Advertisement

An Insight into DNA-free Reprogramming Approaches to Generate Integration-free Induced Pluripotent Stem Cells for Prospective Biomedical Applications

  • Manash P. Borgohain
  • Krishna Kumar Haridhasapavalan
  • Chandrima Dey
  • Poulomi Adhikari
  • Rajkumar P. ThummerEmail author
Article

Abstract

More than a decade ago, a pioneering study reported generation of induced Pluripotent Stem Cells (iPSCs) by ectopic expression of a cocktail of reprogramming factors in fibroblasts. This study has revolutionized stem cell research and has garnered immense interest from the scientific community globally. iPSCs hold tremendous potential for understanding human developmental biology, disease modeling, drug screening and discovery, and personalized cell-based therapeutic applications. The seminal study identified Oct4, Sox2, Klf4 and c-Myc as a potent combination of genes to induce reprogramming. Subsequently, various reprogramming factors were identified by numerous groups. Most of these studies have used integrating viral vectors to overexpress reprogramming factors in somatic cells to derive iPSCs. However, these techniques restrict the clinical applicability of these cells as they may alter the genome due to random viral integration resulting in insertional mutagenesis and tumorigenicity. To circumvent this issue, alternative integration-free reprogramming approaches are continuously developed that eliminate the risk of genomic modifications and improve the prospects of iPSCs from lab to clinic. These methods establish that integration of transgenes into the genome is not essential to induce pluripotency in somatic cells. This review provides a comprehensive overview of the most promising DNA-free reprogramming techniques that have the potential to derive integration-free iPSCs without genomic manipulation, such as sendai virus, recombinant proteins, microRNAs, synthetic messenger RNA and small molecules. The understanding of these approaches shall pave a way for the generation of clinical-grade iPSCs. Subsequently, these iPSCs can be differentiated into desired cell type(s) for various biomedical applications.

Keywords

Induced pluripotent stem cells Cell reprogramming Reprogramming factors Non-integrative approaches Transgene-free Clinical-grade 

Notes

Acknowledgments

We thank all the members of the Laboratory for Stem Cell Engineering and Regenerative Medicine (SCERM) for their excellent support. This work was supported by grants North Eastern Region – Biotechnology Programme Management Cell (NERBPMC), Department of Biotechnology, Government of India (BT/PR16655/NER/95/132/2015), and by IIT Guwahati Institutional Start-Up Grant.

Compliance with ethical standards

Conflict of interest

The authors declare no potential conflicts of interests.

References

  1. 1.
    Gurdon, J. B. (1962). The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. Journal of Embryology and Experimental Morphology, 10, 622–640.PubMedGoogle Scholar
  2. 2.
    Davis, R. L., Weintraub, H., & Lassar, A. B. (1987). Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell, 51(6), 987–1000.PubMedCrossRefGoogle Scholar
  3. 3.
    Wilmut, I., Schnieke, A. E., McWhir, J., Kind, A. J., & Campbell, K. H. (1997). Viable offspring derived from fetal and adult mammalian cells. Nature, 385(6619), 810.PubMedCrossRefGoogle Scholar
  4. 4.
    Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.PubMedCrossRefGoogle Scholar
  5. 5.
    Takahashi, K., Tanabe, K., Ohnuki, M., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861–872.PubMedCrossRefGoogle Scholar
  6. 6.
    Yu, J., Vodyanik, M. A., Smuga-Otto, K., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858), 1917–1920.PubMedCrossRefGoogle Scholar
  7. 7.
    Evans, M. J., & Kaufman, M. H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292, 154.PubMedCrossRefGoogle Scholar
  8. 8.
    Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145–1147.PubMedCrossRefGoogle Scholar
  9. 9.
    Pietronave, S., & Prat, M. (2012). Advances and applications of induced pluripotent stem cells. Canadian Journal of Physiology and Pharmacology, 90(3), 317–325.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Young, W., D’Souza, S., Lemischka, I., & Schaniel, C. (2012). Patient-specific induced pluripotent stem cells as a platform for disease modeling, drug discovery and precision personalized medicine. Journal of Stem Cell Research & Therapy, S10, 010.Google Scholar
  11. 11.
    Ferreira, L. M. R., & Mostajo-Radji, M. A. (2013). How induced pluripotent stem cells are redefining personalized medicine. Gene, 520(1), 1–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Singh, V. K., Kalsan, M., Kumar, N., Saini, A., & Chandra, R. (2015). Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Frontiers in Cell and Developmental Biology, 3(2).Google Scholar
  13. 13.
    Hu, K. (2014). All roads lead to induced pluripotent stem cells: the technologies of ipsc generation. Stem Cells and Development, 23(12), 1285–1300.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Saha, B., Borgohain, M. P., Chandrima, D., & Thummer, R. P. (2018). iPS cell generation: current and future challenges. Annals of Stem Cell Research & Therapy, 1(2), 1–4.Google Scholar
  15. 15.
    Okita, K., Ichisaka, T., & Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448, 313.PubMedCrossRefGoogle Scholar
  16. 16.
    Ben-David, U., & Benvenisty, N. (2011). The tumorigenicity of human embryonic and induced pluripotent stem cells. Nature Reviews Cancer, 11, 268.PubMedCrossRefGoogle Scholar
  17. 17.
    Sommer, C. A., Christodoulou, C., Gianotti-Sommer, A., et al. (2012). Residual expression of reprogramming factors affects the transcriptional program and epigenetic signatures of induced pluripotent stem cells. PLOS ONE, 7(12), e51711.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Kadari, A., Lu, M., Li, M., et al. (2014). Excision of viral reprogramming cassettes by Cre protein transduction enables rapid, robust and efficient derivation of transgene-free human induced pluripotent stem cells. Stem Cell Research & Therapy, 5(2), 47.CrossRefGoogle Scholar
  19. 19.
    Lamb, R. A., & Parks, G. D. (2007). Paramyxoviridae: the viruses and their replication. In B. N. Fields, D. N. Knipe, & P. M. Howley (Eds.), Fields virology: Fifth Edition (5 ed.): Lippincott Williams & Wilkins.Google Scholar
  20. 20.
    Hu, K. (2014). Vectorology and factor delivery in induced pluripotent stem cell reprogramming. Stem Cells Development, 23(12), 1301–1315.PubMedCrossRefGoogle Scholar
  21. 21.
    Vidal, S., Curran, J., & Kolakofsky, D. (1990). A stuttering model for paramyxovirus P mRNA editing. The EMBO Journal, 9(6), 2017–2022.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Kato, A., Ohnishi, Y., Kohase, M., Saito, S., Tashiro, M., & Nagai, Y. (2001). Y2, the smallest of the Sendai virus C proteins, is fully capable of both counteracting the antiviral action of interferons and inhibiting viral RNA synthesis. Journal of Virology, 75(8), 3802–3810.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Nishimura, K., Sano, M., Ohtaka, M., et al. (2011). Development of defective and persistent Sendai virus vector: a unique gene delivery/expression system ideal for cell reprogramming. Journal of Biological Chemistry, 286(6), 4760–4771.PubMedCrossRefGoogle Scholar
  24. 24.
    Plattet, P., Strahle, L., le Mercier, P., Hausmann, S., Garcin, D., & Kolakofsky, D. (2007). Sendai virus RNA polymerase scanning for mRNA start sites at gene junctions. Virology, 362(2), 411–420.PubMedCrossRefGoogle Scholar
  25. 25.
    Inoue, M., Tokusumi, Y., Ban, H., et al. (2003). Nontransmissible virus-like particle formation by F-deficient sendai virus is temperature sensitive and reduced by mutations in M and HN proteins. Journal Virology, 77(5), 3238–3246.CrossRefGoogle Scholar
  26. 26.
    Fusaki, N., Ban, H., Nishiyama, A., Saeki, K., & Hasegawa, M. (2009). Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proceedings of the Japan Academy, Series B, 85(8), 348–362.CrossRefGoogle Scholar
  27. 27.
    Seki, T., Yuasa, S., Oda, M., et al. (2010). Generation of induced pluripotent stem cells from human terminally differentiated circulating t cells. Cell Stem Cell, 7(1), 11–14.PubMedCrossRefGoogle Scholar
  28. 28.
    Yang, W., Mills, J. A., Sullivan, S., Liu, Y., French, D. L., & Gadue, P. (2008). iPSC reprogramming from human peripheral blood using sendai virus mediated gene transfer stembook. Cambridge: Harvard Stem Cell Institute.Google Scholar
  29. 29.
    Tucker, B. A., Anfinson, K. R., Mullins, R. F., Stone, E. M., & Young, M. J. (2012). Use of a synthetic xeno-free culture substrate for induced pluripotent stem cell induction and retinal differentiation. Stem Cells Translational Medicine, 2(1), 16–24.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Tan, X., Dai, Q., Guo, T., Xu, J., & Dai, Q. (2017). Efficient generation of transgene- and feeder-free induced pluripotent stem cells from human dental mesenchymal stem cells and their chemically defined differentiation into cardiomyocytes. Biochemical and Biophysical Research Communications, 495(4), 2490–2497.PubMedCrossRefGoogle Scholar
  31. 31.
    Cristo, F., Inácio, J. M., Rosas, G., et al. (2017). Generation of human iPSC line from a patient with laterality defects and associated congenital heart anomalies carrying a DAND5 missense alteration. Stem Cell Research, 25, 152–156.PubMedCrossRefGoogle Scholar
  32. 32.
    Boonkaew, B., Tapeng, L., Netsrithong, R., Vatanashevanopakorn, C., Pattanapanyasat, K., & Wattanapanitch, M. (2018). Induced pluripotent stem cell line MUSIi006-A derived from hair follicle keratinocytes as a non-invasive somatic cell source. Stem Cell Research, 31, 79–82.PubMedCrossRefGoogle Scholar
  33. 33.
    Ban, H., Nishishita, N., Fusaki, N., et al. (2011). Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors. Proceedings of the National Academy of Sciences USA, 108(34), 14234–14239.CrossRefGoogle Scholar
  34. 34.
    Nishimura, K., Ohtaka, M., Takada, H., et al. (2017). Simple and effective generation of transgene-free induced pluripotent stem cells using an auto-erasable Sendai virus vector responding to microRNA-302. Stem Cell Research, 23, 13–19.PubMedCrossRefGoogle Scholar
  35. 35.
    Suh, M.-R., Lee, Y., Kim, J. Y., et al. (2004). Human embryonic stem cells express a unique set of microRNAs. Developmental Biology, 270(2), 488–498.PubMedCrossRefGoogle Scholar
  36. 36.
    Wilson, K. D., Venkatasubrahmanyam, S., Jia, F., Sun, N., Butte, A. J., & Wu, J. C. (2009). MicroRNA profiling of human-induced pluripotent stem cells. Stem Cells Development, 18(5), 749–758.PubMedCrossRefGoogle Scholar
  37. 37.
    Anokye-Danso, F., Trivedi, C. M., Juhr, D., et al. (2011). Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell, 8(4), 376–388.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Bitzer, M., Armeanu, S., Lauer, U. M., & Neubert, W. J. (2003). Sendai virus vectors as an emerging negative-strand RNA viral vector system. Journal of Gene Medicine, 5(7), 543–553.PubMedCrossRefGoogle Scholar
  39. 39.
    Hosoya, N., Miura, T., Kawana-Tachikawa, A., et al. (2008). Comparison between Sendai virus and adenovirus vectors to transduce HIV-1 genes into human dendritic cells. Journal of Medical Virology, 80(3), 373–382.PubMedCrossRefGoogle Scholar
  40. 40.
    Rao, M. S., & Malik, N. (2012). Assessing iPSC reprogramming methods for their suitability in translational medicine. Journal of Cellular Biochemistry, 113(10), 3061–3068.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Bayart, E., & Cohen-Haguenauer, O. (2013). Technological overview of iPS induction from human adult somatic cells. Current Gene Therapy, 13(2), 73–92.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Schlaeger, T. M., Daheron, L., Brickler, T. R., et al. (2015). A comparison of non-integrating reprogramming methods. Nature Biotechnology, 33(1), 58.PubMedCrossRefGoogle Scholar
  43. 43.
    Beers, J., Linask, K. L., Chen, J. A., et al. (2015). A cost-effective and efficient reprogramming platform for large-scale production of integration-free human induced pluripotent stem cells in chemically defined culture. Scientific Reports, 5, 11319.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Li, X., Zhang, P., Wei, C., & Zhang, Y. (2014). Generation of pluripotent stem cells via protein transduction. The International Journal of Developmental Biology, 58(1), 21–27.PubMedCrossRefGoogle Scholar
  45. 45.
    Kaitsuka, T., & Tomizawa, K. (2015). Cell-penetrating peptide as a means of directing the differentiation of induced-pluripotent stem cells. International Journal of Molecular Sciences, 16(11), 25986.CrossRefGoogle Scholar
  46. 46.
    Dey, C., Narayan, G., Kumar, H. K., Borgohain, M. P., Lenka, N., & Thummer, R. P. (2017). Cell-penetrating peptides as a tool to deliver biologically active recombinant proteins to generate transgene-free induced pluripotent stem cells. Studies on Stem Cells Research and Therapy, 3(1), 006–015.Google Scholar
  47. 47.
    Seo, B., Hong, Y., & Do, J. (2017). Cellular reprogramming using protein and cell-penetrating peptides. International Journal of Molecular Sciences, 18(3), 552.PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Zhou, H., Wu, S., Joo, J. Y., et al. (2009). Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell, 4(5), 381–384.PubMedCrossRefGoogle Scholar
  49. 49.
    Kim, D., Kim, C. H., Moon, J. I., et al. (2009). Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell, 4(6), 472–476.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Cho, H. J., Lee, C. S., Kwon, Y. W., et al. (2010). Induction of pluripotent stem cells from adult somatic cells by protein-based reprogramming without genetic manipulation. Blood, 116(3), 386–395.PubMedCrossRefGoogle Scholar
  51. 51.
    Walev, I., Bhakdi, S. C., Hofmann, F., et al. (2001). Delivery of proteins into living cells by reversible membrane permeabilization with streptolysin-O. Proceedings of the National Academy Sciences U S A, 98(6), 3185–3190.CrossRefGoogle Scholar
  52. 52.
    Zhang, H., Ma, Y., Gu, J., Liao, B., Li, J., Wong, J., & Jin, Y. (2012). Reprogramming of somatic cells via TAT-mediated protein transduction of recombinant factors. Biomaterials, 33(20), 5047–5055.PubMedCrossRefGoogle Scholar
  53. 53.
    Takashina, T., Koyama, T., Nohara, S., et al. (2018). Identification of a cell-penetrating peptide applicable to a protein-based transcription activator-like effector expression system for cell engineering. Biomaterials, 173, 11–21.PubMedCrossRefGoogle Scholar
  54. 54.
    Nemes, C., Varga, E., Polgar, Z., Klincumhom, N., Pirity, M. K., & Dinnyes, A. (2013). Generation of mouse induced pluripotent stem cells by protein transduction. Tissue Engineering Part C: Methods, 20(5), 383–392.CrossRefGoogle Scholar
  55. 55.
    Khan, M., Narayanan, K., Lu, H., et al. (2013). Delivery of reprogramming factors into fibroblasts for generation of non-genetic induced pluripotent stem cells using a cationic bolaamphiphile as a non-viral vector. Biomaterials, 34(21), 5336–5343.PubMedCrossRefGoogle Scholar
  56. 56.
    Fuhrhop, J.-H., & Wang, T. (2004). Bolaamphiphiles. Chemical Reviews, 104(6), 2901–2938.PubMedCrossRefGoogle Scholar
  57. 57.
    Lee, J., Sayed, N., Hunter, A., et al. (2012). Activation of innate immunity is required for efficient nuclear reprogramming. Cell, 151(3), 547–558.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Thier, M., Münst, B., & Edenhofer, F. (2010). Exploring refined conditions for reprogramming cells by recombinant Oct4 protein. The International Journal of Developmental Biology, 54(11-12), 1713–1721.PubMedCrossRefGoogle Scholar
  59. 59.
    Thier, M., Münst, B., Mielke, S., & Edenhofer, F. (2012). Cellular reprogramming employing recombinant Sox2 protein. Stem Cells International, 2012, 10.Google Scholar
  60. 60.
    Ryu, J., Park, H. H., Park, J. H., Lee, H. J., Rhee, W. J., & Park, T. H. (2016). Soluble expression and stability enhancement of transcription factors using 30Kc19 cell-penetrating protein. Applied Microbiology and Biotechnology, 100(8), 3523–3532.PubMedCrossRefGoogle Scholar
  61. 61.
    Konno, M., Masui, S., Hamazaki, T. S., & Okochi, H. (2011). Intracellular reactivation of transcription factors fused with protein transduction domain. Journal of Biotechnology, 154(4), 298–303.PubMedCrossRefGoogle Scholar
  62. 62.
    Steichen, C., Luce, E., Maluenda, J., et al. (2014). Messenger RNA- versus retrovirus-based induced pluripotent stem cell reprogramming strategies: analysis of genomic integrity. Stem Cells Translational Medicine, 3(6), 686–691.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Yakubov, E., Rechavi, G., Rozenblatt, S., & Givol, D. (2010). Reprogramming of human fibroblasts to pluripotent stem cells using mRNA of four transcription factors. Biochemical and Biophysical Research Communications, 394(1), 189–193.PubMedCrossRefGoogle Scholar
  64. 64.
    Plews, J. R., Li, J., Jones, M., Moore, H. D., Mason, C., Andrews, P. W., & Na, J. (2010). Activation of pluripotency genes in human fibroblast cells by a novel mRNA based approach. PLOS ONE, 5(12), e14397.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Drews, K., Tavernier, G., Demeester, J., et al. (2012). The cytotoxic and immunogenic hurdles associated with non-viral mRNA-mediated reprogramming of human fibroblasts. Biomaterials, 33, 4059–4068.PubMedCrossRefGoogle Scholar
  66. 66.
    Angel, M., & Yanik, M. F. (2010). Innate immune suppression enables frequent transfection with rna encoding reprogramming proteins. PLOS ONE, 5(7), e11756.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Warren, L., Manos, P. D., Ahfeldt, T., et al. (2010). Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell, 7(5), 618–630.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Preskey, D., Allison, T. F., Jones, M., Mamchaoui, K., & Unger, C. (2016). Synthetically modified mRNA for efficient and fast human iPS cell generation and direct transdifferentiation to myoblasts. Biochemical and Biophysical Research Communication, 473(3), 743–751.CrossRefGoogle Scholar
  69. 69.
    Rohani, L., Fabian, C., Holland, et al. (2016). Generation of human induced pluripotent stem cells using non-synthetic mRNA. Stem Cell Research, 16(3), 662–672.PubMedCrossRefGoogle Scholar
  70. 70.
    Choi, H. Y., Lee, T. J., Yang, G. M., et al. (2016). Efficient mRNA delivery with graphene oxide-polyethylenimine for generation of footprint-free human induced pluripotent stem cells. Journal of Control Release, 235, 222–235.CrossRefGoogle Scholar
  71. 71.
    Tavernier, G., Wolfrum, K., Demeester, J., De Smedt, S. C., Adjaye, J., & Rejman, J. (2012). Activation of pluripotency-associated genes in mouse embryonic fibroblasts by non-viral transfection with in vitro-derived mRNAs encoding Oct4, Sox2. Klf4 and cMyc. Biomaterials, 33(2), 412–417.PubMedCrossRefGoogle Scholar
  72. 72.
    El-Sayed, A. K., Zhang, Z., Zhang, L., Liu, Z., Abbott, L. C., Zhang, Y., & Li, B. (2014). Pluripotent state induction in mouse embryonic fibroblast using mRNAs of reprogramming factors. International Journal of Molecular Sciences, 15(12), 21840–21864.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Poleganov, M. A., Eminli, S., Beissert, T., et al. (2015). Efficient reprogramming of human fibroblasts and blood-derived endothelial progenitor cells using nonmodified RNA for reprogramming and immune evasion. Human Gene Therapy, 26(11), 751–766.PubMedCrossRefGoogle Scholar
  74. 74.
    Yoshioka, N., Gros, E., Li, H. R., et al. (2013). Efficient generation of human iPSCs by a synthetic self-replicative RNA. Cell Stem Cell, 13(2), 246–254.PubMedCrossRefGoogle Scholar
  75. 75.
    Artero Castro, A., León, M., del Buey Furió, V., Erceg, S., & Lukovic, D. (2018). Generation of a human iPSC line by mRNA reprogramming. Stem Cell Research, 28, 157–160.PubMedCrossRefGoogle Scholar
  76. 76.
    Mandal, P. K., & Rossi, D. J. (2013). Reprogramming human fibroblasts to pluripotency using modified mRNA. Nature Protocols, 8(3), 568–582.PubMedCrossRefGoogle Scholar
  77. 77.
    Yoshioka, N., & Dowdy, S. F. (2017). Enhanced generation of iPSCs from older adult human cells by a synthetic five-factor self-replicative RNA. PLOS ONE, 12(7), e0182018.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Arnold, A., Naaldijk, Y. M., Fabian, C., et al. (2012). Reprogramming of human huntington fibroblasts using mRNA. ISRN Cell Biology, 2012, 12.CrossRefGoogle Scholar
  79. 79.
    Heng, B. C., Heinimann, K., Miny, P., et al. (2013). mRNA transfection-based, feeder-free, induced pluripotent stem cells derived from adipose tissue of a 50-year-old patient. Metabolic Engineering, 18, 9–24.PubMedCrossRefGoogle Scholar
  80. 80.
    Warren, L., Ni, Y., Wang, J., & Guo, X. (2012). Feeder-free derivation of human induced pluripotent stem cells with messenger RNA. Scientific Reports, 2, 657.Google Scholar
  81. 81.
    Warren, L., & Wang, J. (2013). Feeder-free reprogramming of human fibroblasts with messenger RNA. Current Protocols in Stem Cell Biology, 27, Unit 4A.6.CrossRefGoogle Scholar
  82. 82.
    Durruthy-Durruthy, J., Briggs, S. F., Awe, J., et al. (2014). Rapid and efficient conversion of integration-free human induced pluripotent stem cells to GMP-grade culture conditions. PLOS ONE, 9(4), e94231.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Durruthy, J. D., & Sebastiano, V. (2015). Derivation of gmp-compliant integration-free hiPSCs using modified mRNAs. In K. Turksen (Ed.), Stem Cells and Good Manufacturing Practices: Methods, Protocols, and Regulations (pp. 31–42). New York: Springer New York.Google Scholar
  84. 84.
    Lee, K. I., Lee, S. Y., & Hwang, D. Y. (2016). Extracellular matrix-dependent generation of integration- and xeno-free iPS cells using a modified mRNA transfection method. Stem Cells International, 2016, 1–11.Google Scholar
  85. 85.
    Kogut, I., McCarthy, S. M., Pavlova, M., et al. (2018). High-efficiency RNA-based reprogramming of human primary fibroblasts. Nature Communications, 9(1), 745.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    He, L., & Hannon, G. J. (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nature Reviews Genetics, 5, 522.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Wang, Y., Xu, Z., Jiang, J., et al. (2013). Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Developmental Cell, 25(1), 69–80.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Cao, Y., Guo, W. T., Tian, S., et al. (2015). miR-290/371-Mbd2-Myc circuit regulates glycolytic metabolism to promote pluripotency. The EMBO Journal.Google Scholar
  89. 89.
    Ma, Y., Yao, N., Liu, G., et al. (2015). Functional screen reveals essential roles of miR-27a/24 in differentiation of embryonic stem cells. The EMBO Journal, 34(3), 361–378.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Gu, K.-L., Zhang, Q., Yan, Y., et al. (2016). Pluripotency-associated miR-290/302 family of microRNAs promote the dismantling of naive pluripotency. Cell Research, 26, 350.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Li, Z., Yang, C. S., Nakashima, K., & Rana, T. M. (2011). Small RNA-mediated regulation of iPS cell generation. The EMBO Journal, 30(5), 823–834.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Kim, B. M., Thier, M. C., Oh, S., et al. (2012). MicroRNAs are indispensable for reprogramming mouse embryonic fibroblasts into induced stem cell-like cells. PLOS ONE, 7(6), e39239.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Chen, J., Wang, G., Lu, C., et al. (2012). Synergetic cooperation of microRNAs with transcription factors in iPS cell generation. PLOS ONE, 7(7), e40849.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Miyoshi, N., Ishii, H., Nagano, H., et al. (2011). Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell, 8(6), 633–638.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Lu, D., Davis, M. P. A., Abreu-Goodger, C., et al. (2012). MiR-25 regulates Wwp2 and Fbxw7 and promotes reprogramming of mouse fibroblast cells to iPSCs. PLOS ONE, 7(8), e40938.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Lee, M. R., Prasain, N., Chae, H. D., Kim, Y. J., Mantel, C., Yoder, M. C., & Broxmeyer, H. E. (2013). Epigenetic regulation of NANOG by miR-302 cluster-MBD2 completes induced pluripotent stem cell reprogramming. Stem Cells, 31(4), 666–681.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Hu, S., Wilson, K. D., Ghosh, Z., et al. (2013). MicroRNA-302 increases reprogramming efficiency via repression of NR2F2. Stem Cells, 31(2), 259–268.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Judson, R. L., Babiarz, J. E., Venere, M., & Blelloch, R. (2009). Embryonic stem cell-specific microRNAs promote induced pluripotency. Nature Biotechnology, 27(5), 459–461.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Liao, B., Bao, X., Liu, L., et al. (2011). MicroRNA cluster 302-367 enhances somatic cell reprogramming by accelerating a mesenchymal-to-epithelial transition. Journal Biological Chemistry, 286(19), 17359–17364.CrossRefGoogle Scholar
  100. 100.
    Subramanyam, D., Lamouille, S., Judson, R. L., et al. (2011). Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nature Biotechnology, 29(5), 443–448.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Judson, R. L., Greve, T. S., Parchem, R. J., & Blelloch, R. (2013). MicroRNA-based discovery of barriers to dedifferentiation of fibroblasts to pluripotent stem cells. Nature Structural & Molecular Biology, 20, 1227.CrossRefGoogle Scholar
  102. 102.
    Greer Card, D. A., Hebbar, P. B., Li, L., et al. (2008). Oct4/Sox2-regulated miR-302 targets cyclin D1 in human embryonic stem cells. Molecular and Cellular Biology, 28(20), 6426–6438.PubMedCentralCrossRefPubMedGoogle Scholar
  103. 103.
    Zhang, Z., Xiang, D., Heriyanto, F., Gao, Y., Qian, Z., & Wu, W. S. (2013). Dissecting the roles of miR-302/367 cluster in cellular reprogramming using TALE-based repressor and TALEN. Stem Cell Reports, 1(3), 218–225.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Chang, H.-M., & Gregory, R. I. (2010). MicroRNA-induced pluripotent stem cells. Cell Stem Cell, 7(1), 31–35.PubMedCentralCrossRefPubMedGoogle Scholar
  105. 105.
    Li, W., Jiang, K., & Ding, S. (2012). Concise review: A chemical approach to control cell fate and function. Stem Cells, 30(1), 61–68.PubMedCrossRefGoogle Scholar
  106. 106.
    Feng, B., Ng, J.-H., Heng, J.-C. D., & Ng, H.-H. (2009). Molecules that promote or enhance reprogramming of somatic cells to induced pluripotent stem cells. Cell Stem Cell, 4(4), 301–312.PubMedCrossRefGoogle Scholar
  107. 107.
    Huangfu, D., Maehr, R., Guo, W., et al. (2008). Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nature Biotechnology, 26, 795.PubMedCrossRefGoogle Scholar
  108. 108.
    Huangfu, D., Osafune, K., Maehr, R., et al. (2008). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnology, 26(11), 1269–1275.PubMedCrossRefGoogle Scholar
  109. 109.
    Zhai, Y., Chen, X., Yu, D., et al. (2015). Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress. Experimental Cell Research, 337(1), 61–67.PubMedCrossRefGoogle Scholar
  110. 110.
    Mikkelsen, T. S., Hanna, J., Zhang, X., et al. (2008). Dissecting direct reprogramming through integrative genomic analysis. Nature, 454, 49.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Liang, G., Taranova, O., Xia, K., & Zhang, Y. (2010). Butyrate promotes induced pluripotent stem cell generation. Journal of Biological Chemistry, 285(33), 25516–25521.PubMedCrossRefGoogle Scholar
  112. 112.
    Mali, P., Chou, B. K., Yen, J., et al. (2011). Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells, 28(4), 713–720.CrossRefGoogle Scholar
  113. 113.
    Pasha, Z., Haider, H., & Ashraf, M. (2011). Efficient non-viral reprogramming of myoblasts to stemness with a single small molecule to generate cardiac progenitor cells. PLOS ONE, 6(8), e23667.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Esteban, M. A., Wang, T., Qin, B., et al. (2010). Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell, 6(1), 71–79.PubMedCrossRefGoogle Scholar
  115. 115.
    Chung, T.-L., Brena, R. M., Kolle, G., et al. (2010). Vitamin C promotes widespread yet specific DNA demethylation of the epigenome in human embryonic stem cells. Stem Cells, 28(10), 1848–1855.PubMedCrossRefGoogle Scholar
  116. 116.
    Gao, Y., Han, Z., Li, Q., et al. (2015). Vitamin C induces a pluripotent state in mouse embryonic stem cells by modulating microRNA expression. FEBS Journal, 282(4), 685–699.PubMedCrossRefGoogle Scholar
  117. 117.
    Wang, Q., Xu, X., Li, J., et al. (2011). Lithium, an anti-psychotic drug, greatly enhances the generation of induced pluripotent stem cells. Cell Research, 21, 1424.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Li, W., Tian, E., Chen, Z. X., et al. (2012). Identification of Oct4-activating compounds that enhance reprogramming efficiency. Proceedings of the National Academy of Sciences U S A, 109(51), 20853–20858.CrossRefGoogle Scholar
  119. 119.
    Shi, Y., Desponts, C., Do, J. T., Hahm, H. S., Scholer, H. R., & Ding, S. (2008). Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell, 3(5), 568–574.PubMedCrossRefGoogle Scholar
  120. 120.
    Feldman, N., Gerson, A., Fang, J., et al. (2006). G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nature Cell Biology, 8, 188.PubMedCrossRefGoogle Scholar
  121. 121.
    Shi, Y., Do, J. T., Desponts, C., Hahm, H. S., Scholer, H. R., & Ding, S. (2008). A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell, 2(6), 525–528.PubMedCrossRefGoogle Scholar
  122. 122.
    Desponts, C., & Ding, S. (2010). Using Small Molecules to Improve Generation of Induced Pluripotent Stem Cells from Somatic Cells. In S. Ding (Ed.), Cellular Programming and Reprogramming: Methods and Protocols (pp. 207–218). Totowa: Humana Press.CrossRefGoogle Scholar
  123. 123.
    Lyssiotis, C. A., Foreman, R. K., Staerk, J., et al. (2009). Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4. Proceedings of the National Academy of Sciences USA, 106(22), 8912–8917.CrossRefGoogle Scholar
  124. 124.
    Li, W., Zhou, H., Abujarour, R., et al. (2009). Generation of human-induced pluripotent stem cells in the absence of exogenous Sox2. Stem Cells, 27(12), 2992–3000.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Ichida, J. K., Blanchard, J., Lam, K., et al. (2009). A small-molecule inhibitor of Tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell, 5(5), 491–503.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Staerk, J., Lyssiotis, C. A., Medeiro, L. A., et al. (2011). Pan-Src family kinase inhibitors replace Sox2 during the direct reprogramming of somatic cells. Angewandte Chemie International Edition in English, 50(25), 5734–5736.PubMedCrossRefGoogle Scholar
  127. 127.
    Onder, T. T., Kara, N., Cherry, A., et al. (2012). Chromatin modifying enzymes as modulators of reprogramming. Nature, 483(7391), 598–602.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Zhu, S., Li, W., Zhou, H., et al. (2010). Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell, 7(6), 651–655.PubMedCrossRefGoogle Scholar
  129. 129.
    Li, Y., Zhang, Q., Yin, X., et al. (2011). Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Research, 21, 196.PubMedCrossRefGoogle Scholar
  130. 130.
    Hou, P., Li, Y., Zhang, X., et al. (2013). Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science, 341(6146), 651–654.PubMedCrossRefGoogle Scholar
  131. 131.
    Long, Y., Wang, M., Gu, H., & Xie, X. (2015). Bromodeoxyuridine promotes full-chemical induction of mouse pluripotent stem cells. Cell Research, 25, 1171.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Zhao, Y., Zhao, T., Guan, J., et al. (2015). A XEN-like state bridges somatic cells to pluripotency during chemical reprogramming. Cell, 163(7), 1678–1691.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Ye, J., Ge, J., Zhang, X., et al. (2016). Pluripotent stem cells induced from mouse neural stem cells and small intestinal epithelial cells by small molecule compounds. Cell Research, 26(1), 34–45.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Lluis, F., Pedone, E., Pepe, S., & Cosma, M. P. (2008). Periodic activation of Wnt/beta-catenin signaling enhances somatic cell reprogramming mediated by cell fusion. Cell Stem Cell, 3(5), 493–507.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Marson, A., Foreman, R., Chevalier, B., et al. (2008). Wnt signaling promotes reprogramming of somatic cells to pluripotency. Cell Stem Cell, 3(2), 132–135.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Moon, J.-H., Heo, J. S., Kim, J. S., et al. (2011). Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1. Cell Research, 21, 1305.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Maherali, N., & Hochedlinger, K. (2009). Tgf-beta signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc. Current Biology, 19(20), 1718–1723.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Lin, T., Ambasudhan, R., Yuan, X., et al. (2009). A chemical platform for improved induction of human iPSCs. Nature Methods, 6(11), 805–808.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Samavarchi-Tehrani, P., Golipour, A., David, L., et al. (2010). Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell, 7(1), 64–77.PubMedCrossRefGoogle Scholar
  140. 140.
    Yuan, X., Wan, H., Zhao, X., et al. (2011). Brief report: combined chemical treatment enables Oct4-induced reprogramming from mouse embryonic fibroblasts. Stem Cells, 29(3), 549–553.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Silva, J., Barrandon, O., Nichols, J., Kawaguchi, J., Theunissen, T. W., & Smith, A. (2008). Promotion of reprogramming to ground state pluripotency by signal inhibition. PLOS Biology, 6(10), e253.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Li, Z., & Rana, T. M. (2012). A kinase inhibitor screen identifies small-molecule enhancers of reprogramming and iPS cell generation. Nature Communication, 3, 1085.CrossRefGoogle Scholar
  143. 143.
    Kang, P. J., Moon, J. H., Yoon, B. S., et al. (2014). Reprogramming of mouse somatic cells into pluripotent stem-like cells using a combination of small molecules. Biomaterials, 35(26), 7336–7345.PubMedCrossRefGoogle Scholar
  144. 144.
    Lai, W. H., Ho, J. C., Lee, Y. K., et al. (2010). ROCK inhibition facilitates the generation of human-induced pluripotent stem cells in a defined, feeder-, and serum-free system. Cellular Reprogramming, 12(6), 641–653.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Li, W., Wei, W., Zhu, S., et al. (2009). Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell, 4(1), 16–19.PubMedCrossRefGoogle Scholar
  146. 146.
    Yu, J., Chau, K. F., Vodyanik, M. A., Jiang, J., & Jiang, Y. (2011). Efficient feeder-free episomal reprogramming with small molecules. PLOS ONE, 6(3), e17557.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Theunissen, T. W., van Oosten, A. L., Castelo-Branco, G., Hall, J., Smith, A., & Silva, J. C. (2011). Nanog overcomes reprogramming barriers and induces pluripotency in minimal conditions. Current Biology, 21(1), 65–71.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Wei, X., Chen, Y., Xu, Y., et al. (2014). Small molecule compound induces chromatin de-condensation and facilitates induced pluripotent stem cell generation. Journal Molecular Cell Biology, 6(5), 409–420.CrossRefGoogle Scholar
  149. 149.
    Bar-Nur, O., Brumbaugh, J., Verheul, C., et al. (2014). Small molecules facilitate rapid and synchronous iPSC generation. Nature Methods, 11(11), 1170–1176.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Li, D., Wang, L., Hou, J., et al. (2016). optimized approaches for generation of integration-free iPSCs from human urine-derived cells with small molecules and autologous feeder. Stem Cell Reports, 6(5), 717–728.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Guo, Y., Yu, Q., Mathew, S., et al. (2017). Cocktail of chemical compounds and recombinant proteins robustly promote the stemness of adipose-derived stem cells. Cellular Reprograming, 19(6), 363–371.CrossRefGoogle Scholar
  152. 152.
    Zhang, Y., Li, W., Laurent, T., & Ding, S. (2012). Small molecules, big roles – the chemical manipulation of stem cell fate and somatic cell reprogramming. Journal of Cell Science, 125(23), 5609–5620.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Efe, J. A., & Ding, S. (2011). The evolving biology of small molecules: controlling cell fate and identity. Philosophical Transactions of the Royal Society B: Biological Sciences, 366(1575), 2208–2221.CrossRefGoogle Scholar
  154. 154.
    Peterson, B., Collins, A., Vogelzang, N., & Bloomfield, C. (1981). 5-Azacytidine and renal tubular dysfunction. Blood, 57(1), 182–185.PubMedPubMedCentralGoogle Scholar
  155. 155.
    Jackson-Grusby, L., Laird, P. W., Magge, S. N., Moeller, B. J., & Jaenisch, R. (1997). Mutagenicity of 5-aza-2'-deoxycytidine is mediated by the mammalian DNA methyltransferase. Proceedings of the National Academy of Sciences U S A, 94(9), 4681–4685.CrossRefGoogle Scholar
  156. 156.
    Gaudet, F., Hodgson, J. G., Eden, A., et al. (2003). Induction of tumors in mice by genomic hypomethylation. Science, 300(5618), 489–492.PubMedCrossRefGoogle Scholar
  157. 157.
    Marchion, D. C., Bicaku, E., Daud, A. I., Sullivan, D. M., & Munster, P. N. (2005). Valproic acid alters chromatin structure by regulation of chromatin modulation proteins. Cancer Research, 65(9), 3815–3822.PubMedCrossRefGoogle Scholar
  158. 158.
    Chateauvieux, S., Morceau, F., Dicato, M., & Diederich, M. (2010). Molecular and therapeutic potential and toxicity of valproic acid. Journal of Biomedicine and Biotechnology, 2010, 479364.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Maherali, N., & Hochedlinger, K. (2008). Guidelines and Techniques for the Generation of Induced Pluripotent Stem Cells. Cell Stem Cell, 3(6), 595–605.PubMedCrossRefGoogle Scholar
  160. 160.
    Ebrahimi, B. (2016). Chemical-only reprogramming to pluripotency. Frontiers in Biology, 11(2), 75–84.CrossRefGoogle Scholar
  161. 161.
    O’Malley, J., Woltjen, K., & Kaji, K. (2009). New strategies to generate induced pluripotent stem cells. Current Opinion in Biotechnology, 20(5), 516–521.PubMedCrossRefGoogle Scholar
  162. 162.
    Gonzalez, F., Boue, S., & Izpisua Belmonte, J. C. (2011). Methods for making induced pluripotent stem cells: reprogramming a la carte. Nature Reviews Genetics, 12(4), 231–242.PubMedCrossRefGoogle Scholar
  163. 163.
    Sommer, C. A., & Mostoslavsky, G. (2012). The evolving field of induced pluripotency: Recent progress and future challenges. Journal of Cellular Physiology, 228(2), 267–275.CrossRefGoogle Scholar
  164. 164.
    Hasan, M. K., Kato, A., Shioda, T., Sakai, Y., Yu, D., & Nagai, Y. (1997). Creation of an infectious recombinant Sendai virus expressing the firefly luciferase gene from the 3' proximal first locus. Journal of General Virology, 78(Pt 11), 2813–2820.PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Li, H. O., Zhu, Y. F., Asakawa, M., et al. (2000). A cytoplasmic RNA vector derived from nontransmissible Sendai virus with efficient gene transfer and expression. Journal of Virology, 74(14), 6564–6569.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Inoue, M., Tokusumi, Y., Ban, H., et al. (2003). A new Sendai virus vector deficient in the matrix gene does not form virus particles and shows extensive cell-to-cell spreading. Journal of Virology, 77(11), 6419–6429.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Yoshizaki, M., Hironaka, T., Iwasaki, H., et al. (2006). Naked Sendai virus vector lacking all of the envelope-related genes: reduced cytopathogenicity and immunogenicity. Journal of Gene Medicine, 8(9), 1151–1159.PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Lee, Y., Kim, M., Han, J., et al. (2004). MicroRNA genes are transcribed by RNA polymerase II. The EMBO Journal, 23(20), 4051–4060.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Borchert, G. M., Lanier, W., & Davidson, B. L. (2006). RNA polymerase III transcribes human microRNAs. Nature Structural and Molecular Biology, 13(12), 1097–1101.PubMedCrossRefGoogle Scholar
  170. 170.
    Yi, R., & Fuchs, E. (2011). MicroRNAs and their roles in mammalian stem cells. Journal of Cell Science, 124(11), 1775–1783.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Westholm, J. O., & Lai, E. C. (2011). Mirtrons: microRNA biogenesis via splicing. Biochimie, 93(11), 1897–1904.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Macarthur, C. C., Fontes, A., Ravinder, N., et al. (2012). Generation of human-induced pluripotent stem cells by a nonintegrating RNA Sendai virus vector in feeder-free or xeno-free conditions. Stem Cells International, 2012, 564612.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Lieu, P. T., Fontes, A., Vemuri, M. C., & MacArthur, C. C. (2013). generation of induced pluripotent stem cells with CytoTune, a non-integrating sendai virus. In U. Lakshmipathy & M. C. Vemuri (Eds.), Pluripotent Stem Cells: Methods and Protocols (pp. 45–56). Totowa: Humana Press.CrossRefGoogle Scholar
  174. 174.
    Chen, I.-P., Fukuda, K., Fusaki, N., et al. (2013). Induced pluripotent stem cell reprogramming by integration-free sendai virus vectors from peripheral blood of patients with craniometaphyseal dysplasia. Cellular Reprogramming, 15(6), 503–513.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Trokovic, R., Weltner, J., Nishimura, K., et al. (2014). Advanced feeder-free generation of induced pluripotent stem cells directly from blood cells. Stem Cells Translational Medicine, 3(12), 1402–1409.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Trokovic, R., Weltner, J., Manninen, T., et al. (2013). Small molecule inhibitors promote efficient generation of induced pluripotent stem cells from human skeletal myoblasts. Stem Cells and Development, 22(1), 114–123.PubMedCrossRefPubMedCentralGoogle Scholar
  177. 177.
    Tan, H.-K., Toh, C.-X. D., Ma, D., et al. (2014). Human finger-prick induced pluripotent stem cells facilitate the development of stem cell banking. Stem Cells Translational Medicine, 3(5), 586–598.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Jiang, G., Di Bernardo, J., Maiden, M. M., et al. (2014). Human transgene-free amniotic-fluid-derived induced pluripotent stem cells for autologous cell therapy. Stem Cells and Development, 23(21), 2613–2625.PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    Wiley, L. A., Burnight, E. R., DeLuca, A. P., et al. (2016). cGMP production of patient-specific iPSCs and photoreceptor precursor cells to treat retinal degenerative blindness. Scientific Reports, 6, 30742.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Lin, S. L., Chang, D. C., Chang-Lin, S., Lin, C. H., Wu, D. T., Chen, D. T., & Ying, S. Y. (2008). Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state. RNA, 14(10), 2115–2124.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Lin, S. L., Chang, D. C., Lin, C. H., Ying, S. Y., Leu, D., & Wu, D. T. (2011). Regulation of somatic cell reprogramming through inducible mir-302 expression. Nucleic Acids Research, 39(3), 1054–1065.PubMedCrossRefPubMedCentralGoogle Scholar
  182. 182.
    Pfaff, N., Fiedler, J., Holzmann, A., et al. (2011). miRNA screening reveals a new miRNA family stimulating iPS cell generation via regulation of Meox2. EMBO Reports, 12(11), 1153–1159.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Ye, D., Wang, G., Liu, Y., et al. (2012). MiR-138 promotes induced pluripotent stem cell generation through the regulation of the p53 signaling. Stem Cells, 30(8), 1645–1654.PubMedCrossRefPubMedCentralGoogle Scholar
  184. 184.
    Wang, G., Guo, X., Hong, W., et al. (2013). Critical regulation of miR-200/ZEB2 pathway in Oct4/Sox2-induced mesenchymal-to-epithelial transition and induced pluripotent stem cell generation. Proceedings of the National Academy of Sciences, 110(8), 2858–2863.CrossRefGoogle Scholar
  185. 185.
    Guo, X., Liu, Q., Wang, G., et al. (2013). microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming. Cell Research, 23(1), 142–156.PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Li, Z., Dang, J., Chang, K.-Y., & Rana, T. M. (2014). MicroRNA-mediated regulation of extracellular matrix formation modulates somatic cell reprogramming. RNA, 20(12), 1900–1915.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    He, X., Cao, Y., Wang, L., et al. (2014). Human fibroblast reprogramming to pluripotent stem cells regulated by the miR19a/b-PTEN axis. PLOS ONE, 9(4), e95213.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Konno, M., Koseki, J., Kawamoto, K., et al. (2015). Embryonic MicroRNA-369 Controls Metabolic Splicing Factors and Urges Cellular Reprograming. PLOS ONE, 10(7), e0132789.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Lee, M. R., Mantel, C., Lee, S. A., Moon, S. H., & Broxmeyer, H. E. (2016). MiR-31/SDHA axis regulates reprogramming efficiency through mitochondrial metabolism. Stem Cell Reports, 7(1), 1–10.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Nguyen, P. N. N., Choo, K. B., Huang, C.-J., Sugii, S., Cheong, S. K., & Kamarul, T. (2017). miR-524-5p of the primate-specific C19MC miRNA cluster targets TP53IPN1- and EMT-associated genes to regulate cellular reprogramming. Stem Cell Research & Therapy, 8(1), 214.CrossRefGoogle Scholar
  191. 191.
    Wu, F., Tao, L., Gao, S., et al. (2017). miR-6539 is a novel mediator of somatic cell reprogramming that represses the translation of Dnmt3b. Journal of Reproductive Development, 63(4), 415–423.CrossRefGoogle Scholar
  192. 192.
    Cha, Y., Han, M. J., Cha, H. J., et al. (2017). Metabolic control of primed human pluripotent stem cell fate and function by the miR-200c–SIRT2 axis. Nature Cell Biology, 19, 445.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Yang, C. S., Li, Z., & Rana, T. M. (2011). microRNAs modulate iPS cell generation. RNA, 17(8), 1451–1460.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Choi, Y. J., Lin, C. P., Ho, J. J., et al. (2011). miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nature Cell Biology, 13(11), 1353–1360.PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Wang, J., He, Q., Han, C., et al. (2012). p53-facilitated miR-199a-3p regulates somatic cell reprogramming. Stem Cells, 30(7), 1405–1413.PubMedCrossRefPubMedCentralGoogle Scholar
  196. 196.
    Lee, Y. L., Peng, Q., Fong, S. W., et al. (2012). Sirtuin 1 facilitates generation of induced pluripotent stem cells from mouse embryonic fibroblasts through the miR-34a and p53 pathways. PLOS ONE, 7(9), e45633.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Xu, N., Papagiannakopoulos, T., Pan, G., Thomson, J. A., & Kosik, K. S. (2009). MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell, 137(4), 647–658.PubMedCrossRefGoogle Scholar
  198. 198.
    Barta, T., Peskova, L., Collin, J., et al. (2016). Brief report: inhibition of miR-145 enhances reprogramming of human dermal fibroblasts to induced pluripotent stem cells. Stem Cells, 34(1), 246–251.PubMedCrossRefGoogle Scholar
  199. 199.
    Zhang, L., Zheng, Y., Sun, Y., et al. (2016). MiR-134-Mbd3 axis regulates the induction of pluripotency. Journal Cellular and Molecular Medicine, 20(6), 1150–1158.CrossRefGoogle Scholar
  200. 200.
    Hysolli, E., Tanaka, Y., Su, J., et al. (2016). Regulation of the DNA methylation landscape in human somatic cell reprogramming by the miR-29 family. Stem Cell Reports, 7(1), 43–54.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Pfaff, N., Liebhaber, S., Mobus, S., et al. (2017). Inhibition of miRNA-212/132 improves the reprogramming of fibroblasts into induced pluripotent stem cells by de-repressing important epigenetic remodelling factors. Stem Cell Research, 20, 70–75.PubMedCrossRefGoogle Scholar
  202. 202.
    Melton, C., Judson, R. L., & Blelloch, R. (2010). Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature, 463(7281), 621.PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Worringer, K. A., Rand, T. A., Hayashi, Y., et al. (2014). The let-7/LIN-41 pathway regulates reprogramming to human induced pluripotent stem cells by controlling expression of prodifferentiation genes. Cell stem cell, 14(1), 40–52.PubMedCrossRefGoogle Scholar
  204. 204.
    Chen, T., Shen, L., Yu, J., et al. (2011). Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell, 10(5), 908–911.PubMedCrossRefGoogle Scholar
  205. 205.
    Zhang, Z., Gao, Y., Gordon, A., Wang, Z. Z., Qian, Z., & Wu, W. S. (2011). Efficient generation of fully reprogrammed human iPS cells via polycistronic retroviral vector and a new cocktail of chemical compounds. PLOS ONE, 6(10), e26592.PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Wang, Y., & Adjaye, J. (2011). A cyclic amp analog, 8-Br-cAMP, enhances the induction of pluripotency in human fibroblast cells. Stem Cell Reviews and Reports, 7(2), 331–341.PubMedCrossRefGoogle Scholar
  207. 207.
    Lee, J., Xia, Y., Son, M. Y., et al. (2012). A novel small molecule facilitates the reprogramming of human somatic cells into a pluripotent state and supports the maintenance of an undifferentiated state of human pluripotent stem cells. Angewandte Chemie International Edition in English, 51(50), 12509–12513.PubMedCrossRefGoogle Scholar
  208. 208.
    Tan, F., Qian, C., Tang, K., Abd-Allah, S. M., & Jing, N. (2015). Inhibition of transforming growth factor beta (TGF-beta) signaling can substitute for Oct4 protein in reprogramming and maintain pluripotency. Journal of Biological Chemistry, 290(7), 4500–4511.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and BioengineeringIndian Institute of Technology GuwahatiGuwahatiIndia

Personalised recommendations