Skip to main content
PMC home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;15(3):208–216. doi: 10.1111/j.1750-3639.2005.tb00522.x

ES Cell‐Derived Glial Precursors Contribute to Remyelination in Acutely Demyelinated Spinal Cord Lesions

Alberto Perez‐Bouza 1, Tamara Glaser 1, Oliver Brüstle 1,✉
PMCID: PMC8095916  PMID: 16196387

Abstract

Pluripotent embryonic stem (ES) cells have emerged as a powerful tool for disease modeling and neural regeneration. Transplantation studies in rodents indicate that ES cell‐derived glial precursors (ESGPs) efficiently restore myelin in dysmyelinating mutants and chemically induced foci of myelin loss. Here we explore the myelination potential of ESGPs in an antibody/complement‐induced demyelination model. Microinjection of an antibody to myelin oligodendrocyte glycoprotein (MOG) and complement was employed to generate circumscribed areas of demyelination in the adult rat spinal cord. ESGPs transplanted into 2‐day‐old lesions were found to survive and differentiate into both oligodendrocytes and astrocytes. The engrafted cells remained largely confined to the lesion site and showed no evidence of tumor formation up until 4 weeks after transplantation. Within areas of pronounced microglial activation and macrophage extravasation, engrafted ES cell‐derived oligodendrocytes contacted and enwrapped host axons and alongside endogenous glia, contributed to the formation of new myelin sheaths. These findings demonstrate that ESGPs transplanted into acutely demyelinated lesions can contribute to myelin repair.

Full Text

The Full Text of this article is available as a PDF (549.6 KB).

References

  • 1. Adams CW, Poston RN and Buk SJ (1989) Pathology, histochemistry and immunocytochemistry of lesions in acute multiple sclerosis. J Neurol Sci 92:291–306. [DOI] [PubMed] [Google Scholar]
  • 2. Ben‐Hur T, Einstein O, Mizrachi‐Kol R, Ben‐Menachem O, Reinhartz E, Karussis D and Abramsky O (2003) Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis. Glia 41:73–80. [DOI] [PubMed] [Google Scholar]
  • 3. Billon N, Jolicoeur C, Ying QL, Smith A and Raff M (2002) Normal timing of oligodendrocyte development from genetically engineered, lineage‐selectable mouse ES cells. J Cell Sci 115:3657–3665. [DOI] [PubMed] [Google Scholar]
  • 4. Blakemore WF, Crang AJ and Patterson RC (1987) Schwann cell remyelination of CNS axons following injection of cultures of CNS cells into areas of persistent demyelination. Neurosci Lett 77:20–24. [DOI] [PubMed] [Google Scholar]
  • 5. Brüstle O, Jones KN, Learish RD, Karram K, Choudhary K, Wiestler OD, Duncan ID and McKay RD (1999) Embryonic stem cell‐derived glial precursors: a source of myelinating transplants. Science 285:754–756. [DOI] [PubMed] [Google Scholar]
  • 6. Brüstle O, Maskos U and McKay RD (1995) Host‐guided migration allows targeted introduction of neurons into the embryonic brain. Neuron 15:1275–1285. [DOI] [PubMed] [Google Scholar]
  • 7. Chang A, Tourtellotte WW, Rudick R and Trapp BD (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 346:165–173. [DOI] [PubMed] [Google Scholar]
  • 8. Coffey JC and McDermott KW (1997) The regional distribution of myelin oligodendrocyte glycoprotein (MOG) in the developing rat CNS: an in vivo immunohistochemical study. J Neurocytol 26:149–161. [DOI] [PubMed] [Google Scholar]
  • 9. Diemel LT, Copelman CA and Cuzner ML (1998) Macrophages in CNS remyelination: friend or foe Neurochem Res 23:341–347. [DOI] [PubMed] [Google Scholar]
  • 10. Duncan ID, Grever WE and Zhang SC (1997) Repair of myelin disease: strategies and progress in animal models. Mol Med Today 3:554–561. [DOI] [PubMed] [Google Scholar]
  • 11. Evans MJ and Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156. [DOI] [PubMed] [Google Scholar]
  • 12. Franceschini IA, Feigenbaum‐Lacombe V, Casanova P, Lopez‐Lastra M, Darlix JL and Dalcq MD (2001) Efficient gene transfer in mouse neural precursors with a bicistronic retroviral vector. J Neurosci Res 65:208–219. [DOI] [PubMed] [Google Scholar]
  • 13. Franklin RJ (2002) Remyelination of the demyelinated CNS: the case for and against transplantation of central, peripheral and olfactory glia. Brain Res Bull 57:827–832. [DOI] [PubMed] [Google Scholar]
  • 14. Franklin RJ, Gilson JM, Franceschini IA and Barnett SC (1996) Schwann cell‐like myelination following transplantation of an olfactory bulb‐ensheathing cell line into areas of demyelination in the adult CNS. Glia 17:217–224. [DOI] [PubMed] [Google Scholar]
  • 15. Groves AK, Barnett SC, Franklin RJ, Crang AJ, Mayer M, Blakemore WF and Noble M (1993) Repair of demyelinated lesions by transplantation of purified O‐2A progenitor cells. Nature 362:453–455. [DOI] [PubMed] [Google Scholar]
  • 16. Hamilton SP and Rome LH (1994) Stimulation of in vitro myelin synthesis by microglia. Glia 11:326–335. [DOI] [PubMed] [Google Scholar]
  • 17. Hörz W and Altenburger W (1981) Nucleotide sequence of mouse satellite DNA. Nucleic Acids Res 9:683–696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Jemmerson R, Klier FG and Fishman WH (1985) Clustered distribution of human placental alkaline phosphatase on the surface of both placental and cancer cells. Electron microscopic observations using gold‐labeled antibodies. J Histochem Cytochem 33:1227–1234. [DOI] [PubMed] [Google Scholar]
  • 19. Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington C, Schmidbauer M and Lassmann H (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157:267–276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Kotter MR, Setzu A, Sim FJ, van Rooijen N and Franklin RJ (2001) Macrophage depletion impairs oligodendrocyte remyelination following lysolecithin‐induced demyelination. Glia 35:204–212. [DOI] [PubMed] [Google Scholar]
  • 21. Lassmann H (2004) Experimental autoimmune encephalomyelitis. In: Myelin Biology and Disorders (Lazzarini R. A., Griffin, J.W. , Lassmann, H , Nave, K.A. , Miller, R.H. and Trapp, B.D. , ed), pp 1040–1071. San Diego , CA , USA : Elsevier. [Google Scholar]
  • 22. Li E, Bestor TH and Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915–926. [DOI] [PubMed] [Google Scholar]
  • 23. Li G, Crang AJ, Rundle JL and Blakemore WF (2002) Oligodendrocyte progenitor cells in the adult rat CNS express myelin oligodendrocyte glycoprotein (MOG). Brain Pathol 12:463–471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Liu S, Qu Y, Stewart TJ, Howard MJ, Chakrabortty S, Holekamp TF and McDonald JW (2000) Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Proc Natl Acad Sci U S A 97:6126–131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Lopez‐Lastra M, Gabus C and Darlix JL (1997) Characterization of an internal ribosomal entry segment within the 5′ leader of avian reticuloen‐dotheliosis virus type A RNA and development of novel MLV‐REV‐based retroviral vectors. Hum Gene Ther 8:1855–1865. [DOI] [PubMed] [Google Scholar]
  • 26. 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Mason JL, Suzuki K, Chaplin DD and Matsushima GK (2001) Interleukin‐1beta promotes repair of the CNS. J Neurosci 21:7046–7052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Nistor GI, Totoiu MO, Haque N, Carpenter MK and Keirstead HS (2005) Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia 49:385–396. [DOI] [PubMed] [Google Scholar]
  • 29. Okabe S, Forsberg‐Nilsson K, Spiro AC, Segal M and McKay RD (1996) Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech Dev 59:89–102. [DOI] [PubMed] [Google Scholar]
  • 30. Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Del Carro U, Amadio S, Bergami A, Furlan R, Comi G, Vescovi AL and Martino G (2003) Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422:688–694. [DOI] [PubMed] [Google Scholar]
  • 31. Prineas JW, Barnard RO, Kwon EE, Sharer LR and Cho ES (1993) Multiple sclerosis: remyelination of nascent lesions. Ann Neurol 33:137–151. [DOI] [PubMed] [Google Scholar]
  • 32. Scolding N, Franklin R, Stevens S, Heldin CH, Compston A and Newcombe J (1998) Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain 121 (Pt 12):2221–2228. [DOI] [PubMed] [Google Scholar]
  • 33. Scolding NJ, Frith S, Linington C, Morgan BP, Campbell AK and Compston DA (1989) Myelin‐oligodendrocyte glycoprotein (MOG) is a surface marker of oligodendrocyte maturation. J Neuroimmunol 22:169–176. [DOI] [PubMed] [Google Scholar]
  • 34. Slavin AJ, Johns TG, Orian JM and Bernard CC (1997) Regulation of myelin oligodendrocyte glycoprotein in different species throughout development. Dev Neurosci 19:69–78. [DOI] [PubMed] [Google Scholar]
  • 35. Solly SK, Thomas JL, Monge M, Demerens C, Lubetzki C, Gardinier MV, Matthieu JM and Zalc B (1996) Myelin/oligodendrocyte glycoprotein (MOG) expression is associated with myelin deposition. Glia 18:39–48. [DOI] [PubMed] [Google Scholar]
  • 36. Storch MK, Stefferl A, Brehm U, Weissert R, Wallstrom E, Kerschensteiner M, Olsson T, Linington C and Lassmann H (1998) Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol 8:681–694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Swiatek PJ and Gridley T (1993) Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20. Genes Dev 7:2071–2084. [DOI] [PubMed] [Google Scholar]
  • 38. Tourbah A, Linnington C, Bachelin C, Avellana‐Adalid V, Wekerle H and Baron‐Van Evercooren A (1997) Inflammation promotes survival and migration of the CG4 oligodendrocyte progenitors transplanted in the spinal cord of both inflammatory and demyelinated EAE rats. J Neurosci Res 50:853–861. [DOI] [PubMed] [Google Scholar]
  • 39. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S and Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285. [DOI] [PubMed] [Google Scholar]
  • 40. Wekerle H, Kojima K, Lannes‐Vieira J, Lassmann H and Linington C (1994) Animal models. Ann Neurol 36 Suppl: S47–53. [DOI] [PubMed] [Google Scholar]
  • 41. Wernig M, Tucker KL, Gornik V, Schneiders A, Buschwald R, Wiestler OD, Barde YA and Brustle O (2002) Tau EGFP embryonic stem cells: an efficient tool for neuronal lineage selection and transplantation. J Neurosci Res 69:918–924. [DOI] [PubMed] [Google Scholar]
  • 42. Windrem MS, Nunes MC, Rashbaum WK, Schwartz TH, Goodman RA, McKhann G, 2nd , Roy NS and Goldman SA (2004) Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain. Nat Med 10:93–97. [DOI] [PubMed] [Google Scholar]
  • 43. Wolswijk G (1998) Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci 18:601–609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Woodruff RH and Franklin RJ (1999) Demyelination and remyelination of the caudal cerebellar peduncle of adult rats following stereotaxic injections of lysolecithin, ethidium bromide, and complement/anti‐galactocerebroside: a comparative study. Glia 25:216–228. [DOI] [PubMed] [Google Scholar]
  • 45. Xian H and Gottlieb DI (2004) Dividing Olig2‐expressing progenitor cells derived from ES cells. Glia 47:88–101. [DOI] [PubMed] [Google Scholar]
  • 46. Xian HQ, McNichols E, Clair A St and Gottlieb DI (2003) A subset of ES‐cell‐derived neural cells marked by gene targeting. Stem Cells 21:41–49. [DOI] [PubMed] [Google Scholar]
  • 47. Zhang SC, Goetz BD and Duncan ID (2003) Suppression of activated microglia promotes survival and function of transplanted oligodendroglial progenitors. Glia 41:191–198. [DOI] [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES