Generation of Induced Pluripotent Stem Cells and Applications in Regenerative Medicine

Abstract

In 2006, Takahashi and Yamanaka reported that the transfer and expression of four transcription factors (Oct4, Sox2, Klf4, and c-Myc) into fibroblast cells were sufficient to obtain cells similar to embryonic stem cells. The cells obtained by reprogramming of somatic cells are called induced pluripotent stem cells (IPSC). In the following years, various studies were carried out for the optimization of transcription factors and reprogramming conditions. Until now, the introduction of transcription factors to different somatic cells or stem cells by various methods or the effect of using different combinations of transcription factors has been the subject of research. There are many different vector systems to reprogramme somatic cells. The efficiencies of the vector types for obtaining IPSC differ from each other. In this review, the general properties of stem cells and their application areas are discussed, as well as the acquisition of induced pluripotent stem cells and their potential for clinical use.

Keywords

• Stem cells
• Stem cell types
• Induced pluripotent stem cells
• Regenerative medicine
• Generation of induced pluripotent stem cell

İndüklenmiş Pluripotent Kök Hücrelerin Elde Edilmesi ve Rejeneratif Tıpta Uygulanabilirliği

Abstract

2006 yılında Takahashi ve Yamanaka dört transkripsiyon faktörünün (Oct4, Sox2, Klf4 ve c-Myc) fibroblast hücrelerine aktarılması ve bu transkripsiyon faktörlerinin ifadesinin pluripotent kök hücre elde etmek için yeterli olduğunu bildirmiş ve somatik hücrelerin geriye programlanarak elde edilen bu hücreler indüklenmiş pluripotent kök hücreler (İPKH) olarak adlandırılmıştır. Daha sonraki yıllarda transkripsiyon faktörleri ve yeniden programlama şartlarının optimizasyonu ile ilgili birçok çalışma yapılmıştır. Bugüne kadar farklı somatik hücrelere transkripsiyon faktörlerinin farklı metotları ile tanıtımı ya da transkripsiyon faktörlerinin farklı kombinasyonlarının kullanımının etkisi araştırma konusu olmuştur. Somatik hücrelerin yeniden programlanması amacı ile birçok farklı vektör sistemi bulunmaktadır. Bu vektör çeşitlerinin İPKH eldesi için verimlilikleri birbirlerinden farklılık göstermektedir. Bu derlemede, kök hücrelerin genel özellikleri ve uygulama alanlarının irdelenmesinin yanı sıra ağırlıklı olarak indüklenmiş pluripotent kök hücrelerinin elde edilmesi üzerinde durulmuştur. Ayrıca İPKH’lerin klinik amaçlı kullanım potansiyellerine de değinilmektedir.

Keywords

• Kök hücreler
• Kök hücre çeşitleri
• Rejeneratif tıp
• İndüklenmiş pluripotent kök hücreler
• İndüklenmiş kök hücre eldesi.

References

1. 1. El-Badri N, Ghoneim MA. Mesenchymal stem cell therapy in diabetes mellitus: Progress and challenges. J Nucleic Acids. 2013. doi:10.1155/2013/194858
2. 2. Pileggi A. Mesenchymal stem cells for the treatment of diabetes. Diabetes. 2012. doi:10.2337/db12-0355
3. 3. Deshmukh RS, Kovács KA, Dinnyés A. Drug discovery models and toxicity testing using embryonic and induced pluripotent stem-cell-derived cardiac and neuronal cells. Stem Cells Int. 2012. doi:10.1155/2012/379569
4. 4. Spitalieri P, Talarico VR, Murdocca M, Novelli G, Sangiuolo F. Human induced pluripotent stem cells for monogenic disease modelling and therapy. World J Stem Cells. 2016. doi:10.4252/wjsc.v8.i4.118
5. 5. Amabile G, Meissner A. Induced pluripotent stem cells: current progress and potential for regenerative medicine. Trends Mol Med. 2009. doi:10.1016/j.molmed.2008.12.003
6. 6. Soldner F, Hockemeyer D, Beard C, et al. Parkinson’s Disease Patient-Derived Induced Pluripotent Stem Cells Free of Viral Reprogramming Factors. Cell. 2009. doi:10.1016/j.cell.2009.02.013
7. 7. Bunge MB. Novel combination strategies to repair the injured mammalian spinal cord. J Spinal Cord Med. 2008. doi:10.1080/10790268.2008.11760720
8. 8. Thomson JA. Embryonic stem cell lines derived from human blastocysts. Science (80- ). 1998;282(5391):1145-1147. doi:10.1126/science.282.5391.1145

9. 9. Cheung TH, Rando TA. Molecular regulation of stem cell quiescence. Nat Rev Mol Cell Biol. 2013. doi:10.1038/nrm3591
10. 10. Kim JS, Choi HW, Choi S, Do JT. Reprogrammed pluripotent stem cells from somatic cells. Int J Stem Cells. 2011;4(1):1-8. doi:10.15283/ijsc.2011.4.1.1
11. 11. Avcılar H, Saraymen B, Özturan OÖ, Köker MY. Embriyonik Kök Hücreler ve İndüklenmiş Pluripotent Kök Hücreler. Asthma Allergy Immunol. 2017. doi:10.21911/aai.22
12. 12. Ateş U. Kök hücreyi tanıyalım. FNG Bilim Tıp Transplant Derg. 2016. doi:10.5606/fng.transplantasyon.2016.004
13. 13. Kansu Emin. Kök hücre biyolojisi ve plastisitesinde güncel kavramlar. Hacettepe Med J. 2005.
14. 14. Martin-Rendon E, Watt SM. Exploitation of stem cell plasticity. Transfus Med. 2003. doi:10.1111/j.1365-3148.2003.00462.x
15. 15. Santoro A, Vlachou T, Carminati M, Pelicci PG, Mapelli M. Molecular mechanisms of asymmetric divisions in mammary stem cells. EMBO Rep. 2016. doi:10.15252/embr.201643021
16. 16. Kıvanç M, Öztürk Ş, Gökalp S, Özdemir İ, Tuğlu İ. Adipoz Kaynaklı Kök Hücreler ve Uygulama Alanları. Cukurova Med J. 2015. doi:10.17826/cutf.44976
17. 17. Erdal Y, Seçkin UD. Klinik çalışmalar açısından güncel mezenkimal kök hücre uygulamaları. İstanbul Bilim Üniversitesi Florence Nightingale Transplant Derg. 2017.
18. 18. Takahashi K, Yamanaka S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell. 2006. doi:10.1016/j.cell.2006.07.024
19. 19. Doss MX, Koehler CI, Gissel C, Hescheler J, Sachinidis A. Embryonic stem cells: A promising tool for cell replacement therapy. J Cell Mol Med. 2004. doi:10.1111/j.1582-4934.2004.tb00471.x
20. 20. Keller G. Embryonic stem cell differentiation: Emergence of a new era in biology and medicine. Genes Dev. 2005. doi:10.1101/gad.1303605
21. 21. Gardner RL, Brook FA. Reflections on the biology of embryonic stem (ES) cells. Int J Dev Biol. 1997;41(2):235-243. doi:10.1387/ijdb.9184330
22. 22. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981. doi:10.1038/292154a0
23. 23. Shen H, Zhang L, Liu M, Zhang Z. Biomedical applications of graphene. Theranostics. 2012;2(3):283-294. doi:10.7150/thno.3642
24. 24. Nichols J, Evans EP, Smith AG. Establishment of germ-line-competent embryonic stem (ES) cells using Differentiation Inhibiting Activity. Development. 1990.
25. 25. Dahéron L, Opitz SL, Zaehres H, et al. LIF/STAT3 signaling fails to maintain self‐renewal of human embryonic stem cells. Stem Cells. 2004;22(5):770-778.
26. 26. Xiao L, Yuan X, Sharkis SJ. Activin A Maintains Self-Renewal and Regulates Fibroblast Growth Factor, Wnt, and Bone Morphogenic Protein Pathways in Human Embryonic Stem Cells. Stem Cells. 2006. doi:10.1634/stemcells.2005-0299
27. 27. Thomson JA, Itskovitz-eldor J, Shapiro SS, et al. Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature. 2013. doi:10.1101/gad.1811609
28. 28. Canals I, Ginisty A, Quist E, et al. Rapid and efficient induction of functional astrocytes from human pluripotent stem cells. Nat Methods. 2018. doi:10.1038/s41592-018-0103-2
29. 29. Patapoutian A, Wold BJ, Wagner RA. Evidence for developmentally programmed transdifferentiation in mouse esophageal muscle. Science (80- ). 1995. doi:10.1126/science.270.5243.1818
30. 30. González F, Boué S, Belmonte JCI. Methods for making induced pluripotent stem cells: Reprogramming à la carte. Nat Rev Genet. 2011. doi:10.1038/nrg2937
31. 31. Can A. A concise review on the classification and nomenclature of stem cells. Turkish J Hematol. 2008.
32. 32. Pralong D, Mrozik K, Occhiodoro F, et al. A novel method for somatic cell nuclear transfer to mouse embryonic stem cells. Cloning Stem Cells. 2005;7(4):265-271.
33. 33. Fulka J, Loi P, Fulka H, Ptak G, Nagai T. Nucleus transfer in mammals: Noninvasive approaches for the preparation of cytoplasts. Trends Biotechnol. 2004. doi:10.1016/j.tibtech.2004.04.002
34. 34. Briggs R, King TJ. Transplantation of living nuclei from blastula cells into enucleated frogs’ eggs. Proc Natl Acad Sci. 1952. doi:10.1073/pnas.38.5.455
35. 35. Wernig M, Meissner A, Foreman R, et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature. 2007. doi:10.1038/nature05944
36. 36. Seyalioğlu İ, Şenel Eraslan B, Hot İ, Demircan YT, Çetin G. Klonlamaya Genetik, Etik ve Hukuksal Açıdan Yaklaşım. Adli Tıp Derg. 2007.
37. 37. Tada S, Tada T, Lefebvre L, Barton SC, Surani MA. Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells. EMBO J. 1997. doi:10.1093/emboj/16.21.6510
38. 38. Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature. 2010. doi:10.1038/nature08752
39. 39. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell. 2007. doi:10.1016/j.cell.2007.11.019
40. 40. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science (80- ). 2007. doi:10.1126/science.1151526
41. 41. Schöler HR, Ruppert S, Suzuki N, Chowdhury K, Gruss P. New type of POU domain in germ line-specific protein Oct-4. Nature. 1990. doi:10.1038/344435a0
42. 42. Okamoto K, Okazawa H, Okuda A, Sakai M, Muramatsu M, Hamada H. A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell. 1990. doi:10.1016/0092-8674(90)90597-8
43. 43. Abed M, Kenyagin-Karsenti D, Boico O, Orian A. DamID: A methylation-based chromatin profiling approach. Methods Mol Biol. 2009. doi:10.1007/978-1-60327-414-2_11
44. 44. Saigal S, Bhargava A. Stem cell - is there any role in tumorigenic activity. Turk Patoloji Dergisi/Turkish J Pathol. 2011. doi:10.5146/tjpath.2011.01055
45. 45. Boyer LA, Tong IL, Cole MF, et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005. doi:10.1016/j.cell.2005.08.020
46. 46. Loh YH, Wu Q, Chew JL, et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet. 2006. doi:10.1038/ng1760
47. 47. Zhao W, Hisamuddin IM, Nandan MO, Babbin BA, Lamb NE, Yang VW. Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. Oncogene. 2004. doi:10.1038/sj.onc.1207067
48. 48. Rowland BD, Bernards R, Peeper DS. The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene. Nat Cell Biol. 2005. doi:10.1038/ncb1314
49. 49. Li Y, McClintick J, Zhong L, Edenberg HJ, Yoder MC, Chan RJ. Murine embryonic stem cell differentiation is promoted by SOCS-3 and inhibited by the zinc finger transcription factor Klf4. Blood. 2005. doi:10.1182/blood-2004-07-2681
50. 50. Sevim H, Gürpinar ÖA. İndüklenmiş Pluripotent Kök Hücreler Ve Uygulamalari{Dotless}. Marmara Med J. 2012. doi:10.5472/MMJ.2011.01922.1
51. 51. McMahon SB, Wood MA, Cole MD. The Essential Cofactor TRRAP Recruits the Histone Acetyltransferase hGCN5 to c-Myc. Mol Cell Biol. 2000. doi:10.1128/mcb.20.2.556-562.2000
52. 52. Adhikary S, Eilers M. Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol. 2005. doi:10.1038/nrm1703
53. 53. Fernandez PC, Frank SR, Wang L, et al. Genomic targets of the human c-Myc protein. Genes Dev. 2003. doi:10.1101/gad.1067003
54. 54. Huangfu D, Maehr R, Guo W, et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol. 2008. doi:10.1038/nbt1418
55. 55. Silva J, Barrandon O, Nichols J, Kawaguchi J, Theunissen TW, Smith A. Promotion of reprogramming to ground state pluripotency by signal inhibition. PLoS Biol. 2008. doi:10.1371/journal.pbio.0060253
56. 56. Bayart E, Cohen-Haguenauer O. Technological Overview of iPS Induction from Human Adult Somatic Cells. Curr Gene Ther. 2013. doi:10.2174/1566523211313020002
57. 57. Verfaillie C. The undoing of differentiation by four defined factors: A big step forward towards generating patient specific pluripotent stem cells. J Hepatol. 2008. doi:10.1016/j.jhep.2008.08.007
58. 58. Abad M, Mosteiro L, Pantoja C, et al. Human and Mouse Induced Pluripotent Stem Cells Are Differentially Reprogrammed in Response to Kinase Inhibitors. Stem Cell Reports. 2015. doi:10.1002/stem.2071
59. 59. Chatterjee S, Chaklader M, Basak P, et al. An animal model of chronic aplastic bone marrow failure following pesticide exposure in mice. Int J Stem Cells. 2010. doi:10.15283/ijsc.2010.3.1.54
60. 60. Egashira T, Seki T, Yuasa S, et al. Generation of induced pluripotent stem cells in healthy volunteers and patients with hereditary heart disease. J Mol Cell Cardiol. 2010. doi:10.1016/j.yjmcc.2010.03.009
61. 61. Ramos-Mejia V, Mũoz-Lopez M, Garcia-Perez JL, Menendez P. IPSC lines that do not silence the expression of the ectopic reprogramming factors may display enhanced propensity to genomic instability. Cell Res. 2010. doi:10.1038/cr.2010.125
62. 62. Plews JR, Li JL, Jones M, et al. Activation of pluripotency genes in human fibroblast cells by a novel mRNA based approach. PLoS One. 2010. doi:10.1371/journal.pone.0014397
63. 63. Zhou H, Wu S, Joo JY, et al. Generation of Induced Pluripotent Stem Cells Using Recombinant Proteins. Cell Stem Cell. 2009;4(5):381-384. doi:10.1016/j.stem.2009.04.005
64. 64. Warren L, Manos PD, Ahfeldt T, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010. doi:10.1016/j.stem.2010.08.012
65. 65. Kim JS, Choi HW, Choi S, Do JT. Reprogrammed pluripotent stem cells from somatic cells. Int J stem cells. 2011;4(1):1.
66. 66. Varli HS, Alkan F, Demirbilek M, Türkoğlu N. A virus-free vector for the transfection of somatic cells to obtain IPSC. J Nanoparticle Res. 2019;21(11). doi:10.1007/s11051-019-4668-1
67. 67. Maherali N, Sridharan R, Xie W, et al. Directly Reprogrammed Fibroblasts Show Global Epigenetic Remodeling and Widespread Tissue Contribution. Cell Stem Cell. 2007. doi:10.1016/j.stem.2007.05.014
68. 68. Keller GM. In vitro differentiation of embryonic stem cells. Curr Opin Cell Biol. 1995. doi:10.1016/0955-0674(95)80071-9
69. 69. Stojkovic M. Derivation of Human Embryonic Stem Cells from Day-8 Blastocysts Recovered after Three-Step In Vitro Culture. Stem Cells. 2004. doi:10.1634/stemcells.22-5-790
70. 70. Gokhale PJ, Andrews PW. Characterization of human pluripotent stem cells. 2013.
71. 71. Haase A, Olmer R, Schwanke K, et al. Generation of Induced Pluripotent Stem Cells from Human Cord Blood. Cell Stem Cell. 2009. doi:10.1016/j.stem.2009.08.021
72. 72. Lowry WE, Richter L, Yachechko R, et al. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci U S A. 2008. doi:10.1073/pnas.0711983105
73. 73. Aasen T, Raya A, Barrero MJ, et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol. 2008. doi:10.1038/nbt.1503
74. 74. Ebert AD, Yu J, Rose FF, et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature. 2009. doi:10.1038/nature07677
75. 75. Park IH, Arora N, Huo H, et al. Disease-Specific Induced Pluripotent Stem Cells. Cell. 2008. doi:10.1016/j.cell.2008.07.041
76. 76. Singh VK, Kalsan M, Kumar N, et al. Induced pluripotent stem cells : applications in regenerative medicine , disease modeling , and drug discovery. 2015;3(February):1-18. doi:10.3389/fcell.2015.00002
77. 77. Hanna J, Wernig M, Markoulaki S, et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science (80- ). 2007. doi:10.1126/science.1152092
78. 78. Wernig M, Zhao 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 U S A. 2008. doi:10.1073/pnas.0801677105
79. 79. Zhang J, Wilson GF, Soerens AG, et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res. 2009. doi:10.1161/CIRCRESAHA.108.192237
80. 80. Kazuki Y, Hiratsuka M, Takiguchi M, et al. Complete genetic correction of iPS cells from duchenne muscular dystrophy. Mol Ther. 2010. doi:10.1038/mt.2009.274
81. 81. Mahla RS. Stem cells applications in regenerative medicine and disease therapeutics. Int J Cell Biol. 2016. doi:10.1155/2016/6940283
82. 82. Li Y, Tsai YT, Hsu CW, et al. Long-term safety and efficacy of human-induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa. Mol Med. 2012;18(9):1312-1319. doi:10.2119/molmed.2012.00242