Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Induced pluripotent stem cell (iPSCs) and their application in immunotherapy

Cellular & Molecular Immunology volume 11, pages 17–24 (2014)Cite this article

Abstract

The ever-improving technology to generate induced pluripotent stem cells (iPSCs) has increased their potential use as novel candidates for disease modeling, drug screening, regenerative medicine and cell therapy. Indeed, iPSCs offer extensive capacity for self-renewal without the ethical concerns faced by embryonic stem cells (ESCs). With respect to potential applications in the immune system, many studies provide evidence to support that there are exclusive advantages to using iPSCs over other systems. Both hematopoietic stem cells and several types of mature immune cells have successfully been reprogrammed to iPSCs and vice versa, paving a path toward our ability to effectively model patient-specific diseases and provide potentially alternative cell sources for transfusion medicine. Despite these potential advances, some limitations regarding the use of iPSCs in the clinic still remain, including the immunogenicity of iPSCs and their derivatives, which is currently under debate in the field. In this review, we mainly focus on discussing the recent progress being made in the latest differentiation methods and clinical implications of iPSCs with respect to the immune system. Additionally, current issues regarding the clinical application of iPSCs are addressed, especially the controversy surrounding immunogenicity, along with various other perspectives.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Odorico JS, Kaufman DS, Thomson JA . Multilineage differentiation from human embryonic stem cell lines. Stem Cells 2001; 19: 193–204.

    Article  CAS  Google Scholar 

  2. Evans MJ, Kaufman MH . Establishment in culture of pluripotential cells from mouse embryos. Nature 1981; 292: 154–156.

    Article  CAS  Google Scholar 

  3. Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663–676.

    Article  CAS  Google Scholar 

  4. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007; 318: 1917–1920.

    Article  CAS  Google Scholar 

  5. Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K . Induced pluripotent stem cells generated without viral integration. Science 2008; 322: 945–949.

    Article  CAS  Google Scholar 

  6. Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S . Generation of mouse induced pluripotent stem cells without viral vectors. Science 2008; 322: 949–953.

    Article  CAS  Google Scholar 

  7. Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 2009; 324: 797–801.

    Article  CAS  Google Scholar 

  8. Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 2009; 4: 381–384.

    Article  CAS  Google Scholar 

  9. Cho HJ, Lee CS, Kwon YW, Paek JS, Lee SH, Hur J et al. Induction of pluripotent stem cells from adult somatic cells by protein-based reprogramming without genetic manipulation. Blood 2010; 116: 386–395.

    Article  CAS  Google Scholar 

  10. Hou P, Li Y, Zhang X, Liu C, Guan J, Li H et al. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 2013; 341: 651–654.

    Article  CAS  Google Scholar 

  11. Rais Y, Zviran A, Geula S, Gafni O, Chomsky E, Viukov S et al. Deterministic direct reprogramming of somatic cells to pluripotency. Nature 2013; 502: 65–70.

    Article  CAS  Google Scholar 

  12. Abad M, Mosteiro L, Pantoja C, Canamero M, Rayon T, Ors I et al. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature 2013; 502: 340–345.

    Article  CAS  Google Scholar 

  13. Chang KH, Nelson AM, Cao H, Wang L, Nakamoto B, Ware CB et al. Definitive-like erythroid cells derived from human embryonic stem cells coexpress high levels of embryonic and fetal globins with little or no adult globin. Blood 2006; 108: 1515–1523.

    Article  CAS  Google Scholar 

  14. Olivier EN, Qiu C, Velho M, Hirsch RE, Bouhassira EE . Large-scale production of embryonic red blood cells from human embryonic stem cells. Exp Hematol 2006; 34: 1635–1642.

    Article  CAS  Google Scholar 

  15. Lu SJ, Feng Q, Park JS, Vida L, Lee BS, Strausbauch M et al. Biologic properties and enucleation of red blood cells from human embryonic stem cells. Blood 2008; 112: 4475–4484.

    Article  CAS  Google Scholar 

  16. Ma F, Ebihara Y, Umeda K, Sakai H, Hanada S, Zhang H et al. Generation of functional erythrocytes from human embryonic stem cell-derived definitive hematopoiesis. Proc Natl Acad Sci USA 2008; 105: 13087–13092.

    Article  CAS  Google Scholar 

  17. Karlsson KR, Cowley S, Martinez FO, Shaw M, Minger SL, James W . Homogeneous monocytes and macrophages from human embryonic stem cells following coculture-free differentiation in M-CSF and IL-3. Exp Hematol 2008; 36: 1167–1175.

    Article  CAS  Google Scholar 

  18. Zhan X, Dravid G, Ye Z, Hammond H, Shamblott M, Gearhart J et al. Functional antigen-presenting leucocytes derived from human embryonic stem cells in vitro. Lancet 2004; 364: 163–171.

    Article  Google Scholar 

  19. Takayama N, Nishikii H, Usui J, Tsukui H, Sawaguchi A, Hiroyama T et al. Generation of functional platelets from human embryonic stem cells in vitro via ES-sacs, VEGF-promoted structures that concentrate hematopoietic progenitors. Blood 2008; 111: 5298–5306.

    Article  CAS  Google Scholar 

  20. Woll PS, Grzywacz B, Tian X, Marcus RK, Knorr DA, Verneris MR et al. Human embryonic stem cells differentiate into a homogeneous population of natural killer cells with potent in vivo antitumor activity. Blood 2009; 113: 6094–6101.

    Article  CAS  Google Scholar 

  21. Park IH, Zhao R, West JA, Yabuuchi A, Huo H, Ince TA et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 2008; 451: 141–146.

    Article  CAS  Google Scholar 

  22. Ye Z, Zhan H, Mali P, Dowey S, Williams DM, Jang YY et al. Human-induced pluripotent stem cells from blood cells of healthy donors and patients with acquired blood disorders. Blood 2009; 114: 5473–5480.

    Article  CAS  Google Scholar 

  23. Grigoriadis AE, Kennedy M, Bozec A, Brunton F, Stenbeck G, Park IH et al. Directed differentiation of hematopoietic precursors and functional osteoclasts from human ES and iPS cells. Blood 2010; 115: 2769–2776.

    Article  CAS  Google Scholar 

  24. Choi KD, Yu J, Smuga-Otto K, Salvagiotto G, Rehrauer W, Vodyanik M et al. Hematopoietic and endothelial differentiation of human induced pluripotent stem cells. Stem Cells 2009; 27: 559–567.

    Article  CAS  Google Scholar 

  25. Choi KD, Vodyanik MA, Slukvin II . Generation of mature human myelomonocytic cells through expansion and differentiation of pluripotent stem cell-derived lin-CD34+CD43+CD45+ progenitors. J Clin Invest 2009; 119: 2818–2829.

    Article  CAS  Google Scholar 

  26. Lapillonne H, Kobari L, Mazurier C, Tropel P, Giarratana MC, Zanella-Cleon I et al. Red blood cells generation from human induced pluripotent stem cells: perspectives for transfusion medicine. Haematologica 2010; 95: 1651–1659.

    Article  CAS  Google Scholar 

  27. Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 2007; 318: 1920–1923.

    Article  CAS  Google Scholar 

  28. Raya A, Rodriguez-Piza I, Guenechea G, Vassena R, Navarro S, Barrero MJ et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 2009; 460: 53–59.

    Article  CAS  Google Scholar 

  29. Lei F, Haque R, Weiler L, Vrana KE, Song J . T lineage differentiation from induced pluripotent stem cells. Cell Immunol 2009; 260: 1–5.

    Article  CAS  Google Scholar 

  30. Schmitt TM, de Pooter RF, Gronski MA, Cho SK, Ohashi PS, Zuniga-Pflucker JC . Induction of T cell development and establishment of T cell competence from embryonic stem cells differentiated in vitro. Nat Immunol 2004; 5: 410–417.

    Article  CAS  Google Scholar 

  31. La Motte-Mohs RN, Herer E, Zuniga-Pflucker JC . Induction of T-cell development from human cord blood hematopoietic stem cells by Delta-like 1 in vitro. Blood 2005; 105: 1431–1439.

    Article  CAS  Google Scholar 

  32. Ye Z, Cheng L . Potential of human induced pluripotent stem cells derived from blood and other postnatal cell types. Regen Med 2010; 5: 521–530.

    Article  CAS  Google Scholar 

  33. Polo JM, Liu S, Figueroa ME, Kulalert W, Eminli S, Tan KY et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat Biotechnol 2010; 28: 848–855.

    Article  CAS  Google Scholar 

  34. Taniguchi M, Harada M, Kojo S, Nakayama T, Wakao H . The regulatory role of Valpha14 NKT cells in innate and acquired immune response. Annu Rev Immunol 2003; 21: 483–513.

    Article  CAS  Google Scholar 

  35. Fujii S, Shimizu K, Hemmi H, Steinman RM . Innate Valpha14+ natural killer T cells mature dendritic cells, leading to strong adaptive immunity. Immunol Rev 2007; 220: 183–198.

    Article  CAS  Google Scholar 

  36. Watarai H, Fujii S, Yamada D, Rybouchkin A, Sakata S, Nagata Y et al. Murine induced pluripotent stem cells can be derived from and differentiate into natural killer T cells. J Clin Invest 2010; 120: 2610–2618.

    Article  CAS  Google Scholar 

  37. Senju S, Haruta M, Matsunaga Y, Fukushima S, Ikeda T, Takahashi K et al. Characterization of dendritic cells and macrophages generated by directed differentiation from mouse induced pluripotent stem cells. Stem Cells 2009; 27: 1021–1031.

    Article  CAS  Google Scholar 

  38. Ales NC, Katial RK . Vaccines against biologic agents: uses and developments. Respir Care Clin N Am 2004; 10: 123–146.

    Article  Google Scholar 

  39. 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: 861–872.

    Article  CAS  Google Scholar 

  40. Li J, Gao GD, Yuan TF . Cell based vaccination using transplantation of iPSC-derived memory B cells. Vaccine 2009; 27: 5728–5729.

    Article  CAS  Google Scholar 

  41. Zhao T, Zhang ZN, Rong Z, Xu Y . Immunogenicity of induced pluripotent stem cells. Nature 2011; 474: 212–215.

    Article  CAS  Google Scholar 

  42. Guha P, Morgan JW, Mostoslavsky G, Rodrigues NP, Boyd AS . Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. Cell Stem Cell 2013; 12: 407–412.

    Article  CAS  Google Scholar 

  43. Araki R, Uda M, Hoki Y, Sunayama M, Nakamura M, Ando S et al. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 2013; 494: 100–104.

    Article  CAS  Google Scholar 

  44. Chen HF, Yu CY, Chen MJ, Chou SH, Chiang MS, Chou WH et al. Characteristic expression of major histocompatibility complex and immune privilege genes in human pluripotent stem cells and the derivatives. Cell Transplant 2013; in press.

  45. Kulkeaw K, Horio Y, Mizuochi C, Ogawa M, Sugiyama D . Variation in hematopoietic potential of induced pluripotent stem cell lines. Stem Cell Rev 2010; 6: 381–389.

    Article  CAS  Google Scholar 

  46. Taylor CJ, Peacock S, Chaudhry AN, Bradley JA, Bolton EM . Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types. Cell Stem Cell 2012; 11: 147–152.

    Article  CAS  Google Scholar 

  47. Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S et al. A more efficient method to generate integration-free human iPS cells. Nat Methods 2011; 8: 409–412.

    Article  CAS  Google Scholar 

  48. Okita K, Nagata N, Yamanaka S . Immunogenicity of induced pluripotent stem cells. Circ Res 2011; 109: 720–721.

    Article  CAS  Google Scholar 

  49. Kaneko S, Yamanaka S . To be immunogenic, or not to be: that's the iPSC question. Cell Stem Cell 2013; 12: 385–386.

    Article  CAS  Google Scholar 

  50. Taylor CJ, Bolton EM, Pocock S, Sharples LD, Pedersen RA, Bradley JA . Banking on human embryonic stem cells: estimating the number of donor cell lines needed for HLA matching. Lancet 2005; 366: 2019–2025.

    Article  Google Scholar 

  51. Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A et al. Disease-specific induced pluripotent stem cells. Cell 2008; 134: 877–886.

    Article  CAS  Google Scholar 

  52. Ghosh Z, Wilson KD, Wu Y, Hu S, Quertermous T, Wu JC . Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells. PLoS ONE 2010; 5: e8975.

    Article  Google Scholar 

  53. Li JY, Christophersen NS, Hall V, Soulet D, Brundin P . Critical issues of clinical human embryonic stem cell therapy for brain repair. Trends Neurosci 2008; 31: 146–153.

    Article  Google Scholar 

  54. Graf T, Stadtfeld M . Heterogeneity of embryonic and adult stem cells. Cell Stem Cell 2008; 3: 480–483.

    Article  CAS  Google Scholar 

  55. Huang S . Reprogramming cell fates: reconciling rarity with robustness. Bioessays 2009; 31: 546–560.

    Article  CAS  Google Scholar 

  56. Gutierrez-Aranda I, Ramos-Mejia V, Bueno C, Munoz-Lopez M, Real PJ, Macia A et al. Human induced pluripotent stem cells develop teratoma more efficiently and faster than human embryonic stem cells regardless the site of injection. Stem Cells 2010; 28: 1568–1570.

    Article  Google Scholar 

  57. Saric T, Frenzel LP, Hescheler J . Immunological barriers to embryonic stem cell-derived therapies. Cells Tissues Organs 2008; 188: 78–90.

    Article  Google Scholar 

  58. Dressel R, Nolte J, Elsner L, Novota P, Guan K, Streckfuss-Bomeke K et al. Pluripotent stem cells are highly susceptible targets for syngeneic, allogeneic, and xenogeneic natural killer cells. FASEB J 2010; 24: 2164–2177.

    Article  CAS  Google Scholar 

  59. Kuroda Y, Kitada M, Wakao S, Nishikawa K, Tanimura Y, Makinoshima H et al. Unique multipotent cells in adult human mesenchymal cell populations. Proc Natl Acad Sci USA 2010; 107: 8639–8643.

    Article  CAS  Google Scholar 

  60. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M . Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010; 463: 1035–1041.

    Article  CAS  Google Scholar 

  61. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA . In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 2008; 455: 627–632.

    Article  CAS  Google Scholar 

  62. Tang H, Guo Z, Zhang M, Wang J, Chen G, Cao X . Endothelial stroma programs hematopoietic stem cells to differentiate into regulatory dendritic cells through IL-10. Blood 2006; 108: 1189–1197.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Key Basic Research Program of China (2011CB965202, 2013CB530502 and 2013CB944903).

Author information

Authors and Affiliations

  1. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China

    Zhengping Jiang, Yanmei Han & Xuetao Cao

Authors
  1. Zhengping Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanmei Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xuetao Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yanmei Han or Xuetao Cao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jiang, Z., Han, Y. & Cao, X. Induced pluripotent stem cell (iPSCs) and their application in immunotherapy. Cell Mol Immunol 11, 17–24 (2014). https://doi.org/10.1038/cmi.2013.62

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2013.62

Keywords

This article is cited by

Search

Advanced search

Quick links