Skip to main content
SpringerLink
Log in

Pluripotent Stem Cell Heterogeneity

  • Chapter
  • First Online:
Stem Cells Heterogeneity - Novel Concepts

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1123))

Abstract

Pluripotent stem cells (PSCs), including embryonic stem cells and induced pluripotent stem cells, show heterogeneity with respect to their pluripotency, self-renewal ability, and other traits. PSC heterogeneity may exist among cell lines, among cells within a line, and among temporal states of individual cells. Both genetic and epigenetic factors can cause heterogeneity among cell lines. Heterogeneity among cells within a cell line may arise during long-term culturing even when a PSC cell line is derived from a single cell. Moreover, the expression levels of genes and proteins in PSCs fluctuate continuously at a frequency ranging from a few hours to a few days. Such heterogeneity decreases the reproducibility of research. Thus, methods related to the detection, reduction, and control of heterogeneity in experiments involving human PSCs need to be developed. Further, the presupposition that PSCs are highly heterogeneous should be taken into account by all researchers not only when they plan their own studies but also when they review the studies of other researchers in this field.

Author contributions: Sections “Genetic Variability Among PSC Types,” “Epigenetic Differences Among PSC Lines” and “Heterogeneity Among Each Cell in a Cell Line,”(YH); Sections “Introduction,” “Temporal Fluctuation of PSCs,” and “Perspective and Conclusion” (KO), Sections “Imaging Methods for Detecting PSC Heterogeneity” and “Quality control of heterogeneous hPSCs” (MKF).

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Cahan P, Daley GQ (2013) Origins and implications of pluripotent stem cell variability and heterogeneity. Nat Rev Mol Cell Biol 14:357–368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fakunle ES, Loring JF (2012) Ethnically diverse pluripotent stem cells for drug development. Trends Mol Med 18:709–716

    Article  PubMed  Google Scholar 

  3. Kajiwara M et al (2012) Donor-dependent variations in hepatic differentiation from human-induced pluripotent stem cells. Proc Natl Acad Sci U S A 109:12,538–12,543

    Article  Google Scholar 

  4. Howden SE et al (2011) Genetic correction and analysis of induced pluripotent stem cells from a patient with gyrate atrophy. Proc Natl Acad Sci U S A 108:6537–6542

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gore A et al (2011) Somatic coding mutations in human induced pluripotent stem cells. Nature 471:63–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Quinlan AR et al (2011) Genome sequencing of mouse induced pluripotent stem cells reveals retroelement stability and infrequent DNA rearrangement during reprogramming. Cell Stem Cell 9:366–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Abyzov A et al (2012) Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 492:438–442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cheng L et al (2012) Low incidence of DNA sequence variation in human induced pluripotent stem cells generated by nonintegrating plasmid expression. Cell Stem Cell 10:337–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Young MA et al (2012) Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells. Cell Stem Cell 10:570–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Liang G, Zhang Y (2013) Genetic and epigenetic variations in iPSCs: potential causes and implications for application. Cell Stem Cell 13:149–159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hayashi Y (2017) Human mutations affecting reprogramming into induced pluripotent stem cells. AIMS Cell Tissue Eng 1:31–46

    Article  Google Scholar 

  12. Kinoshita T et al (2011) Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells. Biochem Biophys Res Commun 407:321–326

    Article  CAS  PubMed  Google Scholar 

  13. Nayler S et al (2012) Induced pluripotent stem cells from ataxia-telangiectasia recapitulate the cellular phenotype. Stem Cells Transl Med 1:523–535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fukawatase Y et al (2014) Ataxia telangiectasia derived iPS cells show preserved x-ray sensitivity and decreased chromosomal instability. Sci Rep 4:5421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang J et al (2011) A human iPSC model of Hutchinson Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 8:31–45

    Article  CAS  PubMed  Google Scholar 

  16. Liu GH et al (2011) Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 472:221–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Agarwal S et al (2010) Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 464:292–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Winkler T et al (2013) Defective telomere elongation and hematopoiesis from telomerase-mutant aplastic anemia iPSCs. J Clin Invest 123:1952–1963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Batista LF et al (2011) Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. Nature 474:399–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yokota M, Hatakeyama H, Okabe S, Ono Y, Goto Y (2015) Mitochondrial respiratory dysfunction caused by a heteroplasmic mitochondrial DNA mutation blocks cellular reprogramming. Hum Mol Genet 24:4698–4709

    Article  CAS  PubMed  Google Scholar 

  21. Zhou Y et al (2017) Mitochondrial spare respiratory capacity is negatively correlated with nuclear reprogramming efficiency. Stem Cells Dev 26:166–176

    Article  CAS  PubMed  Google Scholar 

  22. Hung SS et al (2016) Study of mitochondrial respiratory defects on reprogramming to human induced pluripotent stem cells. Aging (Albany NY) 8:945–957

    Article  CAS  Google Scholar 

  23. Bershteyn M et al (2014) Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells. Nature 507:99–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yu Y et al (2015) Chromosome microduplication in somatic cells decreases the genetic stability of human reprogrammed somatic cells and results in pluripotent stem cells. Sci Rep 5:10,114

    Article  CAS  Google Scholar 

  25. Hamasaki M et al (2012) Pathogenic mutation of Alk2 inhibits ips cell reprogramming and maintenance: mechanisms of reprogramming and strategy for drug identification. Stem Cells 30:2437–2449

    Article  CAS  PubMed  Google Scholar 

  26. Hayashi Y et al (2016) BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence. Proc Natl Acad Sci U S A 113:13,057–13,062

    Article  CAS  Google Scholar 

  27. Tanaka T et al (2012) Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery. Blood 120:1299–1308

    Article  CAS  PubMed  Google Scholar 

  28. Ji J et al (2012) Elevated coding mutation rate during the reprogramming of human somatic cells into induced pluripotent stem cells. Stem Cells 30:435–440

    Article  CAS  PubMed  Google Scholar 

  29. Sugiura M et al (2014) Induced pluripotent stem cell generation-associated point mutations arise during the initial stages of the conversion of these cells. Stem Cell Rep 2:52–63

    Article  CAS  Google Scholar 

  30. Yoshihara M et al (2017) Hotspots of de novo point mutations in induced pluripotent stem cells. Cell Rep 21:308–315

    Article  CAS  PubMed  Google Scholar 

  31. Rouhani FJ et al (2016) Mutational history of a human cell lineage from somatic to induced pluripotent stem cells. PLoS Genet 12:e1005932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bhutani K et al (2016) Whole-genome mutational burden analysis of three pluripotency induction methods. Nat Commun 7:10,536

    Article  CAS  Google Scholar 

  33. Mandai M et al (2017) Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med 376:1038–1046

    Article  CAS  PubMed  Google Scholar 

  34. Thomson JA et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147

    Article  CAS  PubMed  Google Scholar 

  35. Takahashi K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872

    Article  CAS  PubMed  Google Scholar 

  36. Yu J et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920

    Article  CAS  PubMed  Google Scholar 

  37. Mallon BS et al (2014) Comparison of the molecular profiles of human embryonic and induced pluripotent stem cells of isogenic origin. Stem Cell Res 12:376–386

    Article  CAS  PubMed  Google Scholar 

  38. Koyanagi-Aoi M et al (2013) Differentiation-defective phenotypes revealed by large-scale analyses of human pluripotent stem cells. Proc Natl Acad Sci U S A 110:20569–20574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Riera M et al (2016) Comparative study of human embryonic stem cells (hESC) and human induced pluripotent stem cells (hiPSC) as a treatment for retinal dystrophies. Mol Ther Methods Clin Dev 3:16010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Brons IG et al (2007) Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448:191–195

    Article  CAS  PubMed  Google Scholar 

  41. Tesar PJ et al (2007) New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448:196–199

    Article  CAS  PubMed  Google Scholar 

  42. Smith AG et al (1988) Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336:688–690

    Article  CAS  PubMed  Google Scholar 

  43. Williams RL et al (1988) Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336:684–687

    Article  CAS  PubMed  Google Scholar 

  44. Furue M et al (2005) Leukemia inhibitory factor as an anti-apoptotic mitogen for pluripotent mouse embryonic stem cells in a serum-free medium without feeder cells. In Vitro Cell Dev Biol Anim 41:19–28

    Article  CAS  PubMed  Google Scholar 

  45. Ying QL et al (2008) The ground state of embryonic stem cell self-renewal. Nature 453:519–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li Y, Powell S, Brunette E, Lebkowski J, Mandalam R (2005) Expansion of human embryonic stem cells in defined serum-free medium devoid of animal-derived products. Biotechnol Bioeng 91:688–698

    Article  CAS  PubMed  Google Scholar 

  47. Amit M, Shariki C, Margulets V, Itskovitz-Eldor J (2004) Feeder layer- and serum-free culture of human embryonic stem cells. Biol Reprod 70:837–845

    Article  CAS  PubMed  Google Scholar 

  48. Sumi T, Fujimoto Y, Nakatsuji N, Suemori H (2004) STAT3 is dispensable for maintenance of self-renewal in nonhuman primate embryonic stem cells. Stem Cells 22:861–872

    Article  CAS  PubMed  Google Scholar 

  49. Daheron L et al (2004) LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells. Stem Cells 22:770–778

    Article  CAS  PubMed  Google Scholar 

  50. Humphrey RK et al (2004) Maintenance of pluripotency in human embryonic stem cells is STAT3 independent. Stem Cells 22:522–530

    Article  CAS  PubMed  Google Scholar 

  51. Hanna J et al (2010) Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc Natl Acad Sci U S A 107:9222–9227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Buecker C et al (2010) A murine ESC-like state facilitates transgenesis and homologous recombination in human pluripotent stem cells. Cell Stem Cell 6:535–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hu Z et al (2015) Generation of naivetropic induced pluripotent stem cells from parkinson’s disease patients for high-efficiency genetic manipulation and disease modeling. Stem Cells Dev 24:2591–2604

    Google Scholar 

  54. Zimmerlin L et al (2016) Tankyrase inhibition promotes a stable human naive pluripotent state with improved functionality. Development 143:4368–4380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Chen H et al (2015) Reinforcement of STAT3 activity reprogrammes human embryonic stem cells to naive-like pluripotency. Nat Commun 6:7095

    Article  CAS  PubMed  Google Scholar 

  56. Tomoda K et al (2012) Derivation conditions impact X-inactivation status in female human induced pluripotent stem cells. Cell Stem Cell 11:91–99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pera MF, Tam PP (2010) Extrinsic regulation of pluripotent stem cells. Nature 465:713–720

    Article  CAS  PubMed  Google Scholar 

  58. Yang J et al (2017) Establishment of mouse expanded potential stem cells. Nature 550:393–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kim K et al (2010) Epigenetic memory in induced pluripotent stem cells. Nature 467:285–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Nazor KL et al (2012) Recurrent variations in DNA methylation in human pluripotent stem cells and their differentiated derivatives. Cell Stem Cell 10:620–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Bar-Nur O, Russ HA, Efrat S, Benvenisty N (2011) Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell 9:17–23

    Article  CAS  PubMed  Google Scholar 

  62. Pomp O et al (2011) Unexpected X chromosome skewing during culture and reprogramming of human somatic cells can be alleviated by exogenous telomerase. Cell Stem Cell 9:156–165

    Article  CAS  PubMed  Google Scholar 

  63. Zhao MT et al (2017) Molecular and functional resemblance of differentiated cells derived from isogenic human iPSCs and SCNT-derived ESCs. Proc Natl Acad Sci U S A 114:E11111–E11120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yanagihara K et al (2016) Prediction of differentiation tendency toward hepatocytes from gene expression in undifferentiated human pluripotent stem cells. Stem Cells Dev 25:1884–1897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wen L, Tang F (2016) Single-cell sequencing in stem cell biology. Genome Biol 17:71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. The International Stem Cell Initiative (2011) Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat Biotechnol 29:1132–1144

    Article  CAS  PubMed Central  Google Scholar 

  67. Avery S et al (2013) BCL-XL mediates the strong selective advantage of a 20q11.21 amplification commonly found in human embryonic stem cell cultures. Stem Cell Rep 1:379–386

    Article  CAS  Google Scholar 

  68. Peterson SE et al (2011) Normal human pluripotent stem cell lines exhibit pervasive mosaic aneuploidy. PLoS One 6:e23018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Dekel-Naftali M et al (2012) Screening of human pluripotent stem cells using CGH and FISH reveals low-grade mosaic aneuploidy and a recurrent amplification of chromosome 1q. Eur J Hum Genet 20:1248–1255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Narva E et al (2010) High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity. Nat Biotechnol 28:371–377

    Article  CAS  PubMed  Google Scholar 

  71. Tesarova L, Simara P, Stejskal S, Koutna I (2016) The aberrant DNA methylation profile of human induced pluripotent stem cells is connected to the reprogramming process and is normalized during in vitro culture. PLoS One 11:e0157974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Singh AM (2015) Cell cycle-driven heterogeneity: on the road to demystifying the transitions between “poised” and “restricted” pluripotent cell states. Stem Cells Int 2015:219514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Dalton S (2015) Linking the cell cycle to cell fate decisions. Trends Cell Biol 25:592–600

    Article  PubMed  PubMed Central  Google Scholar 

  74. Mitsui K et al (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113:631–642

    Article  CAS  PubMed  Google Scholar 

  75. Chambers I et al (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113:643–655

    Article  CAS  PubMed  Google Scholar 

  76. The International Stem Cell Initiative (2007) Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nat Biotechnol 25:803–816

    Article  CAS  Google Scholar 

  77. Hatano S-Y et al (2005) Pluripotential competence of cells associated with Nanog activity. Mech Dev 122:67–79

    Article  CAS  PubMed  Google Scholar 

  78. Wu J, Tzanakakis ES (2012) Contribution of stochastic partitioning at human embryonic stem cell division to NANOG heterogeneity. PLoS One 7:e50715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chambers I et al (2007) Nanog safeguards pluripotency and mediates germline development. Nature 450:1230–1234

    Article  CAS  PubMed  Google Scholar 

  80. van den Berg DL et al (2008) Estrogen-related receptor beta interacts with Oct4 to positively regulate Nanog gene expression. Mol Cell Biol 28:5986–5995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Frieda KL et al (2017) Synthetic recording and in situ readout of lineage information in single cells. Nature 541:107–111

    Article  CAS  PubMed  Google Scholar 

  82. Filipczyk A et al (2015) Network plasticity of pluripotency transcription factors in embryonic stem cells. Nat Cell Biol 17:1235–1246

    Article  CAS  PubMed  Google Scholar 

  83. Toyooka Y, Shimosato D, Murakami K, Takahashi K, Niwa H (2008) Identification and characterization of subpopulations in undifferentiated ES cell culture. Development 135:909–918

    Article  CAS  PubMed  Google Scholar 

  84. Kobayashi T et al (2009) The cyclic gene Hes1 contributes to diverse differentiation responses of embryonic stem cells. Genes Dev 23:1870–1875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hayashi K, de Sousa Lopes SMC, Tang F, Surani MA (2008) Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states. Cell Stem Cell 3:391–401

    Article  CAS  PubMed  Google Scholar 

  86. Falco G et al (2007) Zscan4: a novel gene expressed exclusively in late 2-cell embryos and embryonic stem cells. Dev Biol 307:539–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zalzman M et al (2010) Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature 464:858–863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Amano T et al (2013) Zscan4 restores the developmental potency of embryonic stem cells. Nat Commun 4:1966

    Article  CAS  PubMed  Google Scholar 

  89. Nakai-Futatsugi Y, Niwa H (2016) Zscan4 is activated after telomere shortening in mouse embryonic stem cells. Stem Cell Rep 6:483–495

    Article  CAS  Google Scholar 

  90. Yamanaka Y, Lanner F, Rossant J (2010) FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst. Development 137:715–724

    Article  CAS  PubMed  Google Scholar 

  91. Nakamura T et al (2016) A developmental coordinate of pluripotency among mice, monkeys and humans. Nature 537:57

    Article  CAS  PubMed  Google Scholar 

  92. Bhadriraju K et al (2016) Large-scale time-lapse microscopy of Oct4 expression in human embryonic stem cell colonies. Stem Cell Res 17:122–129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Morgani SM et al (2013) Totipotent embryonic stem cells arise in ground-state culture conditions. Cell Rep 3:1945–1957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Pauklin S, Vallier L (2013) The cell-cycle state of stem cells determines cell fate propensity. Cell 155:135–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hough SR et al (2014) Single-cell gene expression profiles define self-renewing, pluripotent, and lineage primed states of human pluripotent stem cells. Stem Cell Rep 2:881–895

    Article  CAS  Google Scholar 

  96. Eldar A, Elowitz MB (2010) Functional roles for noise in genetic circuits. Nature 467:167–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Furusawa C, Kaneko K (2012) A dynamical-systems view of stem cell biology. Science 338:215–217

    Article  CAS  PubMed  Google Scholar 

  98. Semrau S et al (2017) Dynamics of lineage commitment revealed by single-cell transcriptomics of differentiating embryonic stem cells. Nat Commun 8:1096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Macfarlan TS et al (2012) Embryonic stem cell potency fluctuates with endogenous retrovirus activity. Nature 487:57–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Abranches E et al (2014) Stochastic NANOG fluctuations allow mouse embryonic stem cells to explore pluripotency. Development 141:2770–2779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Smith RCG et al (2017) Nanog fluctuations in embryonic stem cells highlight the problem of measurement in cell biology. Biophys J 112:2641–2652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Nakamura S et al (2018) Asymmetry between sister cells of pluripotent stem cells at the onset of differentiation. Stem Cells Dev 27:347–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448:313–317

    Article  CAS  PubMed  Google Scholar 

  104. Na J, Baker D, Zhang J, Andrews PW, Barbaric I (2014) Aneuploidy in pluripotent stem cells and implications for cancerous transformation. Protein Cell 5:569–579

    Article  PubMed  PubMed Central  Google Scholar 

  105. Laurent LC et al (2011) 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 8:106–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Amit M, Itskovitz-Eldor J (2011) Atlas of human pluripotent stem cells derivation and culturing. Humana Press, New York, pp 15–39

    Google Scholar 

  107. Kato R et al (2016) Parametric analysis of colony morphology of non-labelled live human pluripotent stem cells for cell quality control. Sci Rep 6:34009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chan EM et al (2009) Live cell imaging distinguishes bona fide human iPS cells from partially reprogrammed cells. Nat Biotechnol 27:1033–1037

    Article  CAS  PubMed  Google Scholar 

  109. Pfannkuche K, Fatima A, Gupta MK, Dieterich R, Hescheler J (2010) Initial colony morphology-based selection for iPS cells derived from adult fibroblasts is substantially improved by temporary UTF1-based selection. PLoS One 5:e9580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wakao S et al (2012) Morphologic and gene expression criteria for identifying human induced pluripotent stem cells. PLoS One 7:e48677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gu M et al (2012) Microfluidic single-cell analysis shows that porcine induced pluripotent stem cell-derived endothelial cells improve myocardial function by paracrine activation. Circ Res 111:882–893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Tokunaga K et al (2014) Computational image analysis of colony and nuclear morphology to evaluate human induced pluripotent stem cells. Sci Rep 4:6996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Matsuoka F et al (2013) Morphology-based prediction of osteogenic differentiation potential of human mesenchymal stem cells. PLoS One 8:e55082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Matsuoka F et al (2014) Characterization of time-course morphological features for efficient prediction of osteogenic potential in human mesenchymal stem cells. Biotechnol Bioeng 111:1430–1439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Maddah M, Loewke K (2014) Automated, non-invasive characterization of stem cell-derived cardiomyocytes from phase-contrast microscopy. Med Image Comput Comput Assist Interv 17:57–64

    PubMed  Google Scholar 

  116. Suga M, Kii H, Niikura K, Kiyota Y, Furue MK (2015) Development of a monitoring method for nonlabeled human pluripotent stem cell growth by time-lapse image analysis. Stem Cells Transl Med 4:720–730

    Article  PubMed  PubMed Central  Google Scholar 

  117. The International Stem Cell Banking Initiative (2009) Consensus guidance for banking and supply of human embryonic stem cell lines for research purposes. Stem Cell Rev 5:301–314

    Article  Google Scholar 

  118. Suga M, Tachikawa S, Tateyama D, Ohnuma K, Furue MK (2017) Imaging-cytometry revealed spatial heterogeneities of marker expression in undifferentiated human pluripotent stem cells. In Vitro Cell Dev Biol Anim 53:83–91

    Article  CAS  PubMed  Google Scholar 

  119. Draper JS et al (2004) Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells. Nat Biotechnol 22:53–54

    Article  CAS  PubMed  Google Scholar 

  120. Harrison NJ, Baker D, Andrews PW (2007) Culture adaptation of embryonic stem cells echoes germ cell malignancy. Int J Androl 30:275–281. discussion 281

    Article  PubMed  Google Scholar 

  121. Enver T et al (2005) Cellular differentiation hierarchies in normal and culture-adapted human embryonic stem cells. Hum Mol Genet 14:3129–3140

    Article  CAS  PubMed  Google Scholar 

  122. Hyka-Nouspikel N et al (2012) Deficient DNA damage response and cell cycle checkpoints lead to accumulation of point mutations in human embryonic stem cells. Stem Cells 30:1901–1910

    Article  CAS  PubMed  Google Scholar 

  123. Barbaric I et al (2014) Time-lapse analysis of human embryonic stem cells reveals multiple bottlenecks restricting colony formation and their relief upon culture adaptation. Stem Cell Rep 3:142–155

    Article  CAS  Google Scholar 

  124. The International Stem Cell Banking Initiative (2015) Points to consider in the development of seed stocks of pluripotent stem cells for clinical applications: International Stem Cell Banking Initiative (ISCBI). Regen Med 10:1–44

    Google Scholar 

  125. Eliceiri KW et al (2012) Biological imaging software tools. Nat Methods 9:697–710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Chieco P, Jonker A, De Boer BA, Ruijter JM, Van Noorden CJ (2013) Image cytometry: protocols for 2D and 3D quantification in microscopic images. Prog Histochem Cytochem 47:211–333

    Article  PubMed  Google Scholar 

  127. O’Connor MD et al (2008) Alkaline phosphatase-positive colony formation is a sensitive, specific, and quantitative indicator of undifferentiated human embryonic stem cells. Stem Cells 26:1109–1116

    Google Scholar 

  128. Moralli D et al (2011) An improved technique for chromosomal analysis of human ES and iPS cells. Stem Cell Rev 7:471–477

    Article  Google Scholar 

  129. Anguiano A et al (2012) Spectral Karyotyping for identification of constitutional chromosomal abnormalities at a national reference laboratory. Mol Cytogenet 5:3

    Article  PubMed  PubMed Central  Google Scholar 

  130. Das K, Tan P (2013) Molecular cytogenetics: recent developments and applications in cancer. Clin Genet 84:315–325

    Article  CAS  PubMed  Google Scholar 

  131. The International Stem Cell Initiative (2018) Assessment of established techniques to determine developmental and malignant potential of human pluripotent stem cells. Nat Commun 9:1925

    Article  CAS  Google Scholar 

  132. Tsankov AM et al (2015) A qPCR ScoreCard quantifies the differentiation potential of human pluripotent stem cells. Nat Biotechnol 33:1182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bock C et al (2011) Reference Maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144:439–452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ng ES, Davis RP, Azzola L, Stanley EG, Elefanty AG (2005) Forced aggregation of defined numbers of human embryonic stem cells into embryoid bodies fosters robust, reproducible hematopoietic differentiation. Blood 106:1601–1603

    Article  CAS  PubMed  Google Scholar 

  135. Coecke S et al (2005) Guidance on good cell culture practice. a report of the second ECVAM task force on good cell culture practice. Altern Lab Anim 33:261–287

    CAS  PubMed  Google Scholar 

  136. OECD. Draft Guidance Document on Good In Vitro Method Practices (GIVIMP) for the Development and Implementation of In Vitro Methods for Regulatory Use in Human Safety Assessment, 2018

    Book  Google Scholar 

Download references

Author information

Author notes

  1. Yohei Hayashi, Kiyoshi Ohnuma, and Miho K. Furue contributed equally to this work.

Authors and Affiliations

  1. iPS Cell Advanced Characterization and Development Team, Bioresource Research Center, RIKEN, Ibaraki, Japan

    Yohei Hayashi

  2. Department of Bioengineering, Nagaoka University of Technology, Nagaoka, Niigata, Japan

    Kiyoshi Ohnuma

  3. Department of Science of Technology Innovation, Nagaoka University of Technology, Nagaoka, Niigata, Japan

    Kiyoshi Ohnuma

  4. Laboratory of Stem Cell Cultures, National institutes of Biomedical Innovation, Health and Nutrition, Osaka, Ibaraki-City, Japan

    Miho K. Furue

Authors
  1. Yohei Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kiyoshi Ohnuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miho K. Furue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kiyoshi Ohnuma .

Editor information

Editors and Affiliations

  1. Department of Radiology, Columbia University Medical Center, New York, NY, USA

    Alexander Birbrair

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hayashi, Y., Ohnuma, K., Furue, M.K. (2019). Pluripotent Stem Cell Heterogeneity. In: Birbrair, A. (eds) Stem Cells Heterogeneity - Novel Concepts. Advances in Experimental Medicine and Biology, vol 1123. Springer, Cham. https://doi.org/10.1007/978-3-030-11096-3_6

Download citation

Publish with us

Policies and ethics

Search

Navigation