, Weiler L, Vrana KE, Song J. T lineage differentiation from induced pluripotent stem cells:, Cell Immunol. 2009;260:1–5. doi:10.1016/j.cellimm.2009.09.005
48. 48. Raya A, Rodriguez-Piza I, Guenechea G, et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 2009;460:53–9. doi:10.1038/nature08129
49. 49. Soldner F, Hockemeyer D, Beard C, et al. Parkinson’s disease patientderived induced pluripotent stem cells free of viral reprogramming factors, Cell 2009;136:964–77. doi:10.1016/j.cell.2009.02.013.
50. 50. Park IH, Zhao R, West JA, et al. Reprogramming of human somatic cells to pluripotency with defined factors: Nature 2008;451:141–6. doi:10.1038/nature06534.