Induced pluripotent stem cells: new possibilities in neurobiology and neurotransplantaion

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The discovery of embryonic stem cells (ES) and methods of ES handling belong to most significant achievements of science in the 20th century. As mammalian ES represent an essentially unlimited source of non-differentiated cells with normal diploid caryotype, they will remain to be an important object in basic research, including neurobiology, although their use for the purposes of practical neurology meets a number of medical and ethical difficulties. Results of last studies open completely new possibilities in the field of cell therapy of severe human disorders. We are talking about reprogramming of somatic cells in mammalians, including humans, into pluripotent stem cells (so called induced pluripotent stem cells, iPS), with their further differentiation to cells of different types. The practical capability of patients’ iPS to be transformed into dopaminergic and other specific neurons of the CNS is shown, that gives to doctors a fundamentally new technology of getting adequate and genetically identical cell material for neurotransplantation in Parkinson’s disease, Huntington’s disease and other severe neurodegenerative disorders.


About the authors

O. S. Lebedeva

Institute of Molecular Genetics, Russian Academy of Sciences

Author for correspondence.
Russian Federation

M. A. Lagarkova

Vavilov Institute of General Genetics, Russian Academy of Sciences

Russian Federation

S. N. Illarioshkin

Research Center of Neurology, Russian Academy of Medical Sciences (Moscow)

Russian Federation

L. G. Khaspekov

Research Center of Neurology, Russian Academy of Medical Sciences (Moscow)

Russian Federation

I. A. Grivennikov

Institute of Molecular Genetics, Russian Academy of Sciences

Russian Federation


  1. Биология стволовых клеток и клеточные технологии (под ред. М.А. Пальцева). В 2-х т. М.: Медицина, 2009.
  2. Викторов И.В., Савченко Е.А., Ухова О.В. и др. Мультипотентные стволовые и прогениторные клетки обонятельного эпителия. Клет. технол. в биологии и медицине 2006; 4: 185–193.
  3. Гольдберг Е.Д., Дыгай А.М., Жданов В.В. Современные взгляды на проблему стволовых клеток и возможности их использования в медицине. Клет. технол. в биологии и медицине 2005; 4: 184–189.
  4. Гривенников И.А. Эмбриональные стволовые клетки и проблема направленной дифференцировки. Успехи биол. химии 2008; 48: 181–188.
  5. Иллариошкин С.Н. Конформационные болезни мозга. М.: Янус-К, 2003.
  6. Куликов А.В., Степанова М.С., Стволинский С.Л. и др. Применение мультипотентных мезенхимальных стромальных клеток жировой ткани человека для компенсации неврологического дефицита у крыс, вызванного введением 3-нитропропио- новой кислоты. Клет. технол. в биологии и медицине 2008; 2: 83–89.
  7. Малайцев В.В., Богданова И.М., Сухих Г.Т. Современные представления о биологии стволовой клетки. Арх. патол. 2002; 4: 7–11.
  8. Нейродегенеративные заболевания: фундаментальные и при- кладные аспекты (под ред. М.В. Угрюмова). М.: Наука, 2010.
  9. Соколова И.Б., Федотова О.Р., Зинькова Н.Н. и др. Влияние трансплантации мезенхимальных стволовых клеток на когнитивные функции крыс после ишемического инсульта. Клет. технол. в биологии и медицине 2006; 4: 202–205.
  10. Шевченко Ю.Л., Новик А.А., Кузнецов А.Н. и др. Аутологичная трансплантация кроветворных стволовых клеток при рассеянном склерозе: результаты исследования российской кооперативной группы клеточной терапии. Неврол. журн. 2008; 2: 11–18.
  11. Brambrink T., Foreman R., Welstead G.G. et al. Sequential expression of pluripotency markers during direct reprogramming of mouse somatic cells. Cell Stem Cell 2008; 2: 151–159.
  12. Brandenberger R., Khrebtukova I., Thies R.S. et al. MPSS profiling of human embryonic stem cells. BMC Dev. Biol. 2005; 4: 10–26.
  13. Cai J., Yang M., Poremsky E. et al. Dopaminergic neurons derived from human induced pluripotent stem cells survive and integrate into 6- OHDA-lesioned rats. Stem Cells Dev. 2010; 19: 1017–1023.
  14. Caiazzo M., Dell’Anno M.T., Dvoretskova E. et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 2011; 476: 224–227.
  15. Chan A.W., Cheng P.H., Neumann A., Yang J.J. Reprogramming huntington monkey skin cells into pluripotent stem cells. Cell Reprogram. 2010; 12: 509–517.
  16. Chickarmane V., Troein C., Nuber U.A. et al. Transcriptional dynamics of the embryonic stem cell switch. PLOS 2006; 9: 1080–1092.
  17. Dimos J.T., Rodolfa K.T., Niakan K.K. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 2008; 321: 1218–1221.
  18. Ebert A.D., Yu J., Rose F.F. et al. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 2009; 457: 277–280.
  19. Gross R.E., Watts R.L., Hauser R.A. et al. Intrastriatal transplantation of microcarrier-bound human retinal pigment epithelial cells versus sham surgery in patients with advanced Parkinson’s disease: a double- blind, randomised, controlled trial. Lancet Neurol. 2011; 10: 509–519.
  20. Hanna J., Markoulaki S., Schorderet P. et al. Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 2008; 133: 250–264.
  21. Hargus G., Cooper O., Deleidi M. et al. Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc. Natl. Acad. Sci. USA 2010; 107: 15921–15926.
  22. Harris D.T. Non-haematological uses of cord blood stem cells. Br. J. Haematol. 2009; 147: 177–184.
  23. Hatano S.Y., Tada M., Kimura H. et al. Pluripotential competence of cells associated with Nanog activity. Mech Dev. 2005; 122: 67–79.
  24. Hu B.-Y., Weick J.P., Yu J. et al. Neural differentiation of hiPSC follows developmental principles but with variable potency. Proc. Natl. Acad. Sci. USA 2010; 107: 4335–4340.
  25. Hu B.-Y., Zhang S.-C. Differentiation of spinal motor neurons from pluripotent human stem cells. Nat. Protoc. 2009; 4: 1295–1304.
  26. Huangfu D., Maehr R., Guo W. et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat. Biotechnol. 2008a; 26: 795–797.
  27. Huangfu D., Osafune K., Maehr R. et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat. Biotechnol. 2008б; 26: 1269–1275.
  28. Kaji K., Norrby K., Paca A. et al. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 2009; 458: 771–775.
  29. Knight A.L., Daigle J.G. Reprogramming Parkinson’s disease research. Dis Model Mech. 2010; 3: 509–510.
  30. Kondziolka D., Wechsler L., Goldstein S. et al. Transplantation of cultured human neuronal cells for patients with stroke. Neurology 2000; 55: 565–569.
  31. Langston J.W. The promise of stem cells in Parkinson’s disease. J. Clin. Invest. 2005; 115: 23–25.
  32. Lee G., Papapetrou E.P., Kim H. et al. Modeling pathogenesis and treatment of familial dysautonomia using patient specific iPSCs. Nature 2009; 461: 402–406.
  33. Lindvall O., Kokaia Z., Martinez-Serrano A. Stem cell therapy for human neurodegenerative disorders – how to make it work. Nat. Med. 2004; 10 (Suppl.): S42–S50.
  34. Lowry W.E., Richter L., Yachechko R. et al. Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc. Natl. Acad. Sci. USA 2008; 105: 2883–2888.
  35. Lu P., Blesch A., Tuszynski M.H. Induction of bone marrow stromal cells to neurons: differentiation, transdifferentiation, or artifact? J. Neurosci. Res. 2004; 77: 174–191.
  36. Lyssiotis C.A., Foreman R.K., Steark J. et al. Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4. Proc. Natl. Acad. Sci. USA 2009; 106: 8912–8917.
  37. Maherali N., Sridharan R., Xie W. et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell. 2007; 1: 55–70.
  38. Medeiros R.B., Papenfuss K.J., Hoium B. et al. Novel sequential ChiP and simplified ChiP protocols for promoter co-occupancy and target gene identification in human embryonic stem cells. BMC Biotechnology 2009; 9: 59.
  39. Nakagawa M., Koyanagi M., Tanabe K. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat. Biotechnol. 2008; 26: 101–106.
  40. Ohta S., Imaizumi Y., Okada Y. et al. Generation if human melanocytes from induced pluripotent stem cells. PLOS ONE 2011; 6: 1–10.
  41. Okita K., Nakagawa M., Hyenjong H. et al. Generation of mouse induced pluripotent stem cells without viral vectors. Science 2008; 322: 949–953.
  42. O’Mathuna D.P. What to call human cloning: The technical terminology increasingly used in the cloning debate sidesteps the ethical questions raised. EMBO reports 2002; 3: 502–505
  43. Paige S.L., Osugi T., Afanasiev O.K. et al. Endogenous Mnt/ — catenin signaling is required for cardiac differentiation in human embryonic stem cells. PLOS ONE 2010; 5: 1–8.
  44. Park I.-H., Arora N., Huo H. et al. Disease-specific induced pluripotent stem (iPS) cells. Cell 2008; 134: 877–886.
  45. Pesce M., Schöler H.R. Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells 2001; 19: 271–278.
  46. Pfisterer U., Kirkeby A., Torper O. et al. Direct conversion of human fibroblasts to dopaminergic neurons. Proc. Natl. Acad. Sci. USA 2011; 108: 10343–10348.
  47. Qiu C., Ma Y., Wang J. et al. Lin28-mediated post-transcriptional regulation of Oct4 expression in human embryonic stem cells. Nucl. Acids Res. 2010; 38: 1240–1248.
  48. Remenyi A., Lins K., Nissen L.J. et al. Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancars. Genes Dev. 2003; 17: 2048–2059.
  49. Seibler P., Graziotto J., Jeong H. et al. Mitochondrial parkin recruitment in neurons derived from mutant PINK1 iPS cells. J. Neurosci. 2011; 31: 5970–5976.
  50. Sharov A.A., Masui S., Sharova L.V. et al. Identification of Pou5f1, Sox2 and Nanog downstream target genes with statistical confidence by applying a novel algorithm to time course microarray and genome-wide chromatin immunoprecipitation data. BMC Genomics. 2008; 9: 269.
  51. Shi Y., Desponts C., Do J.T. et al. Induction of pluripotent stem cellsfrom mouse embryonic fibroblasts by Oct4 and Klf4 with smallmolecule compounds. Cell Stem Cell. 2008б; 3: 568–574.
  52. Shi Y., Do J.T., Desponts C. et al. A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell. 2008a; 2: 525–528.
  53. Swistowski A., Peng J., Liu Q. et al. Efficient generation of functional dopaminergic neurons from human induced pluripotent stem cells under defined conditions. Stem Cells 2010; 28: 1893–1904.
  54. Takahashi K., Tanabe K., Ohnuki M. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131: 861–872.
  55. Takahashi K., Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663–676.
  56. Vierbuchen T., Ostermeier A., Pang Z.P. et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010; 463: 1035–1041.
  57. Warren L., Manos P. D., Ahfeldt T. et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010; 7: 1–13.
  58. Weissman I.L. Stem cells: units of development, units of regeneration, and units of evolution. Cell 2000; 100: 157–168.
  59. Wernig M., Zhao J.P., Pruszak J. et al. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc. Natl. Acad. Sci. USA 2008; 105: 5856–5861.
  60. Whittemore S.R. Neuronal replacement strategies for spinal cord injury. J. Neurotrauma 1999; 16: 667–673.
  61. Xu B., Zhang K., Huang Y. Lin28 modulates cell growth and associates with a subset of cell cycle regulator mRNAs in mouse embryonic stem cells. RNA 2009; 15: 357–361.
  62. Xu L., Tan Y.Y., Ding J.Q., Chen S.D. The iPS technique provides hope for Parkinson’s disease treatment. Stem Cell Rev. 2010; 6: 398–404.
  63. Yahanta N., Asai M., Kitaoka S. et al. Anti-A drug screening platform using human iPS cell-derived neurons for the treatment of Alzheimer’s disease. PLOS ONE 2011; 6: 1–11.
  64. Yu J., Hu K., Smyga-Otto K. et al. Human induced pluripotent stem cells free of vector and transgene sequence. Science 2009; 324: 797–801.
  65. Yu J., Vodyanik M.A., Smuga-Otto K. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007; 318; 1917.
  66. Yusa K., Rashid S.T., Strick-Marchand H. et al. Targeted gene correction of 1-antitrypsin deficiency in induced pluripotent stem cells. Nature 2011; 478: 391–394.
  67. Zaehres H., Lensch M.W., Daheron L. et al. High-efficiency RNA interference in human embryonic stem cells. Stem Cells 2005; 23: 299–305.
  68. Zhang D., Jiang W., Lu M. et al. Highly efficient differentiation of human ES and iPS cells into mature pancreatic insulin-producing cells. Cell Res. 2009; 19: 429–438.
  69. Zhang N., An M.C., Montoro D., Ellerby L.M. Characterisation of human Huntington’s disease cell model from induced pluripotent stem cells. PLOS Curr. 2010; 2: RRN1193.
  70. Zhou H., Wu S., Joo J.Y. et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell. 2009; 4: 381–384.

Copyright (c) 2011 Lebedeva O.S., Lagarkova M.A., Illarioshkin S.N., Khaspekov L.G., Grivennikov I.A.

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