Systems Biology and Stem Cell Pluripotency: Revisiting the Discovery of Induced Pluripotent Stem Cell

  • Kaveh Mashayekhi
  • Vanessa Hall
  • Kristine Freude
  • Miya K Hoeffding
  • Luminita Labusca
  • Poul HyttelEmail author


Recent breakthroughs in stem cell biology have accelerated research in the area of regenerative medicine. Over the past years, it has become possible to derive patient-specific stem cells which can be used to generate different cell populations for potential cell therapy. Systems biological modeling of stem cell pluripotency and differentiation have largely been based on prior knowledge of signaling pathways, gene regulatory networks, and epigenetic factors. However, there is a great need to extend the complexity of the modeling and to integrate different types of data, which would further improve systems biology and its uses in the field. In this chapter, we first give a general background on stem cell biology and regenerative medicine. Stem cell potency is introduced together with the hierarchy of stem cells ranging from pluripotent embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to tissue-specific multipotent and unipotent stem cells. Secondly, we address some of the systems biological approaches which have already added valuable knowledge to the stem cell field. Particular attention is paid to the most commonly used knowledge-based models as well as to the unsupervised data-driven model. Finally, we will revisit the discovery of the iPSCs by Yamanaka in 2006 and superimpose a data-driven systems biological approach on the data which this amazing discovery was based on. This approach helps to demonstrate how systems biology can complement the field of stem cell biology.


Systems biology Stem cells Pluripotency Cell differentiation Regenerative medicine 



We thank the following for financial support: The Danish National Advanced Technology Foundation (project number 047-2011-1; patient-specific stem cell-derived models for Alzheimer’s disease) and the European Union 7th Framework Program (PIAP-GA-2012-324451-STEMMAD) and Innovation Fund Denmark, BrainStem.


  1. Artyomov MN, Meissner A, Chakraborty AK (2010) A model for genetic and epigenetic regulatory networks identifies rare pathways for transcription factor induced pluripotency. PLoS Comput Biol 6(5), e1000785. doi: 10.1371/journal.pcbi.1000785 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bessonnard S, De Mot L, Gonze D, Barriol M, Dennis C, Goldbeter A, Dupont G, Chazaud C (2014) Gata6, Nanog and Erk signaling control cell fate in the inner cell mass through a tristable regulatory network. Development 141(19):3637–3648. doi: 10.1242/dev.109678 CrossRefPubMedGoogle Scholar
  3. Boland MJ, Nazor KL, Loring JF (2014) Epigenetic regulation of pluripotency and differentiation. Circ Res 115(2):311–324. doi: 10.1161/CIRCRESAHA.115.301517 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bradley A, Evans M, Kaufman MH, Robertson E (1984) Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature 309(5965):255–256CrossRefPubMedGoogle Scholar
  5. Buecker C, Srinivasan R, Wu Z, Calo E, Acampora D, Faial T, Simeone A, Tan M, Swigut T, Wysocka J (2014) Reorganization of enhancer patterns in transition from naive to primed pluripotency. Cell Stem Cell 14(6):838–853. doi: 10.1016/j.stem.2014.04.003 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Buganim Y, Faddah DA, Jaenisch R (2013) Mechanisms and models of somatic cell reprogramming. Nat Rev Genet 14(6):427–439. doi: 10.1038/nrg3473 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Byrne JA, Nguyen HN, Reijo Pera RA (2009) Enhanced generation of induced pluripotent stem cells from a subpopulation of human fibroblasts. PLoS One 4(9), e7118. doi: 10.1371/journal.pone.0007118 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Capecchi MR (2005) Gene targeting in mice: functional analysis of the mammalian genome for the twenty-first century. Nat Rev Genet 6(6):507–512. doi: 10.1038/nrg1619 CrossRefPubMedGoogle Scholar
  9. Chavez L, Bais AS, Vingron M, Lehrach H, Adjaye J, Herwig R (2009) In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach. BMC Genomics 10:314. doi: 10.1186/1471-2164-10-314 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Chickarmane V, Peterson C (2008) A computational model for understanding stem cell, trophectoderm and endoderm lineage determination. PLoS One 3(10), e3478. doi: 10.1371/journal.pone.0003478 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chickarmane V, Troein C, Nuber UA, Sauro HM, Peterson C (2006) Transcriptional dynamics of the embryonic stem cell switch. PLoS Comput Biol 2(9), e123. doi: 10.1371/journal.pcbi.0020123 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Chickarmane V, Olariu V, Peterson C (2012) Probing the role of stochasticity in a model of the embryonic stem cell: heterogeneous gene expression and reprogramming efficiency. BMC Syst Biol 6:98. doi: 10.1186/1752-0509-6-98 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Condic ML (2014) Totipotency: what it is and what it is not. Stem Cells Dev 23(8):796–812. doi: 10.1089/scd.2013.0364 CrossRefPubMedGoogle Scholar
  14. Daheron L, Opitz SL, Zaehres H, Lensch MW, Andrews PW, Itskovitz-Eldor J, Daley GQ (2004) LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells 22(5):770–778. doi: 10.1634/stemcells.22-5-770 CrossRefPubMedGoogle Scholar
  15. De Paepe C, Krivega M, Cauffman G, Geens M, Van de Velde H (2014) Totipotency and lineage segregation in the human embryo. Mol Hum Reprod 20(7):599–618. doi: 10.1093/molehr/gau027 CrossRefPubMedGoogle Scholar
  16. de Wert G, Mummery C (2003) Human embryonic stem cells: research, ethics and policy. Hum Reprod 18(4):672–682CrossRefPubMedGoogle Scholar
  17. Ellison D, Munden A, Levchenko A (2009) Computational model and microfluidic platform for the investigation of paracrine and autocrine signaling in mouse embryonic stem cells. Mol Biosyst 5(9):1004–1012. doi: 10.1039/b905602e CrossRefPubMedGoogle Scholar
  18. Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292(5819):154–156CrossRefPubMedGoogle Scholar
  19. Feng B, Jiang J, Kraus P, Ng JH, Heng JC, Chan YS, Yaw LP, Zhang W, Loh YH, Han J, Vega VB, Cacheux-Rataboul V, Lim B, Lufkin T, Ng HH (2009) Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nat Cell Biol 11(2):197–203. doi: 10.1038/ncb1827 CrossRefPubMedGoogle Scholar
  20. Flottmann M, Scharp T, Klipp E (2012) A stochastic model of epigenetic dynamics in somatic cell reprogramming. Front Physiol 3:216. doi: 10.3389/fphys.2012.00216 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Glauche I, Herberg M, Roeder I (2010) Nanog variability and pluripotency regulation of embryonic stem cells--insights from a mathematical model analysis. PLoS One 5(6), e11238. doi: 10.1371/journal.pone.0011238 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Golipour A, David L, Liu Y, Jayakumaran G, Hirsch CL, Trcka D, Wrana JL (2012) A late transition in somatic cell reprogramming requires regulators distinct from the pluripotency network. Cell Stem Cell 11(6):769–782. doi: 10.1016/j.stem.2012.11.008 CrossRefPubMedGoogle Scholar
  23. Gracio F, Cabral J, Tidor B (2013) Modeling stem cell induction processes. PLoS One 8(5), e60240. doi: 10.1371/journal.pone.0060240 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Gu P, Reid JG, Gao X, Shaw CA, Creighton C, Tran PL, Zhou X, Drabek RB, Steffen DL, Hoang DM, Weiss MK, Naghavi AO, El-daye J, Khan MF, Legge GB, Wheeler DA, Gibbs RA, Miller JN, Cooney AJ, Gunaratne PH (2008) Novel microRNA candidates and miRNA-mRNA pairs in embryonic stem (ES) cells. PLoS One 3(7), e2548. doi: 10.1371/journal.pone.0002548 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Gurdon JB, Elsdale TR, Fischberg M (1958) Sexually mature individuals of Xenopus laevis from the transplantation of single somatic nuclei. Nature 182(4627):64–65CrossRefPubMedGoogle Scholar
  26. Hanna J, Saha K, Pando B, van Zon J, Lengner CJ, Creyghton MP, van Oudenaarden A, Jaenisch R (2009) Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462(7273):595–601. doi: 10.1038/nature08592 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Hanna J, Cheng AW, Saha K, Kim J, Lengner CJ, Soldner F, Cassady JP, Muffat J, Carey BW, Jaenisch R (2010) Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc Natl Acad Sci U S A 107(20):9222–9227. doi: 10.1073/pnas.1004584107 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Hansson J, Rafiee MR, Reiland S, Polo JM, Gehring J, Okawa S, Huber W, Hochedlinger K, Krijgsveld J (2012) Highly coordinated proteome dynamics during reprogramming of somatic cells to pluripotency. Cell Rep 2(6):1579–1592. doi: 10.1016/j.celrep.2012.10.014 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Herberg M, Kalkan T, Glauche I, Smith A, Roeder I (2014) A model-based analysis of culture-dependent phenotypes of mESCs. PLoS One 9(3), e92496. doi: 10.1371/journal.pone.0092496 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Hu Z, Qian M, Zhang MQ (2011) Novel Markov model of induced pluripotency predicts gene expression changes in reprogramming. BMC Syst Biol 5(Suppl 2):S8. doi: 10.1186/1752-0509-5-S2-S8 CrossRefPubMedPubMedCentralGoogle Scholar
  31. James D, Levine AJ, Besser D, Hemmati-Brivanlou A (2005) TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development 132(6):1273–1282. doi: 10.1242/dev.01706 CrossRefPubMedGoogle Scholar
  32. Jung L, Tropel P, Moal Y, Teletin M, Jeandidier E, Gayon R, Himmelspach C, Bello F, Andre C, Tosch A, Mansouri A, Bruant-Rodier C, Bouille P, Viville S (2014) ONSL and OSKM cocktails act synergistically in reprogramming human somatic cells into induced pluripotent stem cells. Mol Hum Reprod 20(6):538–549. doi: 10.1093/molehr/gau012 CrossRefPubMedGoogle Scholar
  33. Krupinski P, Chickarmane V, Peterson C (2011) Simulating the mammalian blastocyst--molecular and mechanical interactions pattern the embryo. PLoS Comput Biol 7(5), e1001128. doi: 10.1371/journal.pcbi.1001128 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Lakatos D, Travis ED, Pierson KE, Vivian JL, Czirok A (2014) Autocrine FGF feedback can establish distinct states of Nanog expression in pluripotent stem cells: a computational analysis. BMC Syst Biol 8:112. doi: 10.1186/s12918-014-0112-4 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Le Novere N (2015) Quantitative and logic modelling of molecular and gene networks. Nat Rev Genet 16(3):146–158. doi: 10.1038/nrg3885 CrossRefPubMedPubMedCentralGoogle Scholar
  36. MacArthur BD, Please CP, Oreffo RO (2008) Stochasticity and the molecular mechanisms of induced pluripotency. PLoS One 3(8), e3086. doi: 10.1371/journal.pone.0003086 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Mahdavi A, Davey RE, Bhola P, Yin T, Zandstra PW (2007) Sensitivity analysis of intracellular signaling pathway kinetics predicts targets for stem cell fate control. PLoS Comput Biol 3(7), e130. doi: 10.1371/journal.pcbi.0030130 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Malik N, Rao MS (2013) A review of the methods for human iPSC derivation. Methods Mol Biol 997:23–33. doi: 10.1007/978-1-62703-348-0_3 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Martin GR (1981) 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 78(12):7634–7638CrossRefPubMedPubMedCentralGoogle Scholar
  40. Medvedev SP, Shevchenko AI, Zakian SM (2010) Induced pluripotent stem cells: problems and advantages when applying them in regenerative medicine. Acta Naturae 2(2):18–28PubMedPubMedCentralGoogle Scholar
  41. Moledina F, Clarke G, Oskooei A, Onishi K, Gunther A, Zandstra PW (2012) Predictive microfluidic control of regulatory ligand trajectories in individual pluripotent cells. Proc Natl Acad Sci U S A 109(9):3264–3269. doi: 10.1073/pnas.1111478109 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Morgani SM, Canham MA, Nichols J, Sharov AA, Migueles RP, Ko MS, Brickman JM (2013) Totipotent embryonic stem cells arise in ground-state culture conditions. Cell Rep 3(6):1945–1957. doi: 10.1016/j.celrep.2013.04.034 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Munoz Descalzo S, Rue P, Faunes F, Hayward P, Jakt LM, Balayo T, Garcia-Ojalvo J, Martinez Arias A (2013) A competitive protein interaction network buffers Oct4-mediated differentiation to promote pluripotency in embryonic stem cells. Mol Syst Biol 9:694. doi: 10.1038/msb.2013.49 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Muraro MJ, Kempe H, Verschure PJ (2013) Concise review: the dynamics of induced pluripotency and its behavior captured in gene network motifs. Stem Cells 31(5):838–848. doi: 10.1002/stem.1340 CrossRefPubMedGoogle Scholar
  45. Nagy A, Gocza E, Diaz EM, Prideaux VR, Ivanyi E, Markkula M, Rossant J (1990) Embryonic stem cells alone are able to support fetal development in the mouse. Development 110(3):815–821PubMedGoogle Scholar
  46. Nichols J, Smith A (2009) Naive and primed pluripotent states. Cell Stem Cell 4(6):487–492. doi: 10.1016/j.stem.2009.05.015 CrossRefPubMedGoogle Scholar
  47. Niwa H, Burdon T, Chambers I, Smith A (1998) Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev 12(13):2048–2060CrossRefPubMedPubMedCentralGoogle Scholar
  48. Papp B, Plath K (2011) Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape. Cell Res 21(3):486–501. doi: 10.1038/cr.2011.28 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Park SJ, Yeo HC, Kang NY, Kim H, Lin J, Ha HH, Vendrell M, Lee JS, Chandran Y, Lee DY, Yun SW, Chang YT (2014) Mechanistic elements and critical factors of cellular reprogramming revealed by stepwise global gene expression analyses. Stem Cell Res 12(3):730–741. doi: 10.1016/j.scr.2014.03.002 CrossRefPubMedGoogle Scholar
  50. Peerani R, Onishi K, Mahdavi A, Kumacheva E, Zandstra PW (2009) Manipulation of signaling thresholds in “engineered stem cell niches” identifies design criteria for pluripotent stem cell screens. PLoS One 4(7), e6438. doi: 10.1371/journal.pone.0006438 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Pir P, Le Novere N (2016) Mathematical models of pluripotent stem cells: at the dawn of predictive regenerative medicine. Methods Mol Biol 1386:331–350. doi: 10.1007/978-1-4939-3283-2_15 CrossRefPubMedGoogle Scholar
  52. Prudhomme W, Daley GQ, Zandstra P, Lauffenburger DA (2004a) Multivariate proteomic analysis of murine embryonic stem cell self-renewal versus differentiation signaling. Proc Natl Acad Sci U S A 101(9):2900–2905. doi: 10.1073/pnas.0308768101 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Prudhomme WA, Duggar KH, Lauffenburger DA (2004b) Cell population dynamics model for deconvolution of murine embryonic stem cell self-renewal and differentiation responses to cytokines and extracellular matrix. Biotechnol Bioeng 88(3):264–272. doi: 10.1002/bit.20244 CrossRefPubMedGoogle Scholar
  54. Qin H, Diaz A, Blouin L, Lebbink RJ, Patena W, Tanbun P, LeProust EM, McManus MT, Song JS, Ramalho-Santos M (2014) Systematic identification of barriers to human iPSC generation. Cell 158(2):449–461. doi: 10.1016/j.cell.2014.05.040 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Raab S, Klingenstein M, Liebau S, Linta L (2014) A comparative view on human somatic cell sources for iPSC generation. Stem Cells Int 2014:768391. doi: 10.1155/2014/768391 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Rasmussen MA, Holst B, Tumer Z, Johnsen MG, Zhou S, Stummann TC, Hyttel P, Clausen C (2014) Transient p53 suppression increases reprogramming of human fibroblasts without affecting apoptosis and DNA damage. Stem Cell Rep 3(3):404–413. doi: 10.1016/j.stemcr.2014.07.006 CrossRefGoogle Scholar
  57. Roy S, Kundu TK (2014) Gene regulatory networks and epigenetic modifications in cell differentiation. IUBMB Life 66(2):100–109. doi: 10.1002/iub.1249 CrossRefPubMedGoogle Scholar
  58. Samavarchi-Tehrani P, Golipour A, David L, Sung HK, Beyer TA, Datti A, Woltjen K, Nagy A, Wrana JL (2010) Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7(1):64–77. doi: 10.1016/j.stem.2010.04.015 CrossRefPubMedGoogle Scholar
  59. Sasai M, Kawabata Y, Makishi K, Itoh K, Terada TP (2013) Time scales in epigenetic dynamics and phenotypic heterogeneity of embryonic stem cells. PLoS Comput Biol 9(12), e1003380. doi: 10.1371/journal.pcbi.1003380 CrossRefPubMedPubMedCentralGoogle Scholar
  60. Sasaki K, Yokobayashi S, Nakamura T, Okamoto I, Yabuta Y, Kurimoto K, Ohta H, Moritoki Y, Iwatani C, Tsuchiya H, Nakamura S, Sekiguchi K, Sakuma T, Yamamoto T, Mori T, Woltjen K, Nakagawa M, Yamamoto T, Takahashi K, Yamanaka S, Saitou M (2015) Robust in vitro induction of human germ cell fate from pluripotent stem cells. Cell Stem Cell 17(2):178–194. doi: 10.1016/j.stem.2015.06.014 CrossRefPubMedGoogle Scholar
  61. Selekman JA, Das A, Grundl NJ, Palecek SP (2013) Improving efficiency of human pluripotent stem cell differentiation platforms using an integrated experimental and computational approach. Biotechnol Bioeng 110(11):3024–3037. doi: 10.1002/bit.24968 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Sheridan C (2014) Stem cell therapy clears first hurdle in AMD. Nat Biotechnol 32(12):1173–1174. doi: 10.1038/nbt1214-1173 CrossRefPubMedGoogle Scholar
  63. Shu J, Wu C, Wu Y, Li Z, Shao S, Zhao W, Tang X, Yang H, Shen L, Zuo X, Yang W, Shi Y, Chi X, Zhang H, Gao G, Shu Y, Yuan K, He W, Tang C, Zhao Y, Deng H (2013) Induction of pluripotency in mouse somatic cells with lineage specifiers. Cell 153(5):963–975. doi: 10.1016/j.cell.2013.05.001 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Singh VK, Kalsan M, Kumar N, Saini A, Chandra R (2015) Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Front Cell Dev Biol 3:2. doi: 10.3389/fcell.2015.00002 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Sun Y, Li H, Liu Y, Mattson MP, Rao MS, Zhan M (2008) Evolutionarily conserved transcriptional co-expression guiding embryonic stem cell differentiation. PLoS One 3(10), e3406. doi: 10.1371/journal.pone.0003406 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676. doi: 10.1016/j.cell.2006.07.024 CrossRefPubMedGoogle Scholar
  67. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872. doi: 10.1016/j.cell.2007.11.019 CrossRefPubMedGoogle Scholar
  68. Tesar PJ, Chenoweth JG, Brook FA, Davies TJ, Evans EP, Mack DL, Gardner RL, McKay RD (2007) New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448(7150):196–199. doi: 10.1038/nature05972 CrossRefPubMedGoogle Scholar
  69. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145–1147CrossRefPubMedGoogle Scholar
  70. Trounson A, McDonald C (2015) Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17(1):11–22. doi: 10.1016/j.stem.2015.06.007 CrossRefPubMedGoogle Scholar
  71. Viswanathan S, Benatar T, Rose-John S, Lauffenburger DA, Zandstra PW (2002) Ligand/receptor signaling threshold (LIST) model accounts for gp130-mediated embryonic stem cell self-renewal responses to LIF and HIL-6. Stem Cells 20(2):119–138. doi: 10.1634/stemcells.20-2-119 CrossRefPubMedGoogle Scholar
  72. Waddington C (1957) The strategy of the genes, Routledge, NYGoogle Scholar
  73. Wakao S, Kitada M, Kuroda Y, Shigemoto T, Matsuse D, Akashi H, Tanimura Y, Tsuchiyama K, Kikuchi T, Goda M, Nakahata T, Fujiyoshi Y, Dezawa M (2011) Multilineage-differentiating stress-enduring (Muse) cells are a primary source of induced pluripotent stem cells in human fibroblasts. Proc Natl Acad Sci U S A 108(24):9875–9880. doi: 10.1073/pnas.1100816108 CrossRefPubMedPubMedCentralGoogle Scholar
  74. Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA, Gough NM (1988) Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336(6200):684–687. doi: 10.1038/336684a0 CrossRefPubMedGoogle Scholar
  75. Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH (1997) Viable offspring derived from fetal and adult mammalian cells. Nature 385(6619):810–813. doi: 10.1038/385810a0 CrossRefPubMedGoogle Scholar
  76. Woolf PJ, Prudhomme W, Daheron L, Daley GQ, Lauffenburger DA (2005) Bayesian analysis of signaling networks governing embryonic stem cell fate decisions. Bioinformatics 21(6):741–753. doi: 10.1093/bioinformatics/bti056 CrossRefPubMedGoogle Scholar
  77. Xu RH, Chen X, Li DS, Li R, Addicks GC, Glennon C, Zwaka TP, Thomson JA (2002) BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat Biotechnol 20(12):1261–1264. doi: 10.1038/nbt761 CrossRefPubMedGoogle Scholar
  78. Xu RH, Peck RM, Li DS, Feng X, Ludwig T, Thomson JA (2005) Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells. Nat Methods 2(3):185–190. doi: 10.1038/nmeth744 CrossRefPubMedGoogle Scholar
  79. Yamanaka S (2009) Elite and stochastic models for induced pluripotent stem cell generation. Nature 460(7251):49–52. doi: 10.1038/nature08180 CrossRefPubMedGoogle Scholar
  80. Yeo JC, Ng HH (2013) The transcriptional regulation of pluripotency. Cell Res 23(1):20–32. doi: 10.1038/cr.2012.172 CrossRefPubMedGoogle Scholar
  81. Yeo D, Kiparissides A, Cha JM, Aguilar-Gallardo C, Polak JM, Tsiridis E, Pistikopoulos EN, Mantalaris A (2013) Improving embryonic stem cell expansion through the combination of perfusion and Bioprocess model design. PLoS One 8(12), e81728. doi: 10.1371/journal.pone.0081728 CrossRefPubMedPubMedCentralGoogle Scholar
  82. Ying QL, Nichols J, Chambers I, Smith A (2003) BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115(3):281–292CrossRefPubMedGoogle Scholar
  83. Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P, Smith A (2008) The ground state of embryonic stem cell self-renewal. Nature 453(7194):519–523. doi: 10.1038/nature06968 CrossRefPubMedGoogle Scholar
  84. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920. doi: 10.1126/science.1151526 CrossRefPubMedGoogle Scholar
  85. Zhang B, Wolynes PG (2014) Stem cell differentiation as a many-body problem. Proc Natl Acad Sci U S A 111(28):10185–10190. doi: 10.1073/pnas.1408561111 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Kaveh Mashayekhi
    • 1
  • Vanessa Hall
    • 2
  • Kristine Freude
    • 2
  • Miya K Hoeffding
    • 3
  • Luminita Labusca
    • 4
    • 5
  • Poul Hyttel
    • 2
    Email author
  1. 1.iGenomix S.L.Parc Cientific Universitat de ValenciaPaternaSpain
  2. 2.Department of Veterinary Clinical and Animal SciencesUniversity of CopenhagenFrederiksberg CDenmark
  3. 3.Copenhagen Consortium for Designer OrganismsUniversity of CopenhagenKoebenhavn NDenmark
  4. 4.Orthopedic and Traumatology ClinicEmergency University Hospital, Saint Spiridon Piaţa Independenţei 1IaşiRomania
  5. 5.National Institute of Research and Development for Technical PhysicsIasiRomania

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