Skip to main content
SpringerLink
Log in

Frontiers of Pluripotency

  • Protocol
  • First Online:
Chimera Research

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2005))

Abstract

Humans develop from a unique group of pluripotent cells in early embryos that can produce all cells of the human body. While pluripotency is only transiently manifest in the embryo, scientists have identified conditions that sustain pluripotency indefinitely in the laboratory. Pluripotency is not a monolithic entity, however, but rather comprises a spectrum of different cellular states. Questions regarding the scientific value of examining the continuum of pluripotent stem (PS) cell states have gained increased significance in light of attempts to generate interspecies chimeras between humans and animals. In this chapter, I review our ever-evolving understanding of the continuum of pluripotency. Historically, the discovery of two different PS cell states in mice fostered a general conception of pluripotency comprised of two distinct attractor states: naïve and primed. Naïve pluripotency has been defined by competence to form germline chimeras and governance by unique KLF-based transcription factor (TF) circuitry, whereas primed state is distinguished by an inability to generate chimeras and alternative TF regulation. However, the discovery of many alternative PS cell states challenges the concept of pluripotency as a binary property. Moreover, it remains unclear whether the current molecular criteria used to classify human naïve-like pluripotency also identify human chimera-competent PS cells. Therefore, I examine the pluripotency continuum more closely in light of recent advances in PS cell research and human interspecies chimera research.

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

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
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. De Los Angeles A, Ferrari F, Xi R, Fujiwara Y, Benvenisty N, Deng H, Hochedlinger K, Jaenisch R, Lee S, Leitch HG, Lensch MW, Lujan E, Pei D, Rossant J, Wernig M, Park PJ, Daley GQ (2015) Hallmarks of pluripotency. Nature 525:469–478

    Article  CAS  PubMed  Google Scholar 

  2. Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156

    Article  CAS  PubMed  Google Scholar 

  3. 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 78:7634–7638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Brons IG, Smithers LE, Trotter MW, Rugg-Gunn P, Sun B, Chuva de Sousa Lopes SM, Howlett SK, Clarkson A, Ahrlund-Richter L, Pedersen RA, Vallier L (2007) Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448:191–195

    Article  CAS  PubMed  Google Scholar 

  5. 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 448:196–199

    Article  CAS  PubMed  Google Scholar 

  6. Takahashi K, Yamanaka S (2007) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    Article  CAS  Google Scholar 

  7. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergel JJ, Marshall VS, Jones JM (1998) Embryonic stem cells derived from human blastocysts. Science 282:1145–1147

    Article  CAS  PubMed  Google Scholar 

  8. Thomson JA, Kalishman J, Golos TG, Durning M, Harris CP, Becker RA, Hearn JP (1995) Isolation of a primate embryonic stem cell line. PNAS 92:7844–7848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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 131:861–872

    Article  CAS  PubMed  Google Scholar 

  10. Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, Croft GF, Saphier G, Leibel R, Goland R, Wichterle H, Henderson CE, Eggan K (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321:1281–1221

    Article  CAS  Google Scholar 

  11. Martello G, Smith A (2014) The nature of embryonic stem cells. Annu Rev Cell Dev Biol 30:647–675

    Article  CAS  PubMed  Google Scholar 

  12. Damjanov I, Andrews PW (2016) Teratomas produced from human pluripotent stem cells xenografted into immunodeficient mice – a histopathology atlas. Int J Dev Biol 60:337–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chan EM, Ratanasirintrawoot S, Park IH, Manos PD, Loh YH, Huo H, Miller JD, Hartung O, Rho J, Ince TA, Daley GQ, Schlaeger TM (2009) Live cell imaging distinguishes bona fide human iPS cells from partially reprogrammed cells. Nat Biotechnol 28:1033–1037

    Article  CAS  Google Scholar 

  14. Theunissen TW, Powell BE, Wang H, Mitalipova M, Faddah DA, Reddy J, Fan ZP, Maetzel D, Ganz K, Shi L, Lungjangwa T, Imsoonthornruksa S, Stelzer Y, Rangarajan S, D’Alessio A, Zhang J, Gao Q, Dawlaty MM, Young RA, Gray NS, Jaenisch R (2014) Systematic identification of culture conditions for induction and maintenance of naïve human pluripotency. Cell Stem Cell 15:471–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Takashima Y, Guo G, Loos R, Nichols J, Ficz G, Krueger F, Oxley D, Santos F, Clarke J, Mansfield W, Reik W, Bertone P, Smith A (2014) Resetting transcription factor control circuitry toward ground-state pluripotency in human. Cell 158:1254–1269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. De Los Angeles A, Ferrari F, Fujiwara Y, Mathieu R, Lee S, Lee S, Tu HC, Ross S, Chou S, Nguyen M, Wu Z, Theunissen TW, Powell BE, Imsoonthornruksa S, Chen J, Borkent M, Krupalnik V, Lujan E, Wernig M, Hanna JH, Hochedlinger K, Pei D, Jaenisch R, Deng H, Orkin SH, Park PJ, Daley GQ (2015) Failure to replicate the STAP cell phenomenon. Nature 525:E6–E9

    Article  PubMed  CAS  Google Scholar 

  17. Nagy A, Rossant J, Nagy R, Abramow-Newerly W, Roder JC (1993) Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci U S A 90:8424–8428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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 110:815–821

    CAS  PubMed  Google Scholar 

  19. Wang Z, Jaenisch R (2004) At most three ES cells contribute to the somatic lineages of chimeric mice produced by ES-tetraploid complementation. Dev Biol 275:192–201

    Article  CAS  PubMed  Google Scholar 

  20. Yang Y, Liu B, Xu J, Wang J, Wu J, Shi C, Xu Y, Dong J, Wang C, Lai W, Zhu J, Xiong L, Zhu D, Li X, Yang W, Yamauchi T, Sugawara A, Li Z, Sun F, Li X, Li C, He A, Du Y, Wang T, Zhao C, Li H, Chi X, Zhang H, Liu Y, Li C, Duo S, Yin M, Shen H, Belmonte JCI, Deng H (2017) Derivation of pluripotent stem cells with in vivo embryonic and extraembryonic potency. Cell 169:243–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sakaki-Yumoto M, Kobayashi C, Sato A, Fujimura S, Matsumoto Y, Takasato M, Kodama T, Aburatani H, Asashima M, Yoshida N, Nishinakamura R (2006) The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with SALL1 in anorectal, heart, brain, and kidney development. Development 133:3005–3013

    Article  CAS  PubMed  Google Scholar 

  22. Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, Gifford DK, Melton DA, Jaenisch R, Young RA (2005) Core regulatory circuitry in human embryonic stem cells. Cell 122:947–956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J, Wong KY, Sung KW, Lee CW, Zhao XD, Chiu KP, Lipovich L, Kuznetsov VA, Robson P, Stanton LW, Wei CL, Ruan Y, Lim B, Ng HH (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38(4):431–440

    Article  CAS  PubMed  Google Scholar 

  24. Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Scholer H, Smith A (1998) Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95:379–391

    Article  CAS  PubMed  Google Scholar 

  25. Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113:643–655

    Article  CAS  PubMed  Google Scholar 

  26. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S (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 

  27. Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J, Loh YH, Yeo HC, Yeo ZX, Narang V, Govindarajan KR, Leong B, Shahab A, Ruan Y, Bourque G, Sung WK, Clarke ND, Wei CL, Ng HH (2008) Integration of external signaling pathway with the core transcriptional network in embryonic stem cells. Cell 133:1106–1117

    Article  CAS  PubMed  Google Scholar 

  28. Kim J, Chu J, Shen X, Wang J, Orkin SH (2008) An extended transcriptional network for pluripotency of embryonic stem cells. Cell 132:1049–1061

    Article  CAS  PubMed  Google Scholar 

  29. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–326

    Article  CAS  PubMed  Google Scholar 

  30. Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim TK, Koche RP, Lee W, Mendenhall E, O’Donovan A, Presser A, Russ C, Xie X, Meissner A, Wernig M, Jaenisch R, Nusbaum C, Lander ES, Bernstein BE (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448:553–560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Marks H, Kalkan T, Menafra R, Dennisov S, Jones K, Hofemeister H, Nichols J, Kranz A, Stewart AF, Smith A, Stunnenberg HG (2012) The transcriptional and epigenomic foundations of ground state pluripotency. Cell 149:590–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Geula S, Moshitch-Moshokovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, Hershkovitz V, Peer E, Mor N, Manor YS, Ben-Haim MS, Eyal E, Yunger S, Pinto Y, Jaitin DA, Viukov S, Rais Y, Krupalnik V, Chomsky E, Zerbib M, Maza I, Rechavi Y, Massarwa R, Hanna S, Amit I, Levanon EY, Amariglio N, Stern-Ginossar N, Novershtern N, Rechavi G, Hanna JH (2015) m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science 347:1002–1006

    Article  CAS  PubMed  Google Scholar 

  33. Liao J, Karnik R, Gu H, Ziller MJ, Clement K, Tsankov AM, Akopian V, Gifford CA, Donaghey J, Galonska C, Pop R, Reyon D, Tsai SQ, Mallard W, Joung JK, Rinn JL, Gnirke A, Meissner A (2015) Targeted disruption of DNMT1, DNMT3A, and DNMT3B in human embryonic stem cells. Nat Genet 47:469–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Smith A (2017) Formative pluripotency: the executive phase in a developmental continuum. Development 144:365–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nichols J, Smith A (2009) Naïve and primed pluripotent states. Cell Stem Cell 4:487–492

    Article  CAS  PubMed  Google Scholar 

  36. Leitch HG, McEwen KR, Turp A, Encheva V, Carroll T, Grabole N, Mansfield W, Nashun B, Knezovich JG, Smith A, Surani MA, Hajkova P (2013) Naïve pluripotency is associated with global DNA hypomethylation. Nat Struct Mol Biol 20:311–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Guo G, Yang J, Nichols J, Hall JS, Eyres I, Mansfield W, Smith A (2009) Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development 136:1063–1069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bao S, Tang F, Li X, Hayashi K, Gillich A, Lao K, Surani MA (2009) Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells. Nature 461:1292–1295

    Article  CAS  PubMed  Google Scholar 

  39. Dunn SJ, Martello G, Yordanov B, Emmott S, Smith AG (2014) Defining an essential transcription factor program for naïve pluripotency. Science 344:1156–1160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Alexandrova S, Kalkan T, Humphreys P, Riddell A, Scognamigliio R, Trumpp A, Nichols J (2016) Selection and dynamics of embryonic stem cell integration into early mouse embryos. Development 143:24–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Han DW, Tapia N, Joo JY, Greber B, Arauzo-Bravo MJ, Bernemann C, Ko K, Wu G, Stehling M, Do JT, Scholer HR (2010) Epiblast stem cell subpopulations represent mouse embryos of distinct pregastrulation stages. Cell 143:617–627

    Article  CAS  PubMed  Google Scholar 

  42. Ficz G, Hore TA, Santos F, Lee HJ, Dean W, Arand J, Krueger F, Oxley D, Paul YL, Walter J, Cook SJ, Andrews S, Branco MR, Reik W (2013) FGF signaling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency. Cell Stem Cell 13:351–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Habibi E, Brinkman AB, Arand J, Kroeze LI, Kerstens HH, Matarese F, Lepikhov K, Gut M, Brun-Heath I, Hubner NC, Benedetti R, Altucci L, Janesen JH, Walter J, Gut IG, Marks H, Stunnenberg HG (2013) Whole-genomebisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells. Cell Stem Cell 13:360–369

    Article  CAS  PubMed  Google Scholar 

  44. Choi J, Huebner AJ, Clement K, Walsh RM, Savol A, Lin K, Gu H, DiStefano B, Brumbaugh J, Kim S-Y, Sharif J, Rose CM, Mohammad A, Odajima J, Charron J, Shioda T, Gnirke A, Gygi S, Koseki H, Sadreyev RI, Xiao A, Meissner A, Hochedlinger K (2017) Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells. Nature 548:219–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yagi M, Kishigami S, Tanaka A, Semi K, Mizutani E, Wakayama S, Wakayama T (2017) Derivation of ground-state female ES cells maintaining gamete-derived DNA methylation. Nature 548:224–227

    Article  CAS  PubMed  Google Scholar 

  46. Li E, Bestor TH, Jaenisch R (1992) Target mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915–926

    Article  CAS  PubMed  Google Scholar 

  47. Jackson-Grusby L, Beard C, Possemato R, Tudor M, Fambrough D, Csankovski G, Dausman J, Lee P, Wilson C, Lander E, Jaenisch R (2001) Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nat Genet 27:31–39

    Article  CAS  PubMed  Google Scholar 

  48. Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R (2007) In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448:318–324

    Article  CAS  PubMed  Google Scholar 

  49. Silva J, Nichols J, Theunissen TW, Guo G, van Oosten AL, Barrandon O, Wray J, Yamanaka S, Chambers I, Smith A (2009) Nanog is the gateway to the pluripotent ground state. Cell 138:722–737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wu J, Okamura D, Li M, Suzuki K, Luo C, Ma L, He Y, Li Z, Benner C, Tamura I, Krause MN, Nery JR, Du T, Zhang Z, Hishida T, Takahashi Y, Aizawa E, Kim NY, Lajara J, Guillen P, Campistol JM, Esteban CR, Ross PJ, Saghatelian A, Ren B, Ecker JR, Izpisua Belmonte JC (2015) An alternative pluripotent state confers interspecies chimeric competency. Nature 521:316–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kojima Y, Kaufman-Francis K, Studdert JB, Steiner KA, Power MD, Loebel DA, Jones V, Hor A, de Alencastro G, Logan GJ, Teber ET, Tam OH, Stutz MD, Alexander IE, Pickett HA, Tam PP (2014) The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak. Cell Stem Cell 14:107–120

    Article  CAS  PubMed  Google Scholar 

  52. Tsukiyama T, Ohinata Y (2014) A modified EpiSC culture condition containing a GSK3 inhibitor can support germline-competent pluripotency in mice. PLoS One 9:e95329

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Wu J, Platero-Luengo A, Sakurai M, Sugawara A, Gil MA, Yamauchi T, Suzuki K, Bogliotti YS, Cuello C, Morales Valencia M, Okumura D, Luo J, Vilarino M, Parrilla I, Soto DA, Martinez CA, Hishida T, Sanchez-Bautista S, Martinez-Martinez ML, Wang H, Nohalez A, Aizawa E, Martinez-Redondo P, Ocampo A, Reddy P, Roca J, Maga EA, Esteban CR, Berggren WT, Nunez Delicado E, Lajara J, Guillen I, Guillen P, Campistol JM, Martinez EA, Ross PJ, Izpisua Belmonte JC (2017) Interspecies chimerism with mammalian pluripotent stem cells. Cell 168:473–486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rathjen J, Lake JA, Bettess MD, Washington JM, Chapman G, Rathjen PD (1999) Formation of a primitive ectoderm like cell population, EPL cells, from ES cells in response to biologically derived factors. J Cell Sci 112:601–612

    CAS  PubMed  Google Scholar 

  55. Gardner RL, Lyon MF, Evans EP, Burtenshaw MD (1985) Clonal analysis of X-chromosome inactivation and the origin of the germ line in the mouse embryo. J Embryol Exp Morphol 88:349–363

    CAS  PubMed  Google Scholar 

  56. Kalkan T, Olova N, Roode M, Mulas C, Lee HJ, Nett I, Marks H, Walker R, Stunnenberg HG, Lilley KS, Nichols J, Reik W, Bertone P, Smith A (2017) Tracking the embryonic stem cell transition from ground state pluripotency. Development 144:1221–1234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hayashi K, Ohta H, Kurimoto K, Aramaki S, Saitou M (2011) Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell 146:519–532

    Article  CAS  PubMed  Google Scholar 

  58. Mulas C, Kalkan T, Smith A (2017) NODAL secures pluripotency upon embryonic stem cell progression from the ground state. Stem Cell Reports 9:77–91

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kurimoto K, Yabuta Y, Hayashi K, Ohta H, Kiyonari H, Mitani T, Moritoki Y, Kohri K, Kimura H, Yamamoto T, Katou Y, Shirahige K, Saitou M (2015) Quantitative dynamics of chromatin remodeling during germ cell specification from mouse embryonic stem cells. Cell Stem Cell 16:517–532

    Article  CAS  PubMed  Google Scholar 

  60. Tachibana M, Sparman M, Ramsey C, Ma H, Lee H-S, Penedo MC, Mitalipov S (2012) Generation of chimeric rhesus monkeys. Cell 148:285–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 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. PNAS 107:9222–9227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Guo H, Zhu P, Yan L, Li R, Hu B, Lian Y, Yan J, Ren X, Lin S, Li J, Jin X, Shi X, Liu P, Wang X, Wang W, Wei Y, Li X, Guo F, Wu X, Fan X, Yong J, Wen L, Xie SX, Tang F, Qiao J (2014) The DNA methylation landscape of human early embryos. Nature 511:606–610

    Article  CAS  PubMed  Google Scholar 

  63. Smith ZD, Chan MM, Humm KC, Karnik R, Mekhoubad S, Regev A, Eggan K, Meissner A (2014) DNA methylation dynamics of the human preimplantation embryo. Nature 511:611–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tang WW, Dietmann S, Irie N, Leitch HG, Floros VI, Bradshaw CR, Hackett JA, Chinnery PF, Surani MA (2015) A unique gene regulatory network resets the human germline epigenome for development. Cell 161:1453–1467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yan L, Yang M, Guo H, Yang L, Wu J, Li R, Liu P, Lian Y, Zheng X, Yan J, Huang J, Li M, Wu X, WenL LK, Li R, Qiao J, Tang F (2013) Single-cell RNA-seq profiling of human preimplantation embryos and embryonic stem cells. Nat Struct Mol Biol 20:1131–1139

    Article  CAS  PubMed  Google Scholar 

  66. Blakeley P, Fogarty NM, del Valle I, Wamaitha SE, Hu TX, Elder K, Snell P, Christie L, Robson P, Niakan KK (2015) Defining the three cell lineages of the human blastocyst by single-cell RNA seq. Development 142:3151–3165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Boroviak T, Loos R, Lombard P, Okahara J, Behr R, Sasaki E, Nichols J, Smith A, Bertone P (2015) Lineage-specific profiling delineates the emergence and progression of naïve pluripotency in mammalian embryogenesis. Dev Cell 35:366–382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gafni O, Weinberger L, Mansour AA, Manor YS, Chomsky E, Ben-Yosef D, Kalma Y, Viukov S, Maza I, Zviran A, Rais Y, Shipony Z, Mukamel Z, Krupalnik V, Zerbib M, Geula S, Caspi I, Schneir D, Shwartz T, Gilad S, Amann-Zalcenstein D, Benjamin S, Amit I, Tanay A, Massarwa R, Novershtern N, Hanna JH (2013) Derivation of novel human ground state naïve pluripotent stem cells. Nature 504:282–286

    Article  CAS  PubMed  Google Scholar 

  69. Chan YS, Goke J, Ng JH, Lu X, Gonzalez KA, Tan CP, Tng WQ, Hong ZZ, Lim YS, Ng HH (2013) Induction of a human pluripotent state with distinct regulatory circuitry that resembles preimplantation epiblast. Cell Stem Cell 13:663–675

    Article  CAS  PubMed  Google Scholar 

  70. Ware CB, Nelson AM, Mecham B, Hesson J, Zhou W, Jonlin EC, Jimenez-Caliani AJ, Deng X, Cavanaugh C, Cook S, Tesar PJ, Okada J, Margaretha L, Sperber H, Choi M, Blau CA, Treuting PM, Hawkins RD, Cirulli V, Ruohola-Baker H (2014) Derivation of naïve human embryonic stem cells. PNAS 111:4484–4489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Valamehr B, Robinson M, Abujarour R, Rezner B, Vranceanu F, Le T, Medcalf A, Lee TT, Fitch M, Robbins D, Flynn P (2014) Platform for induction and maintenance of transgene-free hiPSCs resembling ground state pluripotent stem cells. Stem Cell Reports 2:366–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Duggal G, Warrier S, Ghimire S, Broekaert D, Van der Jeught M, Lierman S, Deroo T, Peelman L, Van Soom A, Cornelissen R, Menten B, Mestdagh P, Vandesompele J, Roost M, Slieker RC, Heijmans BT, Deforce D, De Sutter P, De Sousa Lopes SC, Heindryckx B (2015) Alternative routes to induce naïve pluripotency in human embryonic stem cells. Stem Cells 33:2686–2698

    Article  CAS  PubMed  Google Scholar 

  73. Guo G, von Meyenn F, Rostovskaya M, Clarke J, Dietmann S, Baker D, Sahakyan A, Myers S, Bertone P, Reik W, Plath K, Smith A (2017) Epigenetic resetting of human pluripotency. Development 144:2748–2763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Guo G, von Meyenn F, Santos F, Chen Y, Reik W, Bertone P, Smith A, Nichols J (2016) Naïve pluripotent stem cells derived directly from isolated cells of the human inner cell mass. Stem Cell Reports 6:437–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hotta A, Cheung AY, Farra N, Vijayaragavan K, Seguin CA, Draper JS, Pasceri P, Maksakova IA, Mager DL, Rossant J, Bhatia M, Ellis J (2009) Isolation of human iPS cells using EOS lentiviral vectors to select for pluripotency. Nat Methods 6:370–376

    Article  CAS  PubMed  Google Scholar 

  76. Pastor WA, Liu W, Chen D, Ho J, Kim R, Hunt TJ, Lukianchikov A, Liu X, Polo JM, Jacobsen SE, Clark AT (2018) TFAP2C regulates transcription in human naïve pluripotency by opening enhancers. Nat Cell Biol 20:553–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Theunissen TW, Friedli M, He Y, Planet E, O’Neil RC, Markoulaki S, Pontis J, Wang H, Iouranova A, Imbeault M, Duc J, Cohen MA, Wert KJ, Castanon R, Zhang Z, Huang Y, Nery JR, Drotar J, Lungjangwa T, Trono D, Ecker JR, Jaenisch R (2016) Molecular criteria for defining the naïve human pluripotent state. Cell Stem Cell 19:502–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Okamoto I, Patrat C, Thepot D, Peynot N, Fauque P, Daniel N, Diabangouaya P, Wolf JP, Renard JP, Duranthon V, Heard E (2011) Eutherian mammals use diverse strategies to initiate X-chromosome inactivation during development. Nature 472:370–374

    Article  CAS  PubMed  Google Scholar 

  79. O’Leary T, Heindryckx B, Lierman S, van Bruggen D, Goeman JJ, Vandewoestyne M, Deforce D, de Sousa Lopes SM, De Sutter P (2012) Tracking the progression of the human inner cell mass during embryonic stem cell derivation. Nat Biotechnol 30:278–282

    Article  PubMed  CAS  Google Scholar 

  80. Silva SS, Rowntree RK, Mekhoubad S, Lee JT (2008) X-chromosome inactivation and epigenetic fluidity in human embryonic stem cells. PNAS 105:4820–4825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Anguera MC, Sadreyev R, Zhang Z, Szanto A, Payer B, Sheridan SD, Kwok S, Haggarty SJ, Sur M, Alvarez J, Gimelbrant A, Mitalipova M, Kirby JE, Lee JT (2012) Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes. Cell Stem Cell 11:75–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sahakyan A, Kim R, Chronis C, Sabri S, Bonora G, Theunissen TW, Kuoy E, Langerman J, Clark AT, Jaenisch R, Plath K (2017) Human naïve pluripotent stem cells model X chromosome dampening and X inactivation. Cell Stem Cell 20:87–101

    Article  CAS  PubMed  Google Scholar 

  83. Pastor WA, Chen D, Liu W, Kim R, Sahakyan A, Lukianchikov A, Plath K, Jacobsen SE, Clark AT (2016) Naïve human pluripotent stem cells feature a methylation landscape devoid of blastocyst or germline memory. Cell Stem Cell 18:323–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Nakamura T, Okamoto I, Sasaki K, Yabuta Y, Iwatani C, Tsuchiya H, Seita Y, Nakamura S, Yamomoto T, Saitou M (2016) A developmental coordinate of pluripotency among mice, monkeys and humans. Nature 537:57–62

    Article  CAS  PubMed  Google Scholar 

  85. Irie N, Weinberger L, Tang WW, Kobayashi T, Viukov S, Manor YS, Dietmann S, Hanna JH, Surani MA (2015) SOX17 is a critical specifier of human primordial germ cell fate. Cell 160:253–268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Sasaki K, Nakamura T, Okamoto I, Yabuta Y, Iwatani C, Tsuchiya H, Seita Y, Nakamura S, Shiraki N, Takakuwa T, Yamamoto T, Saitou M (2016) The germ cell fate of cynomolgus monkeys is specified in the nascent amnion. Nature 39:169–185

    CAS  Google Scholar 

  87. 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 17:178–194

    Article  CAS  PubMed  Google Scholar 

  88. Kobayashi T, Zhang H, Tang WWC, Irie N, Withey S, Klisch D, Sybirna A, Dietmann S, Contreras DA, Webb R, Allegrucci C, Alberio R, Surani MA (2017) Principles of early human development and germ cell program from conserved model systems. Nature 546:416–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kobayashi T, Yamaguchi T, Hamanaka S, Kato-Itoh M, Yamazaki Y, Ibata M, Sato H, Lee YS, Usui J, Knisely AS, Hirabayashi M, Nakauchi H (2010) Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell 142:787–799

    Article  CAS  PubMed  Google Scholar 

  90. Cohen MA, Markoulaki S, Jaenisch R (2018) Matched developmental timing of donor cells with the host is crucial for chimera formation. Stem Cell Reports 10:1445–1452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chen Y, Niu Y, Li Y, Ai Z, Kang Y, Shi H, Xiang Z, Yang Z, Tan T, Si W, Li W, Xia X, Zhou Q, Ji W, Li T (2015) Generation of cynomolgus monkey chimeric fetuses using embryonic stem cells. Cell Stem Cell 17:116–124

    Article  CAS  PubMed  Google Scholar 

  92. Fang R, Liu K, Zhao Y, Li H, Zhu D, Du Y, Xiang C, Li X, Liu H, Miao Z, Zhang X, Shi Y, Yang W, Xu J, Deng H (2014) Generation of naïve induced pluripotent stem cells from rhesus monkey fibroblasts. Cell Stem Cell 15:488–496

    Article  CAS  PubMed  Google Scholar 

  93. De Los Angeles A, Pho N, Redmond DE Jr (2018) Generating human organs via interspecies chimera formation: advances and barriers. Yale J Biol Med 91:333–342

    PubMed  PubMed Central  Google Scholar 

  94. De Los Angeles A, Hyun I, Latham S, Elsworth J, Redmond DE Jr (2018) Human-monkey chimeras for modeling human disease: opportunities and challenges. Stem Cells Dev. https://doi.org/10.1089/scd.2018.0162

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Alejandro De Los Angeles

Authors
  1. Alejandro De Los Angeles
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alejandro De Los Angeles .

Editor information

Editors and Affiliations

  1. Department of Bioethics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA

    Insoo Hyun

  2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Alejandro De Los Angeles

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

De Los Angeles, A. (2019). Frontiers of Pluripotency. In: Hyun, I., De Los Angeles, A. (eds) Chimera Research . Methods in Molecular Biology, vol 2005. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9524-0_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9524-0_1

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9523-3

  • Online ISBN: 978-1-4939-9524-0

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation