Induksi Pluripotent Stem Cell dengan Menggunakan Faktor Yamanaka Oct4, Sox2, Klf4, dan c-Myc: Perkembangan dan Tantangan
Abstract
Sel punca embrionik memiliki kemampuan untuk membelah tanpa batas serta bersifat pluripotensi dan dapat berdiferensiasi menjadi sel dari tiga lapisan kecambah. Percobaan Takahashi dan Yamanaka pada tahun 2006 menunjukkan bahwa induced pluripotent stem cells (sel iPS) dapat diperoleh dengan penambahan sekumpulan faktor, yaitu Oct4, Sox2, Klf4, dan c-Myc (faktor Yamanaka). Penulisan tinjauan pustaka ini memiliki tujuan untuk meninjau perkembangan dan tantangan penggunaan faktor Yamanaka dalam pemerolehan sel iPS untuk kepentingan penggunaan klinis. Penelusuran pustaka dilakukan dengan menelusuri jurnal terpublikasi pada tahun 2006 hingga 2019 yang membahas tentang produksi sel iPS dengan faktor Yamanaka. Hasil penelusuran literatur menunjukkan bahwa faktor ini berperan sebagai faktor pionir yang dapat berikatan dengan kromatin dan menyebabkan remodelling wilayah kromatin serta menyebabkan aktivasi ataupun represi ekspresi dari gen. c-Myc berikatan pada gen yang terlibat dalam metabolisme seluler, regulasi siklus sel, dan jalur biosintetik. Oct4, Sox2, dan Klf4 menargetkan gen yang mengkodekan regulator perkembangan dan transkripsional. Mekanisme induksi sel somatik dengan faktor Yamanaka memerlukan penelusuran lebih lanjut. Sejauh ini, sel iPS dihasilkan dari berbagai macam tipe sel serta dapat berpotensi untuk mengobati berbagai penyakit. Uji klinis dari sel iPS telah disetujui oleh Food and Drugs Administration (FDA). Aplikasi dari sel iPS ini memiliki sejumlah rintangan, seperti tingkat efisiensi yang rendah, variabilitas yang tinggi, dan vektor yang digunakan dapat menyebabkan mutasi. Oleh karena itu, diperlukan penelitian lebih lanjut terkait metode yang digunakan agar diperoleh metode yang efisien, efektif, dan aman.
Kata kunci: c-Myc, induced pluripotent stem cell, Klf4, Oct4, Sox2
Induction of Pluripotent Stem Cell Using Yamanaka Factors Oct4, Sox2, Klf4, and c-Myc: Development and Future Challenges
Abstract
Embryonic stem cells have the ability to split indefinitely and have pluripotent properties, also can differentiate into cells from three germ layers. Experiment by Takahashi and Yamanaka 2006 showed that induced pluripotent stem cells (iPS cells) can be obtained by addition of a set of factors, namely Oct4, Sox2, Klf4, and c-Myc (Yamanaka factors). This literature review aimed to review the development and challenges of the use of Yamanaka factors in the acquisition of iPS cells for the benefit of its clinical use. We conducted a systematic review of the studies published from 2006 until 2019 that assesed the generating of iPS cell with the assistance of Yamanaka factors. From this review, it is indicated that the factors act as a pioneering factor that can bind to chromatin and cause chromatin region remodelling, and lead to activation or repression of gene expression. c-Myc binds to genes involved in cellular metabolism, cell cycle regulation, and biosynthetic pathways. Oct4, Sox2, and Klf4 target genes that encode developmental and transcriptional regulators. Somatic cell induction mechanism with Yamanaka factors requires further investigation. Recently, iPS cells are produced from different cell types. It can potentially treat various diseases, including Mendelian and complex heredity disease. Clinical trials of iPS cells have been approved by the Food and Drugs Administration (FDA). The application of these iPS cells acquires a number of obstacles, such as low efficiency, high variability, and commonly used vectors can cause mutations. Therefore, further research is needed related to the methods used in order to obtain an efficient, effective and safe method.
Keywords: c-Myc, induced pluripotent stem cell, Klf4, Oct4, Sox2
Keywords
Full Text:
PDF (Bahasa Indonesia)References
Evans MJ, Kaufman MH. Establishment in cultutre of pluripotential cells from mouse embryos. Nature. 1981;292:154–6.
Vallier L, Pedersen RA. Human embryonic stem cells: An in vitro model to study mechanisms controlling pluripotency in early mammalian developmet. Stem Cell Rev. 2005;1(2):119–30. doi: 10.1385/SCR:1:2:119
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. doi: 10.1016/j.cell.2006.07.024
Conger K. New method allows human embryonic stem cells to avoid immune system rejection, study finds. 2011 [Accessed on: 21 March 2018]. Available from: https://med.stanford.edu/news/all-news/2011/03/new-method-allows-human-embryonic-stem-cells-to-avoid-immu ne-system-rejection-study-finds.html.
Lo B, Parham L. Ethical issues in stem cell research. Endocr Rev. 2009;30(3):204–13. doi: 10.1210/er.2008-0031
Hayashi R, Ishikawa Y, Ito M, Kageyama T, Takashiba K, Fujioka T. Generation of corneal epithelial cells from induced pluripotent stem cells derived from human dermal fibroblast and corneal limbal epithelium. PLoS One. 2012;7(9):e45435. doi: 10.1371/journal.pone.0045435.
Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005; 122(6):947–56. doi: 10.1016/j.cell.2005.08.020
Kim JB, Sebastiano V, Wu G, Marcos J, Aurazo-Bravo MJ, Sasse P, et al. Oct4-induced pluripotency in adult neural stem cells. Cell. 2009;136(3):411–9. doi: 10.1016/j.cell.2009.01.023.
Sterneckert J, Hoing S, Scholer HR. Concise review: Oct4 and more: The reprogramming expressway. Stem Cells. 2012; 30(1):15–21. doi: 10.1002/stem.765.
Niwa H, Miyazaki J, Smith AG. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet. 2000;24:372–6.
Schepers GE, Teasdale RD, Koopman P. Twenty pairs of sox: Extent, homology, and nomenclature of the mouse and human sox transcription factor gene families. Dev Cell. 2002;3(2):167–70. doi: 10.1016/S1534-5807(02)00223-X
Masui S, Nakatake Y, Toyooka Y, Shimosato D, Yagi R, Takahashi K, et al. Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol. 2007;9(6):625–35. doi: 10.1038/ncb1589
Boer B, Kopp J, Malianna S, Desler M, Chakravarthy H, Wilder PJ, et al. Elevating the levels of Sox2 in embryonal carcinoma cells and embryonic stem cells inhibits the expression of Sox2: Oct-3/4 target genes. Nucleic Acids Res. 2007;35(6):1773–86. doi: 10.1093/nar/gkm059
Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell-Badge R. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 2003;17(1):126–40. doi: 10.1101/gad.224503
Kopp JL, Ormsbee BD, Desler M, Rizziono A. Small increases in the level of Sox2 trigger the differentiation of mouse embryonic stem cells. Stem Cells. 2008;26(4):903–11. doi: 10.1634/stemcells.2007-0951.
Chew JL, Loh YH, Zhang WY, Chen X, Tam WL, Yeap LS, et al. Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells. Mol Cell Biol. 2005;25(14):6031–46. doi: 10.1128/MCB.25.14.6031-6046.2005
Mullen AC, Orlando DA, Newman JJ, Loven J, Kumar RMBS, Bilodeau S. Master transcription factors determine cell-type-specific responses to TGF-β signaling. Cell. 2011;147(3):565–76. doi: 10.1016/j.cell.2011.08.050
Tsurozoe S, Ishihara K, Uchimura Y, Watanabe S, Skita Y, Aoto T, et al. Inhibition of DNA binding of Sox2 by the SUMO conjugation. Biochem Biophys Res Common. 2006;351(4):920–6. doi: 10.1016/j.bbrc.2006.10.130
Shields JM, Christy RJ, Yang VW. Identification and characterization of a gene encoding a gut-enriched Kruppel-like factor expressed during growth arrest. J Biol Chem. 1996;271(33):20009–17.
Schietz A, Nana D, Rose C, Zocher G, Milanovic M, Koenigsmann J, et al. The structure of the Klf4 DNA-binding domain links to self-renewal and macrophage differentiation. Cell Mol Life Sci. 2011;68(18):3121–31. doi: 10.1007/s00018-010-0618-x.
Geiman DE, Ton-That H, Johnson JM, Yang VW. Transactivation and growth suppression by the gut-enriched Kruppel-like factor (Kruppel-like factor 4) are dependent on acidic amino acid residues and protein-protein interaction. Nucleic Acids Res. 2000;28(5):1106–13. doi: 10.1093/nar/28.5.1106
Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y. The transcription coactivators p300 and CBP are histone acetyltransferase. Cell. 1996;87(5):953–9. doi: 10.1016/S0092-8674(00)82001-2
Barlev NA, Liu L, Chehb NH, Mansfied K, Harris KG, Halazonetis TD, et al. Acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases. Mol Cell. 2001;8(6):1243–54.
Li D, Yea S, Dolios G, Martignetii JA, Narla G, Wang R, et al. Regulation of Krüppel-like factor 6 tumor suppressor activity by acetylatio. Cancer Res. 2005;65(20):9216–25. doi: 10.1158/0008-5472.CAN-05-1040
Adhikary S, Eilers M. Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol. 2005;6(8):635–45. doi: 10.1038/nrm1703
Sridharan R, Tchieu J, Mason MJ, Yachechko R, Kuoy E, Horvath S, et al. Role of the murine reprogramming factors in the induction of pluripotency. Cell. 2008;136(2):364–77. doi: 10.1016/j.cell.2009.01.001.
Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature. 2003;425(6961):962–7. doi: 10.1038/nature02060
Hynes RO. Integrins: Bidirectional, allosteric signaling machines. Cell. 2002;110(6):673–87. doi: 10.1016/s0092-8674(02)00971-6
Nakagawa M, Koyanagi-Aoi M, Tanabe K, Takahashi K, Ichisaka K, Aoi T. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. 2008;26(1):101–6. doi: 10.1038/nbt1374
Selvakumaran M, Liebermann D, Hoffman B. The proto-oncogene c-myc blocks myeloid differentiation independently of its target gene ornithine decarboxylase. Blood. 1996;88(4):1248–55.
Stadfeld M, Maherali N, Breault DT, Hochedlinger K. Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mous. Cell Stem Cell. 2008;2(3):230–40. doi: 10.1016/j.stem.2 008.02.001.
Soufl A, Donahue C, Zaret KS. Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome. Cell. 2012;151(5):994–1004. doi: 10.1016/j.cell.2012.09.045.
Sridharan R, Plath K. Illuminating the black box of reprogramming. Cell Stem Cell. 2008;2(4):295–7. doi: 10.1016/j.stem.2008.03.015.
Papapetrou EP, Tomishima MJ, Chambers SM, Mica Y, Reed E, Menon J, et al. Stoichiometric and temporal requirements of Oct4, Sox2, Klf4, and c-Myc expression for efficient human iPSC induction and differentiation. Prec Natl Acad Sci U S A. 2009;106(31):12759–64. doi: 10.1073/pn as.0904825106.
Huangfu D, Maehr R, Guo W, Eijekelenboom A, Snitow M, Chen AE, et al. Induction of pluripotent stem cells by defined factors is greatly improved by smallmolecule. Nat Biotechnol. 2008;26(7):795–7. doi: 10.1038/nbt1418.
Li R, Liang J, Ni S, Zhou T, Qing X, Li H, et al. A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell. 2012;7(1):51–63. doi: 10.1016/j.stem.2010.04.014.
Buganim Y, Faddah DA, Cheng AW, Istkovich E, Markoulaki S, Ganz K, et al. Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell. 2012;150(6):1209–22. doi: 10.1016/j.cell.2012.08.023.
Brambink T, Foreman R, Welsted GG, Lengner CG, Wernig , Suh H. Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells. Cell Stem Cell. 2008;2(2):151–9. doi: 10.1016/j.stem.2008.01.004.
Polo JM, Anderssen A, Walsh RM, Shwarrz BA, Nefzger CM, Lim SM, et al. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell. 2012;151(7):1617–32. doi: 10.1016/j.cell.2012.11.039.
Soufl A, Donahue G, Zaret KS. Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome. Cell. 2012;151(5):994–1004. doi: 10.1016/j.cell.2012.09.045.
Takahashi K, Yamanaka S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cel Biol. 2016;17(3):183–93. doi: 10.1038/nrm.2016.8.
Rao M. Conserved and divergent paths that regulate self-renewal in mouse and human embryonic stem cells. Dev Biol. 2004;275(2):269–86. doi: 10.1016/j.ydbio.2004.08.013
Amit M, Carpenter MK, Inokuma MS, Chiu CP, Harris CP, Waknitz MA, et al. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev Biol. 2000;227(2):271–8. doi: 10.1006/dbio.2000.9912
Matsuda T, Nakamura T, Nako K, Arai T, Katsuki M, Heike T. STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. EMBO J. 1999;18(15):4261–9. doi: 10.1093/emboj/18.15.4261
Xu RH, Peck RM, Li DS, Feng X, Ludwig T, Thomson JA. Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells. Nat Methods. 2005;2(3):185–90. doi: 10.1038/nmeth744
Ying QL, Nichols J, Chambers I, Smith A. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell. 2003;115(3):281–92. doi: 10.1016/s0092-8674(03)00847-x
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):861–72. doi: 10.1016/j.cell.2007.11.019
Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to β cells. Nature. 2008;455(7213):627–32. doi: 10.1038/nature07314.
Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K, et al. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science. 2008;321(5889):699–702. doi: 10.1126/science.1154884.
Loh YH, Agarwal S, Park IH, Urbach A, Huo H, Heffner GC, et al. Generation of induced pluripotent stem cells from human blood. Blood. 2009;113(22):5476–9. doi: 10.1182/blood-2009-02-204800.
Aasem T, Raya A, Barrero MJ, Garreta E, Consiglio A, Gonzales F, et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. 2008; 26(11):1276–84. doi: 10.1038/nbt.1503.
Verbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 2010;463:1035–41
Tamaoki N, Takahashi K, Tanaka T, Ichisaka T, Aoki HTKT, et al. Dental pulp cells for induced pluripotent stem cell banking. J Dent Res. 2010;89(8):773–8. doi: 10.1177/0022034510366846
Tanaka T, Shugo T, Mitsushige M, Fumimasa N, Tomoyuki K, Hao C, et al. In vitro pharmacologic testing using human induced pluripotent stem cell-derived cardiomyocytes. Biochem Biophys Res Commun. 2009;385(4):497–502. doi: 10.1016/j.bbrc.2009.05.073.
Lee HK, Peter M, John W, Eugene BH, Weiming X. Induced pluripotent stem cells (iPCSs) derived from frontotemporal dementia patient’s periheral blood mononuclear cells. Stem Cell Res. 2015;15(2):325–7. doi: 10.1016/j.scr.2015.07. 004.
Mao J, Zhang Q, Ye X, Liu K, Liu L. Efficient induction of pluripotent stem cells from granulosa cells by Oct4 and Sox2. Stem Cells Dev. 2014;23(7):779–89. doi: 10.1089/scd.2013.0325.
Verlinsky Y, Strechenko N, Kukarenko V, Rechitsky S, Verlinsky O, Galat V. Human embryonic stem cell lines with genetic disorders. Reprod Biomed Online. 2005;10(1):105–10.
Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura. Disease-spesific induced pluripotent stem cells. Cell. 2008;134(5):877–86. doi: 10.1016/j.cell.2008.07.041.
Fliefel R, Ehrenfeld M, Otto S. Induced pluripotent stem cells (iPSCs) as a new source of bone in reconstructive surgery: A systematic review and meta-analysis of preclinical studies. J Tissue Eng Regen Med. 2018;12(7):1780–97. doi: 10.1002/term.2697.
Hayashi R, Yuki I, Miyuki I, Tomofumi K, Kuniko T, Tsuyoshi F, et al. Generation of corneal epithelial cells from induced pluripotent stem cells derived from human dermal fibroblast and corneal limbal epithelium. PLoS One. 2012;7(9):e45435. doi: 10.1371/journal.pone.0045435.
Hirami Y, Fumitaka O, Kazutoshi T, Keisuke O, Shinya Y, Hanako I, et al. Generation of retinal cells from mouse and human induced pluripotent stem cells. Neurosci Lett. 2009;458(3):126–31. doi: 10.1016/j.neulet.2009.04.035.
Ohta S, Imaizumi Y, Okada Y, Akamatsu W, Kuwahara R, Ohyama M, et al. Generation of human melanocytes from induced pluripotent stem cells. PLoS One. 2011;6(1):e16182. doi: 10.1371/jou rnal.pone.0016182
Shukla V, Rao M, Zhang H, Beers J, Wangsa D, Buishand FO, et al. Identification of novel targets for lung cancer therapy using an induced pluripotent stem cell model. Ann Am Thorac Soc. 2018;15(2):S127–8. doi: 10.1513/AnnalsATS.201707-610MG
Schmitt CE, Morales BM, Schmitz EMH, Hawkins JS, Lizama CO, Zape JP. Fluorescent tagged episomals for stoichiometric induced pluripotent stem cell reprogramming. Stem Cell Res Ther. 2017;8(1):132. doi: 10.1186/s13287-017-0581-7
Lin PY, Hsu SC, Chen HC, Len WB, Hsiao FC, Liu MC, et al. Optimization of reprogramming culture conditions for the generation of induced pluripotent stem cells from Col1a1 4F2A-Oct4-GFP mice with high efficiency. FEBS J. 2018;285(9):1667–83. doi: 10.1111/febs.14436.
Yu J, Thomson JA. Induced pluripotent stem cells in principles of tissue engineering. London: Elsevier Inc; 2014. doi: 10.1016/C2011-0-07193-4
Koyanagi-Aoi M, Ohnuki M, Takahashi K, Okita K, Noma H, Sawamura Y, et al. Differentiation-defective phenotypes revealed by large-scale analyses of human pluripotent stem cells. Proc Natl Acad Sci U S A. 2013;110(51):20569–74. doi: 10.1073/pnas.1319061110.Epub
Wilson KD, Wu JC. Induced Pluripotent Stem Cells. J Am Med Assoc. 2015;313(16):1613–4. doi: 10.1001/jama.2015.1846.
Cox JL, Angie R. Induced pluripotent stem cells: What lies beyond the paradigm shift. Exp Biol Med (Maywood). 2010;235(2):148–58. doi: 10.1258/ebm.2009.009267.
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):651–5. doi: 10.1016/j.stem.2010.11.015.
Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hämäläinen R, et al. piggyBac transposition reprograms fbroblasts to induced pluripotent. Nature. 2009;458(7239):766–70. doi: 10.1038/nature07863.
Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K. Induced pluripotent stem cells generated without vireal integration. Science. 2008;322(5903):945–9. doi: 10.1126/science.1162494.
Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse indeuced pluripotent stem cells without viral vectors. Science. 2008;322(5903):949–53. doi: 10.1126/science.1164270.
Okita K, Hong H, Takahashi K, Yamanaka S. Generation of mouse induced pluripotent stem cells with plasmid vectors. Nat Protoc. 2010;5(3):418–28. doi: 10.1038/nprot.2009.231.
Zhou HY, Wu SL, Joo JY, Zhu SY, Han DW, Lin TX, et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell. 2009;4(5):381–4. doi: 10.1016/j.stem.2009.04.005.
Ban H, Nishishita N, Fusaki N, Tabata T, Sseki K, Shikamura M, et al. Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors. Proc Natl Acad Sci U S A. 2011; 108(34):14234–9. doi: 10.1073/pnas.1103509108.
Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010;7(5):618–30. doi: 10.1016/j.stem.2010.08.012.
Avior Y, Sagi I, Benvenisty N. Pluripotent stem cells in disease modelling and drug testing. Nat Rev Mol Cell Biol. 2016;17 (3):170–82. doi: 10.1038/nrm.2015.27
Trounson A, DeWitt ND. Pluripotent stem cells progressing to the clinic. Nat Rev Mol Cell Biol. 2016;17(3):194–200. doi: 10.1038/nrm.2016.10.
DOI: https://doi.org/10.15416/ijcp.2020.9.1.56
Refbacks
- There are currently no refbacks.
Indonesian Journal of Clinical Pharmacy is indexed by
