Home LiteratureArticle Details
PMID: 15888645 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 25 ·No. 19 ·2005-05-11 ·Pages 4694-705

Keirstead HS, Nistor G, Bernal G, Totoiu M, Cloutier F, Sharp K, Steward O

Abstract

Demyelination contributes to loss of function after spinal cord injury, and thus a potential therapeutic strategy involves replacing myelin-forming cells. Here, we show that transplantation of human embryonic stem cell (hESC)-derived oligodendrocyte progenitor cells (OPCs) into adult rat spinal cord injuries enhances remyelination and promotes improvement of motor function. OPCs were injected 7 d or 10 months after injury. In both cases, transplanted cells survived, redistributed over short distances, and differentiated into oligodendrocytes. Animals that received OPCs 7 d after injury exhibited enhanced remyelination and substantially improved locomotor ability. In contrast, when OPCs were transplanted 10 months after injury, there was no enhanced remyelination or locomotor recovery. These studies document the feasibility of predifferentiating hESCs into functional OPCs and demonstrate their therapeutic potential at early time points after spinal cord injury.

MeSH Terms
Animals Basic Helix-Loop-Helix Transcription Factors/metabolism Bromodeoxyuridine/metabolism Cell Count/methods Cell Differentiation/physiology Cells, Cultured DNA-Binding Proteins/metabolism Disease Models, Animal Female Fibroblasts/physiology Glial Fibrillary Acidic Protein/metabolism High Mobility Group Proteins/metabolism Humans Imaging, Three-Dimensional/methods Immunohistochemistry/methods Locomotion/physiology Myelin Sheath/physiology Nerve Tissue Proteins/metabolism Oligodendroglia/physiology,transplantation Oligopeptides/metabolism Phosphopyruvate Hydratase/metabolism Rats Rats, Sprague-Dawley Recovery of Function/physiology SOXE Transcription Factors Spinal Cord Injuries/pathology,physiopathology,therapy Stem Cell Transplantation Time Factors Transcription Factors/metabolism
Chemicals
Basic Helix-Loop-Helix Transcription Factors DNA-Binding Proteins Glial Fibrillary Acidic Protein High Mobility Group Proteins Nerve Tissue Proteins Olig1 protein, rat Oligopeptides RNAIII inhibiting peptide SOX10 protein, human SOXE Transcription Factors Sox10 protein, rat Transcription Factors Phosphopyruvate Hydratase Bromodeoxyuridine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Keirstead Hans S
Department of Anatomy and Neurobiology, Reeve-Irvine Research Center, College of Medicine, University of California at Irvine, Irvine, California 92697-4292, USA. [email protected]
Nistor Gabriel
Bernal Giovanna
Totoiu Minodora
Cloutier Frank
Sharp Kelly
Steward Oswald
References (51)
51 references, click to expand
  1. The applied neuropathology of human spinal cord injury.
    Spinal Cord. 1999 Feb;37(2):79-88 PMID: 10065745
  2. Behavioural consequences of oligodendrocyte progenitor cell transplantation into experimental demyelinating lesions in the rat spinal cord.
    Eur J Neurosci. 1999 May;11(5):1508-14 PMID: 10215903
  3. Embryonic stem cell-derived glial precursors: a source of myelinating transplants.
    Science. 1999 Jul 30;285(5428):754-6 PMID: 10427001
  4. Polysialylated neural cell adhesion molecule-positive CNS precursors generate both oligodendrocytes and Schwann cells to remyelinate the CNS after transplantation.
    J Neurosci. 1999 Sep 1;19(17):7529-36 PMID: 10460259
  5. Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord.
    Nat Med. 1999 Dec;5(12):1410-2 PMID: 10581084
  6. Oligodendrocytes and the control of myelination in vivo: new insights from the rat anterior medullary velum.
    J Neurosci Res. 2000 Feb 15;59(4):477-88 PMID: 10679786
  7. Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation.
    Proc Natl Acad Sci U S A. 2000 May 23;97(11):6126-31 PMID: 10823956
  8. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells.
    Nat Biotechnol. 2000 Jun;18(6):675-9 PMID: 10835609
  9. Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice.
    Diabetes. 2000 Feb;49(2):157-62 PMID: 10868930
  10. Dysmyelination, demyelination and reactive astrogliosis in the optic nerve of the taiep rat.
    Biol Res. 1999;32(4):253-62 PMID: 10983245
  11. High-yield selection and extraction of two promoter-defined phenotypes of neural stem cells from the fetal human brain.
    Nat Biotechnol. 2001 Sep;19(9):843-50 PMID: 11533643
  12. Enrichment of neurons and neural precursors from human embryonic stem cells.
    Exp Neurol. 2001 Dec;172(2):383-97 PMID: 11716562
  13. In vitro differentiation of transplantable neural precursors from human embryonic stem cells.
    Nat Biotechnol. 2001 Dec;19(12):1129-33 PMID: 11731781
  14. Neural progenitors from human embryonic stem cells.
    Nat Biotechnol. 2001 Dec;19(12):1134-40 PMID: 11731782
  15. Mechanisms of axonal dysfunction after spinal cord injury: with an emphasis on the role of voltage-gated potassium channels.
    Brain Res Brain Res Rev. 2001 Dec;38(1-2):165-91 PMID: 11750932
  16. Glial cells generate neurons: the role of the transcription factor Pax6.
    Nat Neurosci. 2002 Apr;5(4):308-15 PMID: 11896398
  17. Schwann cell remyelination is not replaced by oligodendrocyte remyelination following ethidium bromide induced demyelination.
    Neuroreport. 2002 Jul 2;13(9):1205-8 PMID: 12151770
  18. Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury.
    Exp Neurol. 2003 Jun;181(2):115-29 PMID: 12781986
  19. Dopaminergic neuronal differentiation from rat embryonic neural precursors by Nurr1 overexpression.
    J Neurochem. 2003 Jun;85(6):1443-54 PMID: 12787064
  20. Induction of persistently demyelinated lesions in the rat following the repeated adoptive transfer of encephalitogenic T cells and demyelinating antibody.
    J Neuroimmunol. 1992 Oct;40(2-3):219-24 PMID: 1385471
  21. Reducing inflammation decreases secondary degeneration and functional deficit after spinal cord injury.
    Exp Neurol. 2003 Nov;184(1):456-63 PMID: 14637115
  22. Remyelination, axonal sparing, and locomotor recovery following transplantation of glial-committed progenitor cells into the MHV model of multiple sclerosis.
    Exp Neurol. 2004 Jun;187(2):254-65 PMID: 15144852
  23. Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation.
    Glia. 2005 Feb;49(3):385-96 PMID: 15538751
  24. Specification of motoneurons from human embryonic stem cells.
    Nat Biotechnol. 2005 Feb;23(2):215-21 PMID: 15685164
  25. Spinal cord injury is accompanied by chronic progressive demyelination.
    J Comp Neurol. 2005 Jun 13;486(4):373-83 PMID: 15846782
  26. Multiple sclerosis. Interactions between oligodendrocytes and hypertrophic astrocytes and their occurrence in other, nondemyelinating conditions.
    Lab Invest. 1992 Jul;67(1):88-99 PMID: 1625450
  27. Multiple hematopoietic lineages develop from embryonic stem (ES) cells in culture.
    Development. 1991 Feb;111(2):259-67 PMID: 1893864
  28. Spectra of G ratio, myelin sheath thickness, and axon and fiber diameter in the guinea pig optic nerve.
    J Comp Neurol. 1989 Sep 22;287(4):446-54 PMID: 2794129
  29. Absence of correlations between glutamine-synthetase activity and dysmyelination-associated modifications of astroglia in the brain of murine mutants.
    Neurochem Res. 1986 Apr;11(4):527-33 PMID: 2873519
  30. Relation between myelin sheath thickness and axon size in spinal cord white matter of some vertebrate species.
    J Neurol Sci. 1978 Oct;38(3):421-34 PMID: 310448
  31. Delayed demyelination and macrophage invasion: a candidate for secondary cell damage in spinal cord injury.
    Cent Nerv Syst Trauma. 1985 Winter;2(4):299-315 PMID: 3836014
  32. Effect of macrophage inactivation on the neuropathology of lysolecithin-induced demyelination.
    Br J Exp Pathol. 1985 Jun;66(3):293-301 PMID: 4005147
  33. Optic nerve demyelination induced by human serum: patients with multiple sclerosis or optic neuritis and normal subjects.
    Neurology. 1985 Oct;35(10):1438-42 PMID: 4033926
  34. Central remyelination restores secure conduction.
    Nature. 1979 Aug 2;280(5721):395-6 PMID: 460414
  35. Demyelination and remyelination after acute spinal cord compression.
    Exp Neurol. 1973 Mar;38(3):472-87 PMID: 4696114
  36. Cellular morphology of chronic spinal cord injury in the cat: analysis of myelinated axons by line-sampling.
    Neuroscience. 1983 Oct;10(2):521-43 PMID: 6633870
  37. A sensitive and reliable locomotor rating scale for open field testing in rats.
    J Neurotrauma. 1995 Feb;12(1):1-21 PMID: 7783230
  38. Enhancement of action potential conduction following demyelination: experimental approaches to restoration of function in multiple sclerosis and spinal cord injury.
    Prog Brain Res. 1994;100:233-43 PMID: 7938524
  39. Transplantation of glial cells enhances action potential conduction of amyelinated spinal cord axons in the myelin-deficient rat.
    Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):53-7 PMID: 8278406
  40. Observations on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination.
    Adv Neurol. 1993;59:75-89 PMID: 8420126
  41. Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts.
    J Clin Invest. 1996 Jul 1;98(1):216-24 PMID: 8690796
  42. Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis.
    Brain Pathol. 1996 Jul;6(3):259-74 PMID: 8864283
  43. Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro.
    Mech Dev. 1996 Sep;59(1):89-102 PMID: 8892235
  44. Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys.
    Nat Med. 1997 Jan;3(1):73-6 PMID: 8986744
  45. Locomotor deficits induced by experimental spinal cord demyelination are abolished by spontaneous remyelination.
    Brain. 1997 Jan;120 ( Pt 1):27-37 PMID: 9055795
  46. The Norton Lecture: a review of the oligodendrocyte in the multiple sclerosis lesion.
    J Neuroimmunol. 1997 Aug;77(2):135-52 PMID: 9258244
  47. In vitro-generated neural precursors participate in mammalian brain development.
    Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14809-14 PMID: 9405695
  48. Blastula-stage stem cells can differentiate into dopaminergic and serotonergic neurons after transplantation.
    Exp Neurol. 1998 Jan;149(1):28-41 PMID: 9454612
  49. Growth and fate of PSA-NCAM+ precursors of the postnatal brain.
    J Neurosci. 1998 Aug 1;18(15):5777-88 PMID: 9671666
  50. Embryonic stem cell lines derived from human blastocysts.
    Science. 1998 Nov 6;282(5391):1145-7 PMID: 9804556
  51. Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice.
    J Neuroimmunol. 1998 Dec 1;92(1-2):38-49 PMID: 9916878
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.0311-05.2005
Email
[email protected]
Published
2005-05-11
Pages
4694-705
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6724772
Subset
IM
External Links
PubMed source DOI: 10.1523/JNEUROSCI.0311-05.2005 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2