Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitor Cell Transplants Remyelinate and Restore Locomotion after Spinal Cord Injury

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.

[1]  H. Keirstead,et al.  Spinal cord injury is accompanied by chronic progressive demyelination , 2005, The Journal of comparative neurology.

[2]  M. Carpenter,et al.  Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation , 2005, Glia.

[3]  Robert A Pearce,et al.  Specification of motoneurons from human embryonic stem cells , 2005, Nature Biotechnology.

[4]  H. Keirstead,et al.  Remyelination, axonal sparing, and locomotor recovery following transplantation of glial-committed progenitor cells into the MHV model of multiple sclerosis , 2004, Experimental Neurology.

[5]  C. Fages,et al.  Absence of correlations between glutamine-synthetase activity and dysmyelination-associated modifications of astroglia in the brain of murine mutants , 1986, Neurochemical Research.

[6]  H. Keirstead,et al.  Reducing inflammation decreases secondary degeneration and functional deficit after spinal cord injury , 2003, Experimental Neurology.

[7]  R. McKay,et al.  Dopaminergic neuronal differentiation from rat embryonic neural precursors by Nurr1 overexpression , 2003, Journal of neurochemistry.

[8]  M. Tuszynski,et al.  Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury , 2003, Experimental Neurology.

[9]  W. Blakemore,et al.  Schwann cell remyelination is not replaced by oligodendrocyte remyelination following ethidium bromide induced demyelination , 2002, Neuroreport.

[10]  M. Götz,et al.  Glial cells generate neurons: the role of the transcription factor Pax6 , 2002, Nature Neuroscience.

[11]  R. Nashmi,et al.  Mechanisms of axonal dysfunction after spinal cord injury: with an emphasis on the role of voltage-gated potassium channels , 2001, Brain Research Reviews.

[12]  M. Rao,et al.  Enrichment of Neurons and Neural Precursors from Human Embryonic Stem Cells , 2001, Experimental Neurology.

[13]  Benjamin E. Reubinoff,et al.  Neural progenitors from human embryonic stem cells , 2001, Nature Biotechnology.

[14]  Marius Wernig,et al.  In vitro differentiation of transplantable neural precursors from human embryonic stem cells , 2001, Nature Biotechnology.

[15]  H. Okano,et al.  High-yield selection and extraction of two promoter-defined phenotypes of neural stem cells from the fetal human brain , 2001, Nature Biotechnology.

[16]  R. McKay,et al.  Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells , 2000, Nature Biotechnology.

[17]  T. Holekamp,et al.  Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Berry,et al.  Oligodendrocytes and the control of myelination in vivo: new insights from the rat anterior medullary velum , 2000, Journal of neuroscience research.

[19]  J. Reig,et al.  Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice. , 2000, Diabetes.

[20]  J. Mcdonald,et al.  Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord , 1999, Nature Medicine.

[21]  T. Ben-Hur,et al.  Polysialylated Neural Cell Adhesion Molecule-Positive CNS Precursors Generate Both Oligodendrocytes and Schwann Cells to Remyelinate the CNS after Transplantation , 1999, The Journal of Neuroscience.

[22]  V. Dietz.  The applied neuropathology of human spinal cord injury. , 1999, Spinal cord.

[23]  R. McKay,et al.  Embryonic stem cell-derived glial precursors: a source of myelinating transplants. , 1999, Science.

[24]  A. Crang,et al.  Behavioural consequences of oligodendrocyte progenitor cell transplantation into experimental demyelinating lesions in the rat spinal cord , 1999, The European journal of neuroscience.

[25]  E. Couve,et al.  Dysmyelination, demyelination and reactive astrogliosis in the optic nerve of the taiep rat. , 1999, Biological research.

[26]  K. Suzuki,et al.  Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice , 1998, Journal of Neuroimmunology.

[27]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[28]  G. Rougon,et al.  Growth and Fate of PSA-NCAM+ Precursors of the Postnatal Brain , 1998, The Journal of Neuroscience.

[29]  T. Deacon,et al.  Blastula-Stage Stem Cells Can Differentiate into Dopaminergic and Serotonergic Neurons after Transplantation , 1998, Experimental Neurology.

[30]  R. McKay,et al.  In vitro-generated neural precursors participate in mammalian brain development. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  W. Blakemore,et al.  Locomotor deficits induced by experimental spinal cord demyelination are abolished by spontaneous remyelination. , 1997, Brain : a journal of neurology.

[32]  J. Bresnahan,et al.  Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys , 1997, Nature Medicine.

[33]  M. Segal,et al.  Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro , 1996, Mechanisms of Development.

[34]  Moses Rodriguez,et al.  Distinct Patterns of Multiple Sclerosis Pathology Indicates Heterogeneity in Pathogenesis , 1996, Brain pathology.

[35]  G. Koh,et al.  Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts. , 1996, The Journal of clinical investigation.

[36]  D. Basso,et al.  A sensitive and reliable locomotor rating scale for open field testing in rats. , 1995, Journal of neurotrauma.

[37]  S. Waxman,et al.  Transplantation of glial cells enhances action potential conduction of amyelinated spinal cord axons in the myelin-deficient rat. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[38]  S. Waxman,et al.  Chapter 29 Enhancement of action potential conduction following demyelination: experimental approaches to restoration of function in multiple sclerosis and spinal cord injury , 1994 .

[39]  S. Waxman,et al.  Enhancement of action potential conduction following demyelination: experimental approaches to restoration of function in multiple sclerosis and spinal cord injury. , 1994, Progress in brain research.

[40]  R. Quencer,et al.  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. , 1993, Advances in neurology.

[41]  B. Engelhardt,et al.  Induction of persistently demyelinated lesions in the rat following the repeated adoptive transfer of encephalitogenic T cells and demyelinating antibody , 1992, Journal of Neuroimmunology.

[42]  C. Raine,et al.  Multiple sclerosis. Interactions between oligodendrocytes and hypertrophic astrocytes and their occurrence in other, nondemyelinating conditions. , 1992, Laboratory investigation; a journal of technical methods and pathology.

[43]  G. Keller,et al.  Multiple hematopoietic lineages develop from embryonic stem (ES) cells in culture. , 1991, Development.

[44]  G. M. Hope,et al.  Spectra of G ratio, myelin sheath thickness, and axon and fiber diameter in the guinea pig optic nerve , 1989, The Journal of comparative neurology.

[45]  D. Silberberg,et al.  Optic nerve demyelination induced by human serum , 1985, Neurology.

[46]  R. Herndon,et al.  Effect of macrophage inactivation on the neuropathology of lysolecithin-induced demyelination. , 1985, British journal of experimental pathology.

[47]  A. Blight.  Delayed demyelination and macrophage invasion: a candidate for secondary cell damage in spinal cord injury. , 1985, Central nervous system trauma : journal of the American Paralysis Association.

[48]  A. Blight,et al.  Cellular morphology of chronic spinal cord injury in the cat: Analysis of myelinated axons by line-sampling , 1983, Neuroscience.

[49]  W. Mcdonald,et al.  Central remyelination restores secure conduction , 1979, Nature.

[50]  C. Hildebrand,et al.  Relation between myelin sheath thickness and axon size in spinal cord white matter of some vertebrate species , 1978, Journal of the Neurological Sciences.

[51]  W. Mcdonald,et al.  Demyelination and remyelination after acute spinal cord compression. , 1973, Experimental neurology.