Skip to main content

Advertisement

SpringerLink
Log in

Clinical potential of human-induced pluripotent stem cells

Perspectives of induced pluripotent stem cells

  • Review
  • Published:
Cell Biology and Toxicology Aims and scope Submit manuscript

Abstract

The recent establishment of induced pluripotent stem (iPS) cells promises the development of autologous cell therapies for degenerative diseases, without the ethical concerns associated with human embryonic stem (ES) cells. Initially, iPS cells were generated by retroviral transduction of somatic cells with core reprogramming genes. To avoid potential genotoxic effects associated with retroviral transfection, more recently, alternative non-viral gene transfer approaches were developed. Before a potential clinical application of iPS cell-derived therapies can be planned, it must be ensured that the reprogramming to pluripotency is not associated with genome mutagenesis or epigenetic aberrations. This may include direct effects of the reprogramming method or “off-target” effects associated with the reprogramming or the culture conditions. Thus, a rigorous safety testing of iPS or iPS-derived cells is imperative, including long-term studies in model animals. This will include not only rodents but also larger mammalian model species to allow for assessing long-term stability of the transplanted cells, functional integration into the host tissue, and freedom from undifferentiated iPS cells. Determination of the necessary cell dose is also critical; it is assumed that a minimum of 1 billion transplantable cells is required to achieve a therapeutic effect. This will request medium to long-term in vitro cultivation and dozens of cell divisions, bearing the risk of accumulating replication errors. Here, we review the clinical potential of human iPS cells and evaluate which are the most suitable approaches to overcome or minimize risks associated with the application of iPS cell-derived cell therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ALS:

Amyotrophic lateral sclerosis

AMD:

Age-related macular degeneration

CRISPR/Cas9:

Clustered regularly interspaced short palindromic repeats, CRISPR-associated protein 9

ERK1/ERK2:

Extracellular signal-regulated kinases 1 and 2

ES:

Embryonic stem (cell)

FRM1:

X-linked fragile X mental retardation 1

GMP:

Good manufacturing practice

GSK3ß:

Glycogen synthase kinase 3 beta

HLA:

Human leukocyte antigen

HD:

Huntington’s disease

iPS:

Induced pluripotent stem (cell)

NHP:

Non-human primate

pSC:

Parthenogenetic stem cell

RPE:

Retinal pigment epithelium

SCID:

Severe combined immunodeficiency

SSEA-5:

Stage-specific embryonic antigen-5

TALEN:

Transcription activator-like effector nuclease

References

  • Al-Anazi KA. Induced pluripotent stem cells and their future therapeutic applications in hematology. J Stem Cell Res Ther. 2015;5:258.

    Google Scholar 

  • Anand T, Talluri TR, Kumar D, Garrels W, Mukherjee A, Debowski K, et al. Differentiation of induced pluripotent stem cells to lentoid bodies expressing a lens cell-specific fluorescent reporter. PLoS One. 2016;11(6):e0157570.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Aravalli RN, Cressman EN, Steer CJ. Hepatic differentiation of porcine induced pluripotent stem cells in vitro. Vet J. 2012;194:369–74.

    Article  PubMed  Google Scholar 

  • Azuma K, Yamanaka S. Recent policies that support clinical application of induced pluripotent stem cell-based regenerative therapies. Regenerative Therapy. 2016;4:36–47.

    Article  Google Scholar 

  • Baghbaderani BA, Tian X, Neo BH, Burkall A, Dimezzo T, Sierra G, et al. cGMP-manufactured human induced pluripotent stem cells are available for pre-clinical and clinical applications. Stem Cell Reports. 2015;5(4):647–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baker DE, Harrison NJ, Maltby E, Smith K, Moore HD, Shaw PJ, et al. Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat Biotechnol. 2007;25:207–15.

    Article  CAS  PubMed  Google Scholar 

  • Barral S, Kurian MA. Utility of induced pluripotent stem cells for the study and treatment of genetic diseases: focus on childhood neurological disorders. Front Mol Neurosci. 2016;9:78.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bassols A, Costa C, Eckersall PD, Osada J, Sabrià J, Tibau J. The pig as an animal model for human pathologies: a proteomics perspective. Proteomics Clin Appl. 2014;8:715–31.

    Article  CAS  PubMed  Google Scholar 

  • Ben-David U, Benvenisty N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer. 2011;11:268–77.

    Article  CAS  PubMed  Google Scholar 

  • Ben-David U, Benvenisty N. High prevalence of evolutionarily conserved and species-specific genomic aberrations in mouse pluripotent stem cells. Stem Cells. 2012;30:612–22.

    Article  CAS  PubMed  Google Scholar 

  • Ben-David U, Benvenisty N. Chemical ablation of tumor-initiating human pluripotent stem cells. Nat Protoc. 2014;9(3):729–40.

    Article  CAS  PubMed  Google Scholar 

  • Ben-David U, Nudel N, Benvenisty N. Immunologic and chemical targeting of the tight-junction protein Claudin-6 eliminates tumorigenic human pluripotent stem cells. Nat Commun. 2013;4:1992.

    Article  PubMed  CAS  Google Scholar 

  • Black JB, Adler AF, Wang HG, D’Ippolito AM, Hutchinson HA, Reddy TE, et al. Targeted epigenetic remodeling of endogenous loci by CRISPR/Cas9-based transcriptional activators directly converts fibroblasts to neuronal cells. Cell Stem Cell. 2016;19(3):406–14.

    Article  CAS  PubMed  Google Scholar 

  • Blasco MA, Serrano M, Fernandez-Capetillo O. Genomic instability in iPS: time for a break. EMBO J. 2011;30:991–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bosch P, Forcato DO, Alustiza FE, Alessio AP, Fili AE, Olmos Nicotra MF, et al. Exogenous enzymes upgrade transgenesis and genetic engineering of farm animals. Cell Mol Life Sci. 2015;72(10):1907–29.

    Article  CAS  PubMed  Google Scholar 

  • Brambrink T, Foreman R, Welstead GG, Lengner CJ, Wernig M, Suh H, et al. Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells. Cell Stem Cell. 2008;2(2):151–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buganim Y, Markoulaki S, van Wietmarschen N, Hoke H, Wu T, Ganz K, et al. The developmental potential of iPSCs is greatly influenced by reprogramming factor selection. Cell Stem Cell. 2014;15(3):295–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carpenter L, Carr C, Yang CT, Stuckey DJ, Clarke K, Watt SM. Efficient differentiation of human induced pluripotent stem cells generates cardiac cells that provide protection following myocardial infarction in the rat. Stem Cells Dev. 2012;21:977–86.

    Article  CAS  PubMed  Google Scholar 

  • Cebrian-Serrano A, Stout T, Dinnyes A. Veterinary applications of induced pluripotent stem cells: regenerative medicine and models for disease? Vet J. 2013;198(1):34–42.

    Article  PubMed  Google Scholar 

  • Chan AW, Cheng PH, Neumann A, Yang JJ. Reprogramming Huntington monkey skin cells into pluripotent stem cells. Cell Reprogram. 2010;12:509–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cunningham JJ, Ulbright TM, Pera MF, Looijenga LH. Lessons from human teratomas to guide development of safe stem cell therapies. Nat Biotechnol. 2012;30(9):849–57.

    Article  CAS  PubMed  Google Scholar 

  • Cyranoski D. Stem-cell pioneer banks on future therapies. Nature. 2012;488:139.

    Article  CAS  PubMed  Google Scholar 

  • de Miguel-Beriain I. The ethics of stem cells revisited. Adv Drug Deliv Rev. 2015;82-83:176–80.

    Article  PubMed  CAS  Google Scholar 

  • Daley GQ, Lensch MW, Jaenisch R, Meissner A, Plath K, Yamanaka S. Broader implications of defining standards for the pluripotency of iPSCs. Cell Stem Cell. 2009;4:200–1.

    Article  CAS  PubMed  Google Scholar 

  • Davis RP, Nemes C, Varga E, Freund C, Kosmidis G, Gkatzis K, de Jong D, Szuhai K, Dinnyés A, Mummery CL. Generation of induced pluripotent stem cells from human foetal fibroblasts using the Sleeping Beauty transposon gene delivery system. Differentiation. 2013;86(1–2):30–7.

    Article  CAS  PubMed  Google Scholar 

  • Debowski K, Warthemann R, Lentes J, Salinas-Riester G, Dressel R, Langenstroth D, et al. Non-viral generation of marmoset monkey iPS cells by a six-factor-in-one vector approach. PLoS One. 2015;10(3):e0118424.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Deng W, Cao X, Chen J, Zhang Z, Yu Q, Wang Y, et al. MicroRNA replacing oncogenic Klf4 and c-Myc for generating iPS cells via cationized pleurotus eryngii polysaccharide-based nanotransfection. ACS Appl Mater Interfaces. 2015;7(34):18957–66.

    Article  CAS  PubMed  Google Scholar 

  • Dimmeler S, Ding S, Rando TA, Trounson A. Translational strategies and challenges in regenerative medicine. Nat Med. 2014;20:814–21.

    Article  CAS  PubMed  Google Scholar 

  • Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science. 2008;321:1218–21.

    Article  CAS  PubMed  Google Scholar 

  • Dolezalova D, Hruska-Plochan M, Bjarkam CR, Sørensen JC, Cunningham M, Weingarten D, et al. Pig models of neurodegenerative disorders: utilization in cell replacement-based preclinical safety and efficacy studies. J Comp Neurol. 2014;522(12):2784–801.

    Article  PubMed  Google Scholar 

  • Drukker M. Recent advancements towards the derivation of immune-compatible patient-specific human embryonic stem cell lines. Semin Immunol. 2008;20(2):123–9.

    Article  CAS  PubMed  Google Scholar 

  • Duranthon V, Beaujean N, Brunner M, Odening KE, Santos AN, Kacskovics I, et al. On the emerging role of rabbit as human disease model and the instrumental role of novel transgenic tools. Transgenic Res. 2012;21:699–13.

    Article  CAS  PubMed  Google Scholar 

  • Ebert AD, Yu J, Rose Jr FF, Mattis VB, Lorson CL, Thomson JA, et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature. 2009;457:277–80.

    Article  CAS  PubMed  Google Scholar 

  • Erdo F, Buhrle C, Blunk J, Hoehn M, Xia Y, Fleischmann B, et al. Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J Cerebral Blood Flow and Metabolism. 2003;23:780–5.

    Google Scholar 

  • Espejel S, Eckardt S, Harbell J, Roll GR, McLaughlin KJ, Willenbring H. Parthenogenetic embryonic stem cells are an effective cell source for therapeutic liver repopulation. Stem Cells. 2014;32(7):1983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan N, Lai L. Genetically modified pig models for human diseases. J Genet Genomics. 2013;40(2):67–73.

    Article  CAS  PubMed  Google Scholar 

  • Feng B, Jiang J, Kraus P, Ng JH, Heng JC, Chan YS, et al. Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nat Cell Biol. 2009;11:197–03.

    Article  CAS  PubMed  Google Scholar 

  • Flisikowska T, Kind A, Schnieke A. Pigs as models of human cancers. Theriogenology. 2016;86(1):433–7.

    Article  CAS  PubMed  Google Scholar 

  • Fraser MJ, Ciszczon T, Elick T, Bauser C. Precise excision of TTAA-specific lepidopteran transposons piggyBac (IFP2) and tagalong (TFP3) from the baculovirus genome in cell lines from two species of Lepidoptera. Insect Mol Biol. 1996;5:141–51.

    Article  CAS  PubMed  Google Scholar 

  • Fujishiro SH, Nakano K, Mizukami Y, Azami T, Arai Y, Matsunari H, et al. Generation of naive-like porcine-induced pluripotent stem cells capable of contributing to embryonic and fetal development. Stem Cells Dev. 2013;22:473–82.

    Article  CAS  PubMed  Google Scholar 

  • Gafni O, Weinberger L, Mansour AA, Manor YS, Chomsky E, Ben-Yosef D, et al. Derivation of novel human ground state naive pluripotent stem cells. Nature. 2013;504:282–6.

    Article  CAS  PubMed  Google Scholar 

  • Galat V, Galat Y, Perepitchka M, Jennings LJ, Iannaccone PM, Hendrix MJ. Transgene reactivation in induced pluripotent stem cell derivatives and reversion to pluripotency of induced pluripotent stem cell-derived mesenchymal stem cells. Stem Cells Dev. 2016;25(14):1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gallegos-Cárdenas A, Webb R, Jordan E, West R, West FD, Yang JY, et al. Pig induced pluripotent stem cell-derived neural rosettes developmentally mimic human pluripotent stem cell neural differentiation. Stem Cells Dev. 2015;24(16):1901–11.

    Article  PubMed  CAS  Google Scholar 

  • Garber K. RIKEN suspends first clinical trial involving induced pluripotent stem cells. Nat Biotechnol. 2015;33(9):890–1.

    Article  CAS  PubMed  Google Scholar 

  • Garrels W, Ivics Z, Kues WA. Precision genetic engineering in large mammals. Trends Biotechnol. 2012;30(7):386–93.

    Article  CAS  PubMed  Google Scholar 

  • Garrels W, Mukherjee A, Holler S, Cleve N, Talluri TR, Barg-Kues B, et al. Identification and re-addressing of a transcriptionally permissive locus in the porcine genome. Transgenic Res. 2016;25:63–70.

    Article  CAS  PubMed  Google Scholar 

  • Ghaleb AM, Nandan MO, Chanchevalap S, Dalton WB, Hisamuddin IM, Yang VW. Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation. Cell Res. 2005;15:92–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gogol-Döring A, Ammar I, Gupta S, Bunse M, Miskey C, Chen W, et al. Genome-wide profiling reveals remarkable parallels between insertion site selection properties of the MLV retrovirus and the piggyBac transposon in primary human CD4(+) T cells. Mol Ther. 2016 Mar;24(3):592–606.

    Article  PubMed Central  CAS  Google Scholar 

  • Gore A, Li Z, Fung HL, Young JE, Agarwal S, Antosiewicz-Bourget J, et al. Somatic coding mutations in human induced pluripotent stem cells. Nature. 2011;471:63–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gouda R, Takeishi R. RIKEN cancelled the iPS transplantation for the second case due to gene mutations. Asahi News, 18 June 2015. http://www.asahi.com/ articles/DA3S11812787.html.

  • Grunseich C, Zukosky K, Kats IR, Ghosh L, Harmison GG, Bott LC, et al. Stem cell-derived motor neurons from spinal and bulbar muscular atrophy patients. Neurobiol Dis. 2014;70(C):12–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gu M, Nguyen PK, Lee AS, Xu D, Hu S, et al. Microfluidic single cell analysis show porcine induced pluripotent stem cell-derived endothelial cells improve myocardial function by paracrine activation. Circ Res. 2012;111(7):882–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gün G, Kues WA. Current progress of genetically engineered pig models for biomedical research. Biores Open Access. 2014;3(6):255–64.

    Article  PubMed  PubMed Central  Google Scholar 

  • Habib O, Habib G, Choi HW, Hong KS, Do JT, Moon SH, et al. An improved method for the derivation of high quality iPSCs in the absence of c-Myc. Exp Cell Res. 2013;319:3190–200.

    Article  CAS  PubMed  Google Scholar 

  • Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302:415–9.

    Article  CAS  PubMed  Google Scholar 

  • Han J, Yuan P, Yang H, Zhang J, Soh BS, Li P, Lim SL, et al. Tbx3 improves the germ-line competency of induced pluripotent stem cells. Nature. 2010;463:1096–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haston KM, Finkbeiner S. Clinical trials in a dish: the potential of pluripotent stem cells to develop therapies for neurodegenerative diseases. Annu Rev Pharmacol Toxicol. 2016;56:489–10.

    Article  CAS  PubMed  Google Scholar 

  • Hatefi N, Nouraee N, Parvin M, Ziaee SA, Mowla SJ. Evaluating the expression of oct4 as a prognostic tumor marker in bladder cancer. Iran J Basic Med Sci. 2012;15:1154–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Herberts CA, Kwa MSG, Hermsen HPH. Risk factors in the development of stem cell therapy. J Translational Medicine. 2011;9:29.

    Article  Google Scholar 

  • Hermann A, Kim JB, Srimasorn S, Zaehres H, Reinhardt P, Schöler HR, Storch A. Factor-reduced human induced pluripotent stem cells efficiently differentiate into neurons independent of the number of reprogramming factors. Stem Cells Int. 2016;2016:1–6.

  • Hernandez L, Kozlov S, Piras G, Stewart CL. Paternal and maternal genomes confer opposite effects on proliferation, cell cycle length, senescence, and tumor formation. PNAS. 2003;100:13344–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holm IE, Alstrup AK, Luo Y. Genetically modified pig models for neurodegenerative disorders. J Pathol. 2016;238(2):267–87.

    Article  CAS  PubMed  Google Scholar 

  • Howe SJ, Mansour MR, Schwarzwaelder K, Bartholomae C, Hubank M, Kempski H, et al. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest. 2008;118:3143–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, Muhlestein W, et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnol. 2008;26:1269–75.

    Article  CAS  Google Scholar 

  • Hussein SM, Batada NN, Vuoristo S, Ching RW, Autio R, Närvä E, Ng S, et al. Copy number variation and selection during reprogramming to pluripotency. Nature. 2011;471:58–62.

    Article  CAS  PubMed  Google Scholar 

  • Hussein SM, Elbaz J, Nagy AA. Genome damage in induced pluripotent stem cells: assessing the mechanisms and their consequences. BioEssays. 2013;35(3):152–62.

    Article  CAS  PubMed  Google Scholar 

  • Inada E, Saitoh I, Watanabe S, Aoki R, Miura H, Ohtsuka M, et al. PiggyBac transposon-mediated gene delivery efficiently generates stable transfectants derived from cultured primary human deciduous tooth dental pulp cells (HDDPCs) and HDDPC-derived iPScells. Int J Oral Sci. 2015;7(3):144–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inoue H, Nagata N, Kurokawa H, Yamanaka S. iPS cells: a game changer for future medicine. EMBO J. 2014;33(5):409–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishii T. Human iPS cell-derived germ cells: current status and clinical potential. J Clin Med. 2014;3(4):1064–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang W, Zhang J, Yang X, Gao J. Induced pluripotent stem cells: origins and directions. Human Genet Embryol. 2012;S2:002.

    Google Scholar 

  • Jones TD, Ulbright TM, Eble JN, Baldridge LA, Cheng L. OCT4 staining in testicular tumors: a sensitive and specific marker for seminoma and embryonal carcinoma. Am J Surg Pathol. 2004;28:935–40.

    Article  PubMed  Google Scholar 

  • Jonlin EC. Differing standards for the NIH stem cell registry and FDA approval render most federally funded hESC lines unsuitable for clinical use. Cell Stem Cell. 2014;14:139–40.

    Article  CAS  PubMed  Google Scholar 

  • Josephson R. Molecular cytogenetics: making it safe for human embryonic stem cells to enter the clinic. Expert Rev Mol Diagn. 2007;7:395–06.

    Article  CAS  PubMed  Google Scholar 

  • Kang X, Yu Q, Huang Y, Song B, Chen Y, Gao X, et al. Effects of integrating and non-integrating reprogramming methods on copy number variation and genomic stability of human induced pluripotent stem cells. PLoS One. 2015;10:e0131128.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kastner A, Gauthier P. Are rodents an appropriate pre-clinical model for treating spinal cord injury? Examples from the respiratory system. Exp Neurol. 2008;213:249–56.

    Article  CAS  PubMed  Google Scholar 

  • Kehinde EO. They see a rat, we seek a cure for diseases: the current status of animal experimentation in medical practice. Med Princ Pract. 2013;22:52–61.

    Article  PubMed  Google Scholar 

  • Kempf H, Kropp C, Olmer R, Martin U, Zweigerdt R. Cardiac differentiation of human pluripotent stem cells in scalable suspension culture. Nat Protoc. 2015;10(9):1345–61.

    Article  CAS  PubMed  Google Scholar 

  • Kim K, Zhao R, Doi A, Ng K, Unternaehrer J, Cahan P, et al. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nat Biotechnol. 2011;29(12):1117–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kimbrel EA, Lanza R. Current status of pluripotent stem cells: moving the first therapies to the clinic. Nat Rev Drug Discov. 2015;14:681–92.

    Article  CAS  PubMed  Google Scholar 

  • Knoepfler PS. Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine. Stem Cells. 2009;27:1050–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koh S, Thomas R, Tsai S, Bischoff S, Lim JH, Breen M, et al. Growth requirements and chromosomal instability of induced pluripotent stem cells generated from adult canine fibroblasts. Stem Cells Dev. 2013;22:951–63.

    Article  CAS  PubMed  Google Scholar 

  • Kropp C, Kempf H, Halloin C, Robles-Diaz D, Franke A, Scheper T, et al. Impact of feeding strategies on the scalable expansion of human pluripotent stem cells in single-use stirred tank bioreactors. Stem Cells Transl Med. 2016;5(10):1289–301.

    Article  PubMed  Google Scholar 

  • Kues WA, Herrmann D, Barg-Kues B, Haridoss S, Nowak-Imialek M, Buchholz T, Streeck M, et al. Derivation and characterization of sleeping beauty transposon-mediated porcine induced pluripotent stem cells. Stem Cells Dev. 2013;22(1):124–35.

    Article  CAS  PubMed  Google Scholar 

  • Kumar D, Talluri TR, Anand T, Kues WA. Induced pluripotent stem cells: mechanisms, achievements and perspectives in farm animals. World J Stem Cells. 2015a;7(2):315–28.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kumar D, Talluri TR, Anand T, Kues WA. Transposon-based reprogramming to induced pluripotency. Histol Histopathol. 2015b;30:1397–09.

    CAS  PubMed  Google Scholar 

  • Kurome M, Geistlinger L, Kessler B, Zakhartchenko V, Klymiuk N, Wuensch A, et al. Factors influencing the efficiency of generating genetically engineered pigs by nuclear transfer: multi-factorial analysis of a large data set. BMC Biotechnol. 2013;13:43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuttler F, Mai S. c-Myc, genomic instability and disease. Genome Dyn. 2006;1:171–90.

    Article  CAS  PubMed  Google Scholar 

  • Laurent LC, Ulitsky I, Slavin I, Tran H, Schork A, Morey R, et al. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell. 2011;8:106–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee MO, Moon SH, Jeong HC, Yi JY, Lee TH, Shim SH, et al. Inhibition of pluripotent stem cell-derived teratoma formation by small molecules. Proc Natl Acad Sci U S A. 2013;110(35):E3281–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lengerke C, Daley GQ. Autologous blood therapies from pluripotent stem cells. Blood Rev. 2010;24:27–37.

    Article  PubMed  Google Scholar 

  • Li L, Moshous D, Zhou Y, Wang J, Xie G, Salido E, et al. A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans. J Immunol. 2002;168:6323–9.

    Article  CAS  PubMed  Google Scholar 

  • Li P, Sun X, Ma Z, Liu Y, Jin Y, Ge R, et al. Transcriptional reactivation of OTX2, RX1 and SIX3 during reprogramming contributes to the generation of RPE cells from human iPSCs. Int J Biol Sci. 2016;12(5):505–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu CG, Lu Y, Wang BB, Zhang YJ, Zhang RS, Lu Y, et al. Clinical implications of stem cell gene Oct-4 expression in breast cancer. Ann Surg. 2011;253:1165–71.

    Article  PubMed  Google Scholar 

  • Ma H, Morey R, O’Neil RC, He Y, Daughtry B, Schultz MD, et al. Abnormalities in human pluripotent cells due to reprogramming mechanisms. Nature. 2014;511:177e183.

    Article  CAS  Google Scholar 

  • Maekawa M, Yamaguchi K, Nakamura T, Shibukawa R, Kodanaka I, Ichisaka T, et al. Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1. Nature. 2011;474:225–9.

    Article  CAS  PubMed  Google Scholar 

  • Mayshar Y, Ben-David U, Lavon N, Biancotti JC, Yakir B, Clark AT, et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell. 2010;7:521–31.

    Article  CAS  PubMed  Google Scholar 

  • Montserrat N, Bahima EG, Batlle L, Hafner S, Rodrigues AM, Gonzalez F, et al. Generation of pig iPS cells: a model for cell therapy. J Cardiovascular Translational Res. 2011;4:121–30.

    Article  Google Scholar 

  • Mor-Shaked H, Eiges R. Modeling fragile X syndrome using human pluripotent stem cells. Genes. 2016;7:77.

    Article  PubMed Central  CAS  Google Scholar 

  • Nagy K, Sung HK, Zhang P, Laflamme S, Vincent P, Agha-Mohammadi S, et al. Induced pluripotent stem cell lines derived from equine fibroblasts. Stem Cell Rev. 2011;7:693–02.

    Article  PubMed  PubMed Central  Google Scholar 

  • Nagy K, Nagy A. Derivation of equine-induced pluripotent stem cell lines using a piggyBac transposon delivery system and temporal control of transgene expression. Methods Mol Biol. 2015;1330:79–88.

    Article  PubMed  Google Scholar 

  • Nakatsuji N, Nakajima F, Tokunaga K. HLA-haplotype banking and iPS cells. Nat Biotechnol. 2008;26:739–40.

    Article  CAS  PubMed  Google Scholar 

  • Narva E, Autio R, Rahkonen N, Kong L, Harrison N, Kitsberg D, et al. High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity. Nature Biotechnol. 2010;28:371–7.

    Article  CAS  Google Scholar 

  • Nelson TJ, Martinez-Fernandez A, Yamad S, Ikeda Y, Perez-Terzic C, et al. Induced pluripotent stem cells: advances to applications. Stem Cell Clon. 2010;3:29–37.

    CAS  Google Scholar 

  • Neofytou E, O’Brien CG, Couture LA, Wu JC. Hurdles to clinical translation of human induced pluripotent stem cells. J Clin Invest. 2015;125(7):2551–7.

    Article  PubMed  PubMed Central  Google Scholar 

  • Nishio M, Nakahara M, Yuo A, Saeki K. Human pluripotent stem cells: towards therapeutic development for the treatment of lifestyle diseases. World J Stem Cells. 2016;8(2):56–61.

    Article  PubMed  PubMed Central  Google Scholar 

  • Nordin N, Lai MI, Veerakumarasivam A, Ramasamy R, Abdullah S. Induced pluripotent stem cells: history, properties and potential applications. Med J Malaysia. 2011;66:4–9.

    CAS  PubMed  Google Scholar 

  • Okita K, Ichiaka T, Yamanaka S. Generation of germline competent induced pluripotent stem cells. Nature. 2007;448:313–7.

    Article  CAS  PubMed  Google Scholar 

  • 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;8:409–12.

    Article  CAS  PubMed  Google Scholar 

  • 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;451:141–6.

    Article  CAS  PubMed  Google Scholar 

  • Pellegrini G, De Luca M. Eyes on the prize: limbal stem cells and corneal restoration. Cell Stem Cell. 2014;15:121–2.

    Article  CAS  PubMed  Google Scholar 

  • Plews JR, Gu M, Longaker MT, Wu JC. Large animal induced pluripotent stem cells as pre-clinical models for studying human disease. J Cell Mol Med. 2012;16(6):1196–02.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prockop DJ, Olson SD. Clinical trials with adult stem/progenitor cells for tissue repair: Let’s not overlook some essential precautions. Blood. 2007;109:3147–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prokhorova TA, Harkness LM, Frandsen U, Ditzel N, Schroder HD, Burns JS, et al. Teratoma formation by human embryonic stem cells is site dependent and enhanced by the presence of Matrigel. Stem Cells Dev. 2009;18:47–54.

    Article  CAS  PubMed  Google Scholar 

  • Robinton DA, Daley GQ. The promise of induced pluripotent stem cells in research and therapy. Nature. 2012;481(7381):295–05.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruau D, Ensenat-Waser R, Dinger TC, Vallabhapurapu DS, Rolletschek A, Hacker C, et al. Pluripotency associated genes are reactivated by chromatin-modifying agents in neurosphere cells. Stem Cells. 2008;26(4):920–6.

    Article  CAS  PubMed  Google Scholar 

  • Ruiz S, Lopez-Contreras AJ, Gabut M, Marion RM, Gutierrez-Martinez P, Bua S, et al. Limiting replication stress during somatic cell reprogramming reduces genomic instability in induced pluripotent stem cells. Nat Commun. 2015;6:8036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santostefano KE, Hamazaki T, Biel NM, Jin S, Umezawa A, Terada N. A practical guide to induced pluripotent stem cell research using patient samples. Lab Investig. 2014;95(1):4–13.

    Article  PubMed  CAS  Google Scholar 

  • Sareen D, O’Rourke JG, Meera P, Muhammad AK, Grant S, Simpkinson M, et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med. 2013;5(208):208ra149.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schmitt J, Eckardt S, Schlegel PG, Sirén AL, Bruttel VS, et al. Human parthenogenetic embryonic stem cell-derived neural stem cells express HLA-G and show unique resistance to NK cell-mediated killing. Mol Med. 2015;2(1):185–96.

    Google Scholar 

  • Schook LB, Rund L, Begnini KR, Remião MH, Seixas FK, Collares T. Emerging technologies to create inducible and genetically defined porcine cancer models. Front Genet. 2016;7:28.

    Article  PubMed  PubMed Central  Google Scholar 

  • Schroeder MA, DiPersio JF. Mouse models of graft-versus-host disease: advances and limitations. Dis Model Mech. 2011;4:318–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seki T, Fukuda K. Methods of induced pluripotent stem cells for clinical application. World J Stem Cells. 2015;7(1):116–25.

    Article  PubMed  PubMed Central  Google Scholar 

  • Seki T, Fukuda K. Induced pluripotent stem cells for clinical use. Intech. 2016; 175–191. doi:10.5772/62505.

  • Shi Y, Desponts C, Do JT, Hahm HS, Scholer HR, Ding S. Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small molecule compounds. Cell Stem Cell. 2008;3:568–74.

    Article  CAS  PubMed  Google Scholar 

  • Shih CC, Forman SJ, Chu P, Slovak M. Human embryonic stem cells are prone to generate primitive, undifferentiated tumors in engrafted human fetal tissues in severe combined immune-deficient mice. Stem Cells Dev. 2007;16:893–02.

    Article  CAS  PubMed  Google Scholar 

  • Simonson OE, Domogatskaya A, Volchkov P, Rodin S. The safety of human pluripotent stem cells in clinical treatment. Ann Med. 2015;47:370–80.

    Article  PubMed  Google Scholar 

  • Singh VK, Kalsan M, Kumar N, Saini A, Chandra R. Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Front Cell Dev Biol. 2015;3:2.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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;8(4):118–35.

    Article  PubMed  PubMed Central  Google Scholar 

  • Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K. Induced pluripotent stem cells generated without viral integration. Science. 2008;322:945–9.

  • Steliou K, Boosalis MS, Perrine SP, Sangerman J, Faller DV. Butyrate histone deacetylase inhibitors. Biores Open Access. 2012;1(4):192–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sugai K, Fukuzawa R, Shofuda T, Fukusumi H, Kawabata S, Nishiyama Y, et al. Pathological classification of human iPSC-derived neural stem/progenitor cells towards safety assessment of transplantation therapy for CNS diseases. Mol Brain. 2016;9(1):85.

    Article  PubMed  PubMed Central  Google Scholar 

  • Taapken SM, Nisler BS, Newton MA, Sampsell-Barron TL, Leonhard KA, McIntire EM, et al. Karyotypic abnormalities in human induced pluripotent stem cells and embryonic stem cells. Nat Biotechnol. 2011;29(4):313–4.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.

    Article  CAS  PubMed  Google Scholar 

  • Talluri TR, Kumar D, Glage S, Garrels W, Ivics Z, Debowski K, et al. Derivation and characterization of bovine induced pluripotent stem cells by transposon-mediated reprogramming. Cell Reprogram. 2015;17(2):131–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang C, Lee AS, Volkmer JP, Sahoo D, Nag D, Mosley AR, et al. An antibody against SSEA-5 glycan on human pluripotent stem cells enables removal of teratoma-forming cells. Nat Biotechnol. 2011;29(9):829–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tapia N, Schöler HR. Molecular obstacles to clinical translation of iPSCs. Cell Stem Cell. 2016;19(3):298–09.

    Article  CAS  PubMed  Google Scholar 

  • 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;11:147–52.

    Article  CAS  PubMed  Google Scholar 

  • Templin C, Zweigerdt R, Schwanke K, Olmer R, Ghadri JR, Emmert MY, et al. Transplantation and tracking of human-induced pluripotent stem cells in a pig model of myocardial infarction: assessment of cell survival, engraftment, and distribution by hybrid single photon emission computed tomography/computed tomography of sodium iodide symporter transgene expression. Circulation. 2012;126:430–9.

    Article  CAS  PubMed  Google Scholar 

  • Teoh HK, Cheong SK. Induced pluripotent stem cells in research and therapy. Malaysian J Pathol. 2012;34:1–13.

    Google Scholar 

  • Theunissen TW, Powell BE, Wang H, Mitalipova M, Faddah DA, Reddy J, et al. Systematic identification of culture conditions for induction and maintenance of naive human pluripotency. Cell Stem Cell. 2014;15(4):471–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomson AJ, Itskovitz-Eldor J, Shapiro SS, Waknitz AM, Swiergiel JJ, Marshall SV, Jones MJ. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–7.

    Article  CAS  PubMed  Google Scholar 

  • Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17(1):11–22.

    Article  CAS  PubMed  Google Scholar 

  • Trounson A, DeWitt ND. Pluripotent stem cells progressing to the clinic. Nat Rev Mol Cell Biol. 2016;17(3):194–200.

    Article  CAS  PubMed  Google Scholar 

  • Urschitz J, Moisyadi S. Transpositional transgenesis with piggyBac. Mob Genet Elements. 2013;3(3):e25167.

    Article  PubMed  PubMed Central  Google Scholar 

  • Vargas JE, Chicaybam L, Tetelbom Stein R, Tanuri A, Delgado-Cañedo A, Martin H, Bonamino MH. Retroviral vectors and transposons for stable gene therapy: advances, current challenges and perspectives. J Translat Med. 2016;14:288.

    Article  Google Scholar 

  • Wang P, Na J. Mechanism and methods to induce pluripotency. Protein Cell. 2011;2:792–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang YD, Cai N, Wu XL, Cao HZ, Xie LL, Zheng PS. OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway. Cell Death Dis. 2013;4:e760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J, Hao J, Bai D, Gu Q, Han W, Wang L, et al. Generation of clinical-grade human induced pluripotent stem cells in xeno-free conditions. Stem Cell Res Ther. 2015;6:223.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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;7:618–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watson AL, Carlson DF, Largaespada DA, Hackett PB, Fahrenkrug SC. Engineered swine models of cancer. Front Genet. 2016;7:78.

    Article  PubMed  PubMed Central  Google Scholar 

  • Werbowetski-Ogilvie TE, Bosse M, Stewart M, Schnerch A, Ramos-Mejia V, Rouleau A, et al. Characterization of human embryonic stem cells with features of neoplastic progression. Nature Biotechnol. 2009;27:91–7.

    Article  CAS  Google Scholar 

  • West FD, Terlouw SL, Kwon DJ, Mumaw JL, Dhara SK, Hasneen K, et al. Porcine induced pluripotent stem cells produce chimeric offspring. Stem Cells Dev. 2010;19:1211–20.

    Article  CAS  PubMed  Google Scholar 

  • Wolf E, Braun-Reichhart C, Streckel E, Renner S. Genetically engineered pig models for diabetes research. Transgenic Res. 2014;23(1):27–38.

    Article  CAS  PubMed  Google Scholar 

  • Woltjen K, Hämäläinen R, Kibschull M, Mileikovsky M, Nagy A. Transgene-free production of pluripotent stem cells using piggyBac transposons. Methods Mol Biol. 2011;767:87–103.

    Article  CAS  PubMed  Google Scholar 

  • Wu C, Dunbar CE. Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity. Front Med. 2011;5(4):356–71.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yao J, Huang J, Zhao J. Genome editing revolutionize the creation of genetically modified pigs for modeling human diseases. Hum Genet. 2016;135(9):1093–105.

    Article  CAS  PubMed  Google Scholar 

  • Ye L, Chang YH, Xiong Q, Zhang P, Zhang L, Somasundaram P, et al. Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cells. Cell Stem Cell. 2014;15(6):750–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yea CH, Jeong HC, Moon SH, Lee MO, Kim KJ, Choi JW, et al. In situ label-free quantification of human pluripotent stem cells with electrochemical potential. Biomaterials. 2016;75:250–9.

    Article  CAS  PubMed  Google Scholar 

  • Yoshihara M, Hayashizaki Y, Murakawa Y. Genomic instability of iPSCs: challenges towards their clinical applications. Stem Cell Rev and Rep. 2016; doi:10.1007/s12015-016-9680-6.

    Google Scholar 

  • 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 tissue. Science. 2007;318:1917–20.

    Article  CAS  PubMed  Google Scholar 

  • Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, Thomson JA. Human induced pluripotent stem cells free of vector and transgene sequences. Science. 2009;324:797–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang G, Shang B, Yang P, Cao Z, Pan Y, Zhou Q. Induced pluripotent stem cell consensus genes: implication for the risk of tumorigenesis and cancers in induced pluripotent stem cell therapy. Stem Cells Dev. 2012;21:955–64.

    Article  CAS  PubMed  Google Scholar 

  • 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;4:381–4.

    Article  CAS  PubMed  Google Scholar 

  • Zhou L, Wang W, Liu Y, de Castro JF, Ezashi T, Telugu BPVL, et al. Differentiation of induced pluripotent stem cells of swine into rod photoreceptors and their integration into the retina. Stem Cells. 2011;29:972–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

DK and TA acknowledge ICAR and DBT for providing facilities and support.

Author information

Authors and Affiliations

  1. Animal Physiology and Reproduction Division, ICAR-Central Institute for Research on Buffaloes, Hisar, Haryana, 125001, India

    Dharmendra Kumar

  2. NCVTCC, ICAR-National Research Centre on Equines, Hisar, Haryana, 125001, India

    Taruna Anand

  3. Institute of Farm Animal Genetics, Friedrich-Loeffler-Institut, Federal Reseach Institute for Animal Health, Höltystr. 10, 31535, Neustadt, Germany

    Wilfried A. Kues

Authors
  1. Dharmendra Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Taruna Anand
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wilfried A. Kues
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wilfried A. Kues.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumar, D., Anand, T. & Kues, W.A. Clinical potential of human-induced pluripotent stem cells. Cell Biol Toxicol 33, 99–112 (2017). https://doi.org/10.1007/s10565-016-9370-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-016-9370-9

Keywords

Search

Navigation