Skip to main content
SpringerLink
Log in

Stem Cell Plasticity, Beyond Alchemy

  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Cell plasticity is a central issue in stem cell biology. Differentiated somatic nuclei have the flexibility to dedifferentiate when transferred into oocytes or when fused to pluripotent embryonic stem cells. Recent publications also claim that somatic stem cells can convert into developmentally unrelated cell types both in vivo and ex vivo without such drastic cell manipulations. Some of these claims are still controversial, making it difficult for us to determine the reality of somatic stem cell plasticity. Indeed, we have heard enough about the “potentials” of cell plasticity; how much do we know about mechanisms? A fundamental issue in current stem cell biology is to understand the mechanisms underlying cell plasticity. In this short review, we overview three research fields related to cell plasticity: nuclear transfer, transdifferentiation, and cell fusion, with an emphasis on studies of molecular mechanisms underlying cell plasticity.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH. Viable offspring derived from fetal and adult mammalian cells.Nature. 1997;385:810–813.

    Article  CAS  PubMed  Google Scholar 

  2. Wilmut I, Beaujean N, de Sousa PA, et al. Somatic cell nuclear transfer.Nature. 2002;419:583–586.

    Article  CAS  PubMed  Google Scholar 

  3. Hill JR, Winger QA, Long CR, Looney CR, Thompson JA, Westhusin ME. Development rates of male bovine nuclear transfer embryos derived from adult and fetal cells.Biol Reprod. 2000;62:1135–1140.

    Article  CAS  PubMed  Google Scholar 

  4. Tanaka S, Oda M, Toyoshima Y, et al. Placentomegaly in cloned mouse concepti caused by expansion of the spongiotrophoblast layer.Biol Reprod. 2001;65:1813–1821.

    Article  CAS  PubMed  Google Scholar 

  5. Young LE, Fairburn HR. Improving the safety of embryo technologies: possible role of genomic imprinting.Theriogenology. 2000;53:627–648.

    Article  CAS  PubMed  Google Scholar 

  6. Philpott A, Krude T, Laskey RA. Nuclear chaperones.Semin Cell Dev Biol. 2000;11:714.

    Article  Google Scholar 

  7. Dilworth SM, Black SJ, Laskey RA. Two complexes that contain histones are required for nucleosome assembly in vitro: role of nucleoplasmin and N1 in Xenopus egg extracts.Cell. 1987;51:1009–1018.

    Article  CAS  PubMed  Google Scholar 

  8. Ray-Gallet D, Quivy JP, Scamps C, Martini EM, Lipinski M, Almouzni G. HIRA is critical for a nucleosome assembly pathway independent of DNA synthesis.Mol Cell. 2002;9:1091–1100.

    Article  CAS  PubMed  Google Scholar 

  9. Ito T, Bulger M, Kobayashi R, Kadonaga JT. Drosophila NAP-1 is a core histone chaperone that functions in ATP-facilitated assembly of regularly spaced nucleosomal arrays.Mol Cell Biol. 1996;16:3112–3124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kawasaki K, Philpott A, Avilion AA, Berrios M, Fisher PA. Chromatin decondensation in Drosophila embryo extracts.J Biol Chem. 1994;269:10169–10176.

    PubMed  CAS  Google Scholar 

  11. Kikyo N, Wade PA, Guschin D, Hui G,Wolffe AP. Active remodeling of somatic nuclei in egg cytoplasm by the nucleosomal ATPase ISWI.Science. 2000;289:2360–2362.

    Article  CAS  PubMed  Google Scholar 

  12. Burns KH, Viveiros MM, Ren Y, et al. Roles of NPM2 in chromatin and nucleolar organization in oocytes and embryos.Science. 2003;300:633–636.

    Article  CAS  PubMed  Google Scholar 

  13. Wu X, Viveiros MM, Eppig JJ, Bai Y, Fitzpatrick SL, Matzuk MM. Zygote arrest 1 (Zar1) is a novel maternal-effect gene critical for the oocyte-to-embryo transition.Nat Genet. 2003;33:187–191

    Article  CAS  PubMed  Google Scholar 

  14. Dean W, Santos F, Stojkovic M, et al. Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos.Proc Natl Acad Sci USA. 2001; 98:13734–13738.

    Article  CAS  PubMed  Google Scholar 

  15. Bourc'his D, Le Bourhis D, Patin D, et al. Delayed and incomplete reprogramming of chromosome methylation patterns in bovine cloned embryos.Curr Biol. 2001;11:1542–1546.

    Article  CAS  PubMed  Google Scholar 

  16. Kang YB, Koo DB, Park JS, et al. Aberrant methylation of donor genome in cloned bovine embryos.Nat Genet. 2001;28:173–177.

    Article  CAS  PubMed  Google Scholar 

  17. Shi W, Zakhartchenko V, Wolf E. Epigenetic reprogramming in mammalian nuclear transfer.Differentiation. 2003;71:91–113.

    Article  CAS  PubMed  Google Scholar 

  18. Humpherys D, Eggan K, Akutsu H, et al. Abnormal gene expression in cloned mice derived from embryonic stem cell and cumulus cell nuclei.Proc Natl Acad Sci USA. 2002;99:12889–12894.

    Article  CAS  PubMed  Google Scholar 

  19. Adenot PG, Mercier Y, Renard JP, Thompson EM. Differential H4 acetylation of paternal and maternal chromatin precedes DNA replication and differential transcriptional activity in pronuclei of 1-cell mouse embryos.Development. 1997;124:4615–4625.

    PubMed  CAS  Google Scholar 

  20. O'Neill LP, Turner BM. Histone H4 acetylation distinguishes coding regions of the human genome from heterochromatin in a differentiation-dependent but transcription-independent manner.EMBO J. 1995;14:3946–3957.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Bannister AJ, Zegerman P, Partridge JF, et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain.Nature. 2001;410:120–124.

    Article  CAS  PubMed  Google Scholar 

  22. Lachner M, O'Carroll D, Rea S, Mechtler K, JenuweinT Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins.Nature. 2001;410:116–120.

    Article  CAS  PubMed  Google Scholar 

  23. Wade PA, Kikyo N. Chromatin remodeling in nuclear cloning.Eur J Biochem. 2002;269:2284–2287.

    Article  CAS  PubMed  Google Scholar 

  24. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals.Nat Genet. 2003;33(suppl):245–254.

    Article  CAS  Google Scholar 

  25. Enright BP, Kubota C, Yang X, Tian XC. Epigenetic characteristics and development of embryos cloned from donor cells treated by trichostatin A or 5-aza-2'-deoxycytidine.Biol Reprod. 2003;69:896–901.

    Article  CAS  PubMed  Google Scholar 

  26. Cheong HT, Takahashi Y, Kanagawa H. Birth of mice after transplantation of early cell-cycle-stage embryonic nuclei into enucleated oocytes.Biol Reprod. 1993;48:958–963.

    Article  CAS  PubMed  Google Scholar 

  27. Mann MR, Chung YG, Nolen LD, Verona RI, Latham KE, Bartolomei MS. Disruption of imprinted gene methylation and expression in cloned preimplantation stage mouse embryos.Biol Reprod. 2003;69:902–914.

    Article  CAS  PubMed  Google Scholar 

  28. Humpherys D, Eggan K, Akutsu H, et al. Epigenetic instability in ES cells and cloned mice.Science. 2001;293:95–97.

    Article  CAS  PubMed  Google Scholar 

  29. Lee J, Inoue K, Ono R, et al. Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells.Development. 2002;129:1807–1817.

    Article  CAS  PubMed  Google Scholar 

  30. Yamazaki Y, Mann MR, Lee SS, et al. Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning.Proc Natl Acad Sci USA. 2003;100:12207–12212.

    Article  CAS  PubMed  Google Scholar 

  31. Campbell KH. Nuclear transfer in farm animal species.Semin Cell Dev Biol. 1999;10:245–252.

    Article  CAS  PubMed  Google Scholar 

  32. Kato Y, Tani T, Sotomaru Y, et al. Eight calves cloned from somatic cells of a single adult.Science. 1998;282:2095–2098.

    Article  CAS  PubMed  Google Scholar 

  33. Kato Y, Tani T, Tsunoda Y. Cloning of calves from various somatic cell types of male and female adult, newborn and fetal cows.J Reprod Fertil. 2000;120:231–237.

    Article  CAS  PubMed  Google Scholar 

  34. Reggio BC, James AN, Green HL, et al. Cloned transgenic offspring resulting from somatic cell nuclear transfer in the goat: oocytes derived from both follicle-stimulating hormone-stimulated and nonstimulated abattoir-derived ovaries.Biol Reprod. 2001; 65:1528–1533.

    Article  CAS  PubMed  Google Scholar 

  35. Keefer CL, Baldassarre H, Keyston R, et al. Generation of dwarf goat (Capra hircus) clones following nuclear transfer with transfected and nontransfected fetal fibroblasts and in vitro-matured oocytes.Biol Reprod. 2001;64:849–856.

    Article  CAS  PubMed  Google Scholar 

  36. Keefer CL, Keyston R, Lazaris A, et al. Production of cloned goats after nuclear transfer using adult somatic cells.Biol Reprod. 2002;66:199–203.

    Article  CAS  PubMed  Google Scholar 

  37. Jeanisch R, Eggan K, Humpherys D, Rideout W, Hochedlinger K. Nuclear cloning, stem cells, and genomic reprogramming.Cloning Stem Cells. 2002;4:389–396.

    Article  PubMed  Google Scholar 

  38. Eggan K, Akutsu H, Loring J, et al. Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation.Proc Natl Acad Sci USA. 2001;98:6209–6214.

    Article  CAS  PubMed  Google Scholar 

  39. Rideout WM 3rd, Wakayama T, Wutz A, et al. Generation of mice from wild-type and targeted ES cells by nuclear cloning.Nat Genet. 2000;24:109–110.

    Article  CAS  PubMed  Google Scholar 

  40. Sullivan EJ, Kasinathan S, Kasinathan P, Robl JM, Collas P. Cloned calves from chromatin remodeled in vitro.Biol Reprod [Epub ahead of print]. September 17, 2003.

  41. Lucas JJ,Terada N. Cell fusion and plasticity.Cytotechnology. 2003;41:103–109.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Weissman IL, Anderson DJ, Gage F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiation.Annu Rev Cell Dev Biol. 2001;17:387–403.

    Article  CAS  PubMed  Google Scholar 

  43. Lemiscka I. Rethinking somatic stem cell plasticity [commentary].Nature Biotechnol. 2002;20:425.

    Article  CAS  Google Scholar 

  44. Ying QL, Nichols J, Evans EP, Smith AG. Changing potency by spontaneous fusion.Nature. 2002;416:545–548.

    Article  CAS  PubMed  Google Scholar 

  45. Terada N, Hamazaki T, Oka M, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous fusion.Nature. 2002;416:542–545.

    Article  CAS  PubMed  Google Scholar 

  46. Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes.Nature. 2003;422:897–901.

    Article  CAS  PubMed  Google Scholar 

  47. Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion.Nature. 2003;422:901–904.

    Article  CAS  PubMed  Google Scholar 

  48. Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes [advance online publication].Nature. October 12,2003.

  49. Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells.Science. 2002;297:2256–2259.

    Article  CAS  PubMed  Google Scholar 

  50. Ianus A, Holz GG, Theise ND, Hussain MA.In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion.J Clin Invest. 2003;111:843–850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cogle CR, Wainman DA, Jorgensen ML, Guthrie SM, Mames RN, Scott EW. Adult human hematopoietic cells provide functional hemangioblast activity.Blood [Epub ahead of print]. September 11, 2003.

  52. Reyes M, Lund T, Lenvik T, Aguiar D, Koodie L, Verfaillie CM. Purification andex vivo expansion of postnatal human marrow mesodermal progenitor cells.Blood. 2001;98:2615–2625.

    Article  CAS  PubMed  Google Scholar 

  53. Jiang Y, Jahagirdar BN, Reinhardt RL, et al. Pluripotency of mesenchymal stem cells derived from adult marrow.Nature. 2002;418:41–49.

    Article  CAS  PubMed  Google Scholar 

  54. Schwartz RE, Reyes M, Koodie L, et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J ClinInvest. 2002;109:1291–1302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bjornson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cellsin vivo. Science. 1999;283:534–537.

    PubMed  CAS  Google Scholar 

  56. Morshead CM, Benveniste P, Iscove NN, van der Kooy D. Hematopoietic competence is a rare property of neural stem cells that may depend on genetic and epigenetic alterations.Nat Med. 2002;8:268–273.

    Article  CAS  PubMed  Google Scholar 

  57. Boukamp P, Chen J, Gonzales F, Jones PA, Fusenig NE. Progressive stages of “transdifferentiation” from epidermal to mesenchymal phenotype induced by MyoD1 transfection, 5-aza-2'-deoxycytidine treatment, and selection for reduced cell attachment in the human keratinocyte line HaCaT.J Cell Biol. 1992;116:1257–1271.

    Article  CAS  PubMed  Google Scholar 

  58. Makino S, Fukuda K, Miyoshi S, et al. Cardiomyocytes can be generated from marrow stromal cellsin vitro.J Clin Invest. 1999;103:697–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Finch BW, Ephrussi B. Retention of multiple developmental potentialities by cells of a mouse testicular teratocarcinoma during prolonged culture in vitro and their extinction upon hybridization with cells of permanent lines.Proc Natl Acad Sci USA. 1967;57:615–621.

    Article  CAS  PubMed  Google Scholar 

  60. Jami J, Failly C, Ritz E. Lack of expression of differentiation in mouse teratoma-fibroblast somatic cell hybrids.Exp Cell Res. 1973;76:191–199.

    Article  CAS  PubMed  Google Scholar 

  61. McBurney MW, Strutt B. Fusion of embryonal carcinoma cells to fibroblast cells, cytoplasts, and karyoplasts. Developmental properties of viable fusion products.Exp Cell Res. 1979;124:171–180.

    Article  CAS  PubMed  Google Scholar 

  62. Miller RA, Ruddle FH. Pluripotent teratocarcinoma-thymus somatic cell hybrids.Cell. 1976;9:45–55.

    Article  CAS  PubMed  Google Scholar 

  63. McBurney MW. Hemoglobin synthesis in cell hybrids formed between teratocarcinoma and Friend erythroleukemia cells.Cell. 1977;12:653–662.

    Article  CAS  PubMed  Google Scholar 

  64. Iwakura Y, Nozaki M, Asano M, et al. Pleiotropic phenotypic expression in cybrids derived from mouse teratocarcinoma cells fused with rat myoblast cytoplasts.Cell. 1985;43:777–791.

    Article  CAS  PubMed  Google Scholar 

  65. Takagi N, Yoshida MA, Sugawara O, Sasaki M. Reversal of X inactivation in female mouse somatic cells hybridized with murine teratocarcinoma cells in vitro.Cell. 1983;34:1053–1062.

    Article  CAS  PubMed  Google Scholar 

  66. Surani MA. Reprogramming of genome function through epigenetic inheritance.Nature. 2001;414:122–128.

    Article  CAS  PubMed  Google Scholar 

  67. Tada M, Takahama Y, Abe K, Nakatsuji N, Tada T. Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells.Current Biology. 2001;11:1553–1558.

    Article  CAS  PubMed  Google Scholar 

  68. Tada M,Tada T, Lefebvre L, Barton SC, Surani M. Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells.EMBO Journal. 1997;16:6510–6520.

    Article  CAS  PubMed  Google Scholar 

  69. Tada M, Morizane A, Kimura H, et al. Pluripotency of reprogrammed somatic genomes in embryonic stem hybrid cells.Dev Dyn. 2003;227:504–510.

    Article  CAS  PubMed  Google Scholar 

  70. Blau HM, Chiu CP, Webster C. Cytoplasmic activation of human nuclear genes in stable heterokaryons.Cell. 1983;32:1171–1180.

    Article  CAS  PubMed  Google Scholar 

  71. Blau HM, Parlath GK, Hardeman EC, et al. Plasticity of the differentiated state.Science. 1985;230:758–766.

    Article  CAS  PubMed  Google Scholar 

  72. Lipsich LA, Kates JR, Lucas JJ. Expression of a liver-specific function by mouse fibroblast nuclei transplanted into rat hepatoma cytoplasts.Nature. 1979;281:74–76.

    Article  CAS  PubMed  Google Scholar 

  73. Hakelien AM, Landsverk HB, Robl JM, Skalhegg BS, Collas P. Reprogramming fibroblasts to express T-cell functions using cell extracts.Nat Biotechnol. 2002;20:460–466.

    Article  CAS  PubMed  Google Scholar 

  74. Kikyo N, Wolffe AP. Reprogramming nuclei: insights from cloning, nuclear transfer and heterokaryons.J Cell Sci. 2000;113:11–20.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University of Florida College of Medicine, 1600 SW Archer Rd, 32610, Gainesville, FL, USA

    Michael S. Rutenberg, Takashi Hamazaki, Amar M. Singh & Naohiro Terada

Authors
  1. Michael S. Rutenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takashi Hamazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amar M. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Naohiro Terada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naohiro Terada.

About this article

Cite this article

Rutenberg, M.S., Hamazaki, T., Singh, A.M. et al. Stem Cell Plasticity, Beyond Alchemy. Int J Hematol 79, 15–21 (2004). https://doi.org/10.1007/BF02983528

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02983528

Key words

Search

Navigation