Cell Biology and Toxicology

, Volume 33, Issue 4, pp 351–360 | Cite as

Clinical potentials of human pluripotent stem cells

  • Cristina Mora
  • Marialaura Serzanti
  • Antonella Consiglio
  • Maurizio Memo
  • Patrizia Dell’Era


Aging, injuries, and diseases can be considered as the result of malfunctioning or damaged cells. Regenerative medicine aims to restore tissue homeostasis by repairing or replacing cells, tissues, or damaged organs, by linking and combining different disciplines including engineering, technology, biology, and medicine. To pursue these goals, the discipline is taking advantage of pluripotent stem cells (PSCs), a peculiar type of cell possessing the ability to differentiate into every cell type of the body. Human PSCs can be isolated from the blastocysts and maintained in culture indefinitely, giving rise to the so-called embryonic stem cells (ESCs). However, since 2006, it is possible to restore in an adult cell a pluripotent ESC-like condition by forcing the expression of four transcription factors with the rejuvenating reprogramming technology invented by Yamanaka. Then the two types of PSC can be differentiated, using standardized protocols, towards the cell type necessary for the regeneration. Although the use of these derivatives for therapeutic transplantation is still in the preliminary phase of safety and efficacy studies, a lot of efforts are presently taking place to discover the biological mechanisms underlying genetic pathologies, by differentiating induced PSCs derived from patients, and new therapies by challenging PSC-derived cells in drug screening.


Embryonic stem cells Induced pluripotent stem cells Disease modeling Drug screening Cell transplantation 


Compliance with ethical standards


This work was supported by a grant by Fondazione Cariplo to P.D.E. (ref. no. 2014-0822) and by BFU2013-49157-P and RETICTerCel grants from MINECO and the European Research Council (ERC) 2012-StG (311736- PD-HUMMODEL) to A.C.


  1. Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A, et al. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol. 2008;26(11):1276–84.CrossRefPubMedGoogle Scholar
  2. Agulnick AD, Ambruzs DM, Moorman MA, Bhoumik A, Cesario RM, et al. Insulin-producing endocrine cells differentiated in vitro from human embryonic stem cells function in macroencapsulation devices in vivo. Stem Cells Transl Med. 2015;4(10):1214–22.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, et al. Lentiviral hematopoietic stem cell gene therapy in patients with wiskott-aldrich syndrome. Science. 2013;341(6148):1233151-1233151.Google Scholar
  4. Annas GJ, Caplan A, Elias S. The politics of human-embryo research—avoiding ethical gridlock. N Engl J Med. 1996;334(20):1329–32.CrossRefPubMedGoogle Scholar
  5. Ban H, Nishishita N, Fusaki N, Tabata T, Saeki K, et al. Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors. Proc Natl Acad Sci U S A. 2011;108(34):14234–9.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bhonde RR, Sheshadri P, Sharma S, Kumar A. Making surrogate β-cells from mesenchymal stromal cells: perspectives and future endeavors. Int J Biochem Cell Biol. 2014;46:90–102.CrossRefPubMedGoogle Scholar
  7. Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013;341(6148):1233158.CrossRefPubMedGoogle Scholar
  8. Bitzer M, Armeanu S, Lauer UM, Neubert WJ. Sendai virus vectors as an emerging negative-strand RNA viral vector system. J Gene Med. 2003;5(7):543–53.CrossRefPubMedGoogle Scholar
  9. Brouwer M, Zhou H, Nadif KN. Choices for induction of pluripotency: recent developments in human induced pluripotent stem cell reprogramming strategies. Stem Cell Rev. 2016;12(1):54–72.CrossRefPubMedGoogle Scholar
  10. Bulic-Jakus F, Katusic Bojanac A, Juric-Lekic G, Vlahovic M, Sincic N. Teratoma: from spontaneous tumors to the pluripotency/malignancy assay. Wiley Interdiscip Rev Dev Biol. 2016;5(2):186–209.CrossRefPubMedGoogle Scholar
  11. Chang CW, Lai YS, Pawlik KM, Liu K, Sun CW, et al. Polycistronic lentiviral vector for “hit and run” reprogramming of adult skin fibroblasts to induced pluripotent stem cells. Stem Cells. 2009;27(5):1042–9.CrossRefPubMedGoogle Scholar
  12. Choi YS, Dusting GJ, Stubbs S, Arunothayaraj S, Han XL, et al. Differentiation of human adipose-derived stem cells into beating cardiomyocytes. J Cell Mol Med. 2010;14(4):878–89.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Choi SM, Kim Y, Shim JS, Park JT, Wang RH, et al. Efficient drug screening and gene correction for treating liver disease using patient-specific stem cells. Hepatology. 2013;57(6):2458–68.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Chung YG, Eum JH, Lee JE, Shim SH, Sepilian V, et al. Human somatic cell nuclear transfer using adult cells. Cell Stem Cell. 2014;14(6):777–80.CrossRefPubMedGoogle Scholar
  15. Crotti L, Celano G, Dagradi F, Schwartz PJ. Congenital long QT syndrome. Orphanet J Rare Dis. 2008;3:18.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987;51(6):987–1000.CrossRefPubMedGoogle Scholar
  17. Dell'Era P, Benzoni P, Crescini E, Valle M, Xia E, et al. Cardiac disease modeling using induced pluripotent stem cell-derived human cardiomyocytes. World J Stem Cells. 2015;7(2):329–42.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Doerflinger RM. The ethics of funding embryonic stem cell research: a Catholic viewpoint. Kennedy Inst Ethics J. 1999;9(2):137–50.CrossRefPubMedGoogle Scholar
  19. Drawnel FM, Boccardo S, Prummer M, Delobel F, Graff A, et al. Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells. Cell Rep. 2014;9(3):810–21.CrossRefPubMedGoogle Scholar
  20. Dye BR, Hill DR, Ferguson MA, Tsai YH, Nagy MS, et al. In vitro generation of human pluripotent stem cell derived lung organoids. Elife. 2015;4. Google Scholar
  21. Egawa N, Kitaoka S, Tsukita K, Naitoh M, Takahashi K, et al. Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci Transl Med. 2012;4(145):145ra104.CrossRefPubMedGoogle Scholar
  22. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154–6.CrossRefPubMedGoogle Scholar
  23. Fusaki N, Ban H, Nishiyama A, Saeki K, Hasegawa M. 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. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85(8):348–62.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Giri S, Bader A. A low-cost, high-quality new drug discovery process using patient-derived induced pluripotent stem cells. Drug Discov Today. 2015;20(1):37–49.CrossRefPubMedGoogle Scholar
  25. González F, Boué S, Izpisúa Belmonte JC. Methods for making induced pluripotent stem cells: reprogramming à la carte. Nat Rev Genet. 2011;12(4):231–42.CrossRefPubMedGoogle Scholar
  26. Grabundzija I, Wang J, Sebe A, Erdei Z, Kajdi R, et al. Sleeping beauty transposon-based system for cellular reprogramming and targeted gene insertion in induced pluripotent stem cells. Nucleic Acids Res. 2013;41(3):1829–47.CrossRefPubMedGoogle Scholar
  27. Hockemeyer D, Soldner F, Cook EG, Gao Q, Mitalipova M, Jaenisch R. A drug-inducible system for direct reprogramming of human somatic cells to pluripotency. Cell Stem Cell. 2008;3(3):346-353.Google Scholar
  28. Ilic D, Devito L, Miere C, Codognotto S. Human embryonic and induced pluripotent stem cells in clinical trials. Br Med Bull. 2015;116:19–27.PubMedGoogle Scholar
  29. Jia F, Wilson KD, Sun N, Gupta DM, Huang M, et al. A nonviral minicircle vector for deriving human iPS cells. Nat Methods. 2010;7(3):197–9.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kim D, Kim CH, Moon JI, Chung YG, Chang MY, et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell. 2009;4(6):472–6.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Klimanskaya I, Hipp J, Rezai KA, West M, Atala A, et al. Derivation and comparative assessment of retinal pigment epithelium from human embryonic stem cells using transcriptomics. Cloning Stem Cells. 2004;6(3):217–45.CrossRefPubMedGoogle Scholar
  32. Ko HC, Gelb BD. Concise review: drug discovery in the age of the induced pluripotent stem cell. Stem Cells Transl Med. 2014;3(4):500–9.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Kulessa H, Frampton J, Graf T. GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts. Genes Dev. 1995;9(10):1250–62.CrossRefPubMedGoogle Scholar
  34. Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science. 2014;345(6194):1247125.CrossRefPubMedGoogle Scholar
  35. Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501(7467):373–9.CrossRefPubMedGoogle Scholar
  36. Lebkowski J. GRNOPC1: the world’s first embryonic stem cell-derived therapy interview with Jane Lebkowski. Regen Med. 2011;6(6 Suppl):11–3.CrossRefPubMedGoogle Scholar
  37. Lee MO, Moon SH, Jeong HC, Yi JY, Lee TH, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Lu B, Malcuit C, Wang S, Girman S, Francis P, et al. Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration. Stem Cells. 2009;27(9):2126–35.CrossRefPubMedGoogle Scholar
  39. Maherali N, Hochedlinger K. Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell. 2008;3(6):595–605.CrossRefPubMedGoogle Scholar
  40. Maherali N, Ahfeldt T, Rigamonti A, Utikal J, Cowan C, et al. A high-efficiency system for the generation and study of human induced pluripotent stem cells. Cell Stem Cell. 2008;3(3):340–5.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Mallon BS, Hamilton RS, Kozhich OA, Johnson KR, Fann YC, et al. Comparison of the molecular profiles of human embryonic and induced pluripotent stem cells of isogenic origin. Stem Cell Res. 2014;12(2):376–86.CrossRefPubMedGoogle Scholar
  42. Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A. 1981;78(12):7634–8.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Matreyek KA, Engelman A. Viral and cellular requirements for the nuclear entry of retroviral preintegration nucleoprotein complexes. Viruses. 2013;5(10):2483–511.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Mitani K, Kubo S. Adenovirus as an integrating vector. Curr Gene Ther. 2002;2(2):135–44. ReviewCrossRefPubMedGoogle Scholar
  45. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell. 2003;113(5):631–42.CrossRefPubMedGoogle Scholar
  46. Moretti A, Bellin M, Welling A, Jung CB, Lam JT, et al. Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med. 2010;363(15):1397–409.CrossRefPubMedGoogle Scholar
  47. Nakanishi M, Otsu M. Development of Sendai virus vectors and their potential applications in gene therapy and regenerative medicine. Curr Gene Ther. 2012;12(5):410–6.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Nakano T, Ando S, Takata N, Kawada M, Muguruma K, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell. 2012;10(6):771–85.CrossRefPubMedGoogle Scholar
  49. Narsinh KH, Jia F, Robbins RC, Kay MA, Longaker MT, et al. Generation of adult human induced pluripotent stem cells using nonviral minicircle DNA vectors. Nat Protoc. 2011;6(1):78–88.CrossRefPubMedGoogle Scholar
  50. Niwa H. Molecular mechanism to maintain stem cell renewal of ES cells. Cell Struct Funct. 2001;26(3):137–48.CrossRefPubMedGoogle Scholar
  51. Nutt SL, Heavey B, Rolink AG, Busslinger M. Pillars article: commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature. 1999;401: 556–562. J Immunol. 2015;195(3):766–72.Google Scholar
  52. Park HJ, Shin J, Kim J, Cho SW. Nonviral delivery for reprogramming to pluripotency and differentiation. Arch Pharm Res. 2014;37(1):107–19.CrossRefPubMedGoogle Scholar
  53. Ramalingam S, London V, Kandavelou K, Cebotaru L, Guggino W, et al. Generation and genetic engineering of human induced pluripotent stem cells using designed zinc finger nucleases. Stem Cells Dev. 2013;22(4):595–610.CrossRefPubMedGoogle Scholar
  54. Robertson JA. Human embryonic stem cell research: ethical and legal issues. Nat Rev Genet. 2001;2(1):74–8. ReviewCrossRefPubMedGoogle Scholar
  55. Sánchez-Danés A, Richaud-Patin Y, Carballo-Carbajal I, Jiménez-Delgado S, Caig C, et al. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson’s disease. EMBO Mol Med. 2012;4(5):380–95.CrossRefPubMedPubMedCentralGoogle Scholar
  56. Schwartz SD, Regillo CD, Lam BL, Eliott D, Rosenfeld PJ, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet. 2015;385(9967):509–16.CrossRefPubMedGoogle Scholar
  57. Scuteri A, Miloso M, Foudah D, Orciani M, Cavaletti G, et al. Mesenchymal stem cells neuronal differentiation ability: a real perspective for nervous system repair? Curr Stem Cell Res Ther. 2011;6(2):82–92.CrossRefPubMedGoogle Scholar
  58. Solnica-Krezel L, Sepich DS. Gastrulation: making and shaping germ layers. Annu Rev Cell Dev Biol. 2012;28:687–717.CrossRefPubMedGoogle Scholar
  59. Spence JR, Mayhew CN, Rankin SA, Kuhar MF, Vallance JE, et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature. 2011;470(7332):105–9.CrossRefPubMedGoogle Scholar
  60. Stadtfeld M, Hochedlinger K. Induced pluripotency: history, mechanisms, and applications. Genes Dev. 2010;24(20):2239–63.CrossRefPubMedPubMedCentralGoogle Scholar
  61. Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K. Induced pluripotent stem cells generated without viral integration. Science. 2008;322(5903):945–9.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Struhl G. A homoeotic mutation transforming leg to antenna in Drosophila. Nature. 1981;292(5824):635–8.CrossRefPubMedGoogle Scholar
  63. Tachibana M, Amato P, Sparman M, Gutierrez NM, Tippner-Hedges R, et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell. 2013;153(6):1228–38.CrossRefPubMedPubMedCentralGoogle Scholar
  64. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.CrossRefPubMedGoogle Scholar
  65. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.CrossRefPubMedGoogle Scholar
  66. Takebe T, Zhang RR, Koike H, Kimura M, Yoshizawa E, et al. Generation of a vascularized and functional human liver from an iPSC-derived organ bud transplant. Nat Protoc. 2014;9(2):396–409.CrossRefPubMedGoogle Scholar
  67. Tang C, Lee AS, Volkmer JP, Sahoo D, Nag D, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  68. Tapscott SJ, Davis RL, Thayer MJ, Cheng PF, Weintraub H, et al. MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. Science. 1988;242(4877):405–11.CrossRefPubMedGoogle Scholar
  69. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.CrossRefPubMedGoogle Scholar
  70. Wobus AM, Löser P. Present state and future perspectives of using pluripotent stem cells in toxicology research. Arch Toxicol. 2011;85(2):79–117.CrossRefPubMedPubMedCentralGoogle Scholar
  71. Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature. 2009;458(7239):766–70.CrossRefPubMedPubMedCentralGoogle Scholar
  72. Wu XB, Tao R. Hepatocyte differentiation of mesenchymal stem cells. Hepatobiliary Pancreat Dis Int. 2012;11(4):360–71.CrossRefPubMedGoogle Scholar
  73. Xie H, Ye M, Feng R, Graf T. Stepwise reprogramming of B cells into macrophages. Cell. 2004;117(5):663–76.CrossRefPubMedGoogle Scholar
  74. Yakubov E, Rechavi G, Rozenblatt S, Givol D. Reprogramming of human fibroblasts to pluripotent stem cells using mRNA of four transcription factors. Biochem Biophys Res Commun. 2010;394(1):189–93.CrossRefPubMedGoogle Scholar
  75. Yoshioka N, Gros E, Li H-R, Kumar S, Deacon DC, Maron C, et al. Efficient generation of human iPSCs by a synthetic self-replicative RNA. Cell Stem Cell. 2013;13(2):246-254.Google Scholar
  76. Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science. 2009;324(5928):797-801.Google Scholar
  77. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.CrossRefPubMedGoogle Scholar
  78. Zhong X, Gutierrez C, Xue T, Hampton C, Vergara MN, et al. Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun. 2014;5:4047.PubMedPubMedCentralGoogle Scholar
  79. Zhou W, Freed CR. Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells. 2009;27(11):2667–74.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  • Cristina Mora
    • 1
  • Marialaura Serzanti
    • 1
  • Antonella Consiglio
    • 1
  • Maurizio Memo
    • 2
  • Patrizia Dell’Era
    • 1
  1. 1.Cellular Fate Reprogramming Unit, Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
  2. 2.Pharmacology Unit, Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly

Personalised recommendations