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REVIEW
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Human pluripotent stem cells: tools for regenerative medicine

Peter W. Andrews1*
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1 The Centre for Stem Cell Biology, The School of Bioscience, The University of Sheffield, Sheffield, UK
Submitted: 13 November 2021 | Revised: 12 December 2021 | Accepted: 20 December 2021 | Published: 28 December 2021
Copyright © 2021 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution–NonCommercial–ShareAlike 4.0 License.
Abstract

Human embryonic stem cells and induced pluripotent stem cells, together denoted as pluripotent stem cells have opened up unprecedented opportunities for developments in human healthcare over the past 20 years. Although much about the properties and behaviour of these cells required to underpin their applications has been discovered over this time, a number of issues remain. This brief review considers the history of these developments and some of the underlying biology, pointing out some of the problems still to be resolved, particularly in relation to their genetic stability and possible malignancy.

Keywords
embryonic stem cell ; induced pluripotent stem cell ; human ; pluripotency ; differentiation
References

Below is the content of the Citations in the paper which has been de-formatted, however, the content stays consistent with the original.

1. Thomson, J. A.; Itskovitz-Eldor, J.; Shapiro, S. S.; Waknitz, M. A.; Swiergiel, J. J.; Marshall, V. S.; Jones, J. M. Embryonic stem cell lines derived from human blastocysts. Science. 1998, 282, 1145-1147.  
2. Gearhart, J. D. New potential for human embryonic stem cells. Science. 1998, 282, 1061-1062.  
3. Trounson, A.; Pera, M. Potential benefits of cell cloning for human medicine. Reprod Fertil Dev. 1998, 10, 121-125.  
4. Takahashi, K.; Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006, 126, 663-676.  
5. 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, 861-872.  
6. Yu, J.; Vodyanik, M. A.; Smuga-Otto, K.; Antosiewicz-Bourget, J.; Frane, J. L.; Tian, S.; Nie, J.; Jonsdottir, G. A.; Ruotti, V.; Stewart, R.; Slukvin, II; Thomson, J. A. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007, 318, 1917-1920.  
7. Halliwell, J.; Barbaric, I.; Andrews, P. W. Acquired genetic changes in human pluripotent stem cells: origins and consequences. Nat Rev Mol Cell Biol. 2020, 21, 715-728.  
8. Damjanov, I.; Solter, D. Experimental teratoma. Curr Top Pathol. 1974, 59, 69-130.  
9. Andrews, P. W. From teratocarcinomas to embryonic stem cells. Philos Trans R Soc Lond B Biol Sci. 2002, 357, 405-417.  
10. Einhorn, L. H. Treatment strategies of testicular cancer in the United States. Int J Androl. 1987, 10, 399-405.  
11. Stevens, L. C.; Little, C. C. Spontaneous testicular teratomas in an inbred strain of mice. Proc Natl Acad Sci U S A. 1954, 40, 1080-1087.  
12. Kleinsmith, L. J.; Pierce, G. B., Jr. Multipotentiality of single embryonal carcinoma cells. Cancer Res. 1964, 24, 1544-1551.  
13. Damjanov, I.; Andrews, P. W. The terminology of teratocarcinomas and teratomas. Nat Biotechnol. 2007, 25, 1212; discussion 1212.  
14. Evans, M. J. The isolation and properties of a clonal tissue culture strain of pluripotent mouse teratoma cells. J Embryol Exp Morphol. 1972, 28, 163-176.  
15. Martin, G. R.; Evans, M. J. Differentiation of clonal lines of teratocarcinoma cells: formation of embryoid bodies in vitro. Proc Natl Acad Sci U S A. 1975, 72, 1441-1445.  
16. Nicolas, J. F.; Dubois, P.; Jakob, H.; Gaillard, J.; Jacob, F. Tératocarcinome de la souris: différenciation en culture d’une lignée de cellules primitives à potentialities multiples. Ann Microbiol Inst Pasteur A. 1975, 126, 3-22.  
17. Brinster, R. L. The effect of cells transferred into the mouse blastocyst on subsequent development. J Exp Med. 1974, 140, 1049-1056.  
18. Evans, M. J.; Kaufman, M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981, 292, 154-156.  
19. Martin, G. R. 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, 7634-7638.  
20. Hogan, B.; Fellous, M.; Avner, P.; Jacob, F. Isolation of a human teratoma cell line which expresses F9 antigen. Nature. 1977, 270, 515-518.  
21. Andrews, P. W.; Bronson, D. L.; Benham, F.; Strickland, S.; Knowles, B. B. A comparative study of eight cell lines derived from human testicular teratocarcinoma. Int J Cancer. 1980, 26, 269-280.  
22. Andrews, P. W.; Damjanov, I.; Simon, D.; Banting, G. S.; Carlin, C.; Dracopoli, N. C.; Føgh, J. Pluripotent embryonal carcinoma clones derived from the human teratocarcinoma cell line Tera-2. Differentiation in vivo and in vitro. Lab Invest. 1984, 50, 147-162.  
23. Pera, M. F.; Cooper, S.; Mills, J.; Parrington, J. M. Isolation and characterization of a multipotent clone of human embryonal carcinoma cells. Differentiation. 1989, 42, 10-23.  
24. Andrews, P. W.; Casper, J.; Damjanov, I.; Duggan-Keen, M.; Giwercman, A.; Hata, J.; von Keitz, A.; Looijenga, L. H.; Millán, J. L.; Oosterhuis, J. W.; Pera, M.; Sawada, M.; Schmoll, H. J.; Skakkebaek, N. E.; van Putten, W.; Stern, P. Comparative analysis of cell surface antigens expressed by cell lines derived from human germ cell tumours. Int J Cancer. 1996, 66, 806-816.  
25. Reubinoff, B. E.; Pera, M. F.; Fong, C. Y.; Trounson, A.; Bongso, A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol. 2000, 18, 399-404.  
26. Draper, J. S.; Pigott, C.; Thomson, J. A.; Andrews, P. W. Surface antigens of human embryonic stem cells: changes upon differentiation in culture. J Anat. 2002, 200, 249-258.  
27. Damjanov, I.; Andrews, P. W. Teratomas produced from human pluripotent stem cells xenografted into immunodeficient mice - a histopathology atlas. Int J Dev Biol. 2016, 60, 337-419.  
28. International Stem Cell Initiative; Adewumi, O.; Aflatoonian, B.; Ahrlund-Richter, L.; Amit, M.; Andrews, P. W.; Beighton, G.; Bello, P. A.; Benvenisty, N.; Berry, L. S.; Bevan, S.; Blum, B.; Brooking, J.; Chen, K. G.; Choo, A. B.; Churchill, G. A.; Corbel, M.; Damjanov, I.; Draper, J. S.; Dvorak, P.; Emanuelsson, K.; Fleck, R. A.; Ford, A.; Gertow, K.; Gertsenstein, M.; Gokhale, P. J.; Hamilton, R. S.; Hampl, A.; Healy, L. E.; Hovatta, O.; Hyllner, J.; Imreh, M. P.; Itskovitz-Eldor, J.; Jackson, J.; Johnson, J. L.; Jones, M.; Kee, K.; King, B. L.; Knowles, B. B.; Lako, M.; Lebrin, F.; Mallon, B. S.; Manning, D.; Mayshar, Y.; McKay, R. D.; Michalska, A. E.; Mikkola, M.; Mileikovsky, M.; Minger, S. L.; Moore, H. D.; Mummery, C. L.; Nagy, A.; Nakatsuji, N.; O’Brien, C. M.; Oh, S. K.; Olsson, C.; Otonkoski, T.; Park, K. Y.; Passier, R.; Patel, H.; Patel, M.; Pedersen, R.; Pera, M. F.; Piekarczyk, M. S.; Pera, R. A.; Reubinoff, B. E.; Robins, A. J.; Rossant, J.; Rugg-Gunn, P.; Schulz, T. C.; Semb, H.; Sherrer, E. S.; Siemen, H.; Stacey, G. N.; Stojkovic, M.; Suemori, H.; Szatkiewicz, J.; Turetsky, T.; Tuuri, T.; van den Brink, S.; Vintersten, K.; Vuoristo, S.; Ward, D.; Weaver, T. A.; Young, L. A.; Zhang, W. Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nat Biotechnol. 2007, 25, 803-816.  
29. International Stem Cell Initiative. Assessment of established techniques to determine developmental and malignant potential of human pluripotent stem cells. Nat Commun. 2018, 9, 1925.  
30. Itskovitz-Eldor, J.; Schuldiner, M.; Karsenti, D.; Eden, A.; Yanuka, O.; Amit, M.; Soreq, H.; Benvenisty, N. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol Med. 2000, 6, 88-95.  
31. Schuldiner, M.; Yanuka, O.; Itskovitz-Eldor, J.; Melton, D. A.; Benvenisty, N. Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A. 2000, 97, 11307-11312.  
32. Bock, C.; Kiskinis, E.; Verstappen, G.; Gu, H.; Boulting, G.; Smith, Z. D.; Ziller, M.; Croft, G. F.; Amoroso, M. W.; Oakley, D. H.; Gnirke, A.; Eggan, K.; Meissner, A. Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell. 2011, 144, 439-452.  
33. Tsankov, A. M.; Akopian, V.; Pop, R.; Chetty, S.; Gifford, C. A.; Daheron, L.; Tsankova, N. M.; Meissner, A. A qPCR ScoreCard quantifies the differentiation potential of human pluripotent stem cells. Nat Biotechnol. 2015, 33, 1182-1192.  
34. Avior, Y.; Biancotti, J. C.; Benvenisty, N. TeratoScore: assessing the differentiation potential of human pluripotent stem cells by quantitative expression analysis of teratomas. Stem Cell Reports. 2015, 4, 967-974.  
35. Tippett, P.; Andrews, P. W.; Knowles, B. B.; Solter, D.; Goodfellow, P. N. Red cell antigens P (globoside) and Luke: identification by monoclonal antibodies defining the murine stage-specific embryonic antigens -3 and -4 (SSEA-3 and SSEA-4). Vox Sang. 1986, 51, 53-56.  
36. Andrews, P. W.; Banting, G.; Damjanov, I.; Arnaud, D.; Avner, P. Three monoclonal antibodies defining distinct differentiation antigens associated with different high molecular weight polypeptides on the surface of human embryonal carcinoma cells. Hybridoma. 1984, 3, 347-361.  
37. Müller, F. J.; Schuldt, B. M.; Williams, R.; Mason, D.; Altun, G.; Papapetrou, E. P.; Danner, S.; Goldmann, J. E.; Herbst, A.; Schmidt, N. O.; Aldenhoff, J. B.; Laurent, L. C.; Loring, J. F. A bioinformatic assay for pluripotency in human cells. Nat Methods. 2011, 8, 315-317.  
38. Vugler, A.; Carr, A. J.; Lawrence, J.; Chen, L. L.; Burrell, K.; Wright, A.; Lundh, P.; Semo, M.; Ahmado, A.; Gias, C.; da Cruz, L.; Moore, H.; Andrews, P.; Walsh, J.; Coffey, P. Elucidating the phenomenon of HESC-derived RPE: anatomy of cell genesis, expansion and retinal transplantation. Exp Neurol. 2008, 214, 347-361.  
39. Schwartz, S. D.; Regillo, C. D.; Lam, B. L.; Eliott, D.; Rosenfeld, P. J.; Gregori, N. Z.; Hubschman, J. P.; Davis, J. L.; Heilwell, G.; Spirn, M.; Maguire, J.; Gay, R.; Bateman, J.; Ostrick, R. M.; Morris, D.; Vincent, M.; Anglade, E.; Del Priore, L. V.; Lanza, R. 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, 509-516.  
40. da Cruz, L.; Fynes, K.; Georgiadis, O.; Kerby, J.; Luo, Y. H.; Ahmado, A.; Vernon, A.; Daniels, J. T.; Nommiste, B.; Hasan, S. M.; Gooljar, S. B.; Carr, A. F.; Vugler, A.; Ramsden, C. M.; Bictash, M.; Fenster, M.; Steer, J.; Harbinson, T.; Wilbrey, A.; Tufail, A.; Feng, G.; Whitlock, M.; Robson, A. G.; Holder, G. E.; Sagoo, M. S.; Loudon, P. T.; Whiting, P.; Coffey, P. J. Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration. Nat Biotechnol. 2018, 36, 328-337.  
41. Kimbrel, E. A.; Lanza, R. Pluripotent stem cells: the last 10 years. Regen Med. 2016, 11, 831-847.  
42. Rossant, J.; Tam, P. P. L. New insights into early human development: lessons for stem cell derivation and differentiation. Cell Stem Cell. 2017, 20, 18-28.  
43. Chen, G.; Gulbranson, D. R.; Hou, Z.; Bolin, J. M.; Ruotti, V.; Probasco, M. D.; Smuga-Otto, K.; Howden, S. E.; Diol, N. R.; Propson, N. E.; Wagner, R.; Lee, G. O.; Antosiewicz-Bourget, J.; Teng, J. M.; Thomson, J. A. Chemically defined conditions for human iPSC derivation and culture. Nat Methods. 2011, 8, 424-429.  
44. Hackland, J. O. S.; Frith, T. J. R.; Thompson, O.; Marin Navarro, A.; Garcia-Castro, M. I.; Unger, C.; Andrews, P. W. Top-down inhibition of BMP signaling enables robust induction of hPSCs into neural crest in fully defined, xeno-free conditions. Stem Cell Reports. 2017, 9, 1043-1052.  
45. Enver, T.; Pera, M.; Peterson, C.; Andrews, P. W. Stem cell states, fates, and the rules of attraction. Cell Stem Cell. 2009, 4, 387-397.  
46. Tonge, P. D.; Olariu, V.; Coca, D.; Kadirkamanathan, V.; Burrell, K. E.; Billings, S. A.; Andrews, P. W. Prepatterning in the stem cell compartment. PLoS One. 2010, 5, e10901.  
47. Allison, T. F.; Smith, A. J. H.; Anastassiadis, K.; Sloane-Stanley, J.; Biga, V.; Stavish, D.; Hackland, J.; Sabri, S.; Langerman, J.; Jones, M.; Plath, K.; Coca, D.; Barbaric, I.; Gokhale, P.; Andrews, P. W. Identification and single-cell functional characterization of an endodermally biased pluripotent substate in human embryonic stem cells. Stem Cell Reports. 2018, 10, 1895-1907.  
48. Stavish, D.; Böiers, C.; Price, C.; Frith, T. J. R.; Halliwell, J.; Saldaña-Guerrero, I.; Wray, J.; Brown, J.; Carr, J.; James, C.; Barbaric, I.; Andrews, P. W.; Enver, T. Generation and trapping of a mesoderm biased state of human pluripotency. Nat Commun. 2020, 11, 4989.  
49. Ahmed, T.; Bosl, G. J.; Hajdu, S. I. Teratoma with malignant transformation in germ cell tumors in men. Cancer. 1985, 56, 860-863.  
50. Rouhani, F. J.; Nik-Zainal, S.; Wuster, A.; Li, Y.; Conte, N.; Koike-Yusa, H.; Kumasaka, N.; Vallier, L.; Yusa, K.; Bradley, A. Mutational history of a human cell lineage from somatic to induced pluripotent stem cells. PLoS Genet. 2016, 12, e1005932.  
51. International Stem Cell Initiative; Amps, K.; Andrews, P. W.; Anyfantis, G.; Armstrong, L.; Avery, S.; Baharvand, H.; Baker, J.; Baker, D.; Munoz, M. B.; Beil, S.; Benvenisty, N.; Ben-Yosef, D.; Biancotti, J. C.; Bosman, A.; Brena, R. M.; Brison, D.; Caisander, G.; Camarasa, M. V.; Chen, J.; Chiao, E.; Choi, Y. M.; Choo, A. B.; Collins, D.; Colman, A.; Crook, J. M.; Daley, G. Q.; Dalton, A.; De Sousa, P. A.; Denning, C.; Downie, J.; Dvorak, P.; Montgomery, K. D.; Feki, A.; Ford, A.; Fox, V.; Fraga, A. M.; Frumkin, T.; Ge, L.; Gokhale, P. J.; Golan-Lev, T.; Gourabi, H.; Gropp, M.; Lu, G.; Hampl, A.; Harron, K.; Healy, L.; Herath, W.; Holm, F.; Hovatta, O.; Hyllner, J.; Inamdar, M. S.; Irwanto, A. K.; Ishii, T.; Jaconi, M.; Jin, Y.; Kimber, S.; Kiselev, S.; Knowles, B. B.; Kopper, O.; Kukharenko, V.; Kuliev, A.; Lagarkova, M. A.; Laird, P. W.; Lako, M.; Laslett, A. L.; Lavon, N.; Lee, D. R.; Lee, J. E.; Li, C.; Lim, L. S.; Ludwig, T. E.; Ma, Y.; Maltby, E.; Mateizel, I.; Mayshar, Y.; Mileikovsky, M.; Minger, S. L.; Miyazaki, T.; Moon, S. Y.; Moore, H.; Mummery, C.; Nagy, A.; Nakatsuji, N.; Narwani, K.; Oh, S. K.; Oh, S. K.; Olson, C.; Otonkoski, T.; Pan, F.; Park, I. H.; Pells, S.; Pera, M. F.; Pereira, L. V.; Qi, O.; Raj, G. S.; Reubinoff, B.; Robins, A.; Robson, P.; Rossant, J.; Salekdeh, G. H.; Schulz, T. C.; Sermon, K.; Sheik Mohamed, J.; Shen, H.; Sherrer, E.; Sidhu, K.; Sivarajah, S.; Skottman, H.; Spits, C.; Stacey, G. N.; Strehl, R.; Strelchenko, N.; Suemori, H.; Sun, B.; Suuronen, R.; Takahashi, K.; Tuuri, T.; Venu, P.; Verlinsky, Y.; Ward-van Oostwaard, D.; Weisenberger, D. J.; Wu, Y.; Yamanaka, S.; Young, L.; Zhou, Q. Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat Biotechnol. 2011, 29, 1132-1144.  
52. Merkle, F. T.; Ghosh, S.; Kamitaki, N.; Mitchell, J.; Avior, Y.; Mello, C.; Kashin, S.; Mekhoubad, S.; Ilic, D.; Charlton, M.; Saphier, G.; Handsaker, R. E.; Genovese, G.; Bar, S.; Benvenisty, N.; McCarroll, S. A.; Eggan, K. Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations. Nature. 2017, 545, 229-233.  
53. Sillars-Hardebol, A. H.; Carvalho, B.; Beliën, J. A.; de Wit, M.; Delis-van Diemen, P. M.; Tijssen, M.; van de Wiel, M. A.; Pontén, F.; Fijneman, R. J.; Meijer, G. A. BCL2L1 has a functional role in colorectal cancer and its protein expression is associated with chromosome 20q gain. J Pathol. 2012, 226, 442-450.  
54. Baugh, E. H.; Ke, H.; Levine, A. J.; Bonneau, R. A.; Chan, C. S. Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ. 2018, 25, 154-160.  
55. Baker, D.; Hirst, A. J.; Gokhale, P. J.; Juarez, M. A.; Williams, S.; Wheeler, M.; Bean, K.; Allison, T. F.; Moore, H. D.; Andrews, P. W.; Barbaric, I. Detecting genetic mosaicism in cultures of human pluripotent stem cells. Stem Cell Reports. 2016, 7, 998-1012.  
56. Thompson, O.; von Meyenn, F.; Hewitt, Z.; Alexander, J.; Wood, A.; Weightman, R.; Gregory, S.; Krueger, F.; Andrews, S.; Barbaric, I.; Gokhale, P. J.; Moore, H. D.; Reik, W.; Milo, M.; Nik-Zainal, S.; Yusa, K.; Andrews, P. W. Low rates of mutation in clinical grade human pluripotent stem cells under different culture conditions. Nat Commun. 2020, 11, 1528.  
57. Halliwell, J. A.; Frith, T. J. R.; Laing, O.; Price, C. J.; Bower, O. J.; Stavish, D.; Gokhale, P. J.; Hewitt, Z.; El-Khamisy, S. F.; Barbaric, I.; Andrews, P. W. Nucleosides rescue replication-mediated genome instability of human pluripotent stem cells. Stem Cell Reports. 2020, 14, 1009-1017.  
58. Desmarais, J. A.; Hoffmann, M. J.; Bingham, G.; Gagou, M. E.; Meuth, M.; Andrews, P. W. Human embryonic stem cells fail to activate CHK1 and commit to apoptosis in response to DNA replication stress. Stem Cells. 2012, 30, 1385-1393.  

Conflict of interest
The authors declare they have no competing interests.
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