Accelerated and enhanced effect of CCR5-transduced bone marrow neural stem cells on autoimmune encephalomyelitis

Acta Neuropathol. 2012 Oct;124(4):491-503. doi: 10.1007/s00401-012-0989-1. Epub 2012 Apr 22.

Abstract

The suppressive effect of neural stem cells (NSCs) on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), has been reported. However, the migration of NSCs to inflammatory sites was relatively slow as was the onset of rather limited clinical benefit. Lack of, or low expression of particular chemokine receptors on NSCs could be an important factor underlying the slow migration of NSCs. To enhance the therapeutic effect of NSCs, in the present study we transduced bone marrow (BM)-derived NSCs with CCR5, a receptor for CCL3, CCL4, and CCL5, chemokines that are abundantly produced in CNS-inflamed foci of MS/EAE. After i.v. injection, CCR5-NSCs rapidly reached EAE foci in larger numbers, and more effectively suppressed CNS inflammatory infiltration, myelin damage, and clinical EAE than GFP-NSCs used as controls. CCR5-NSC-treated mice also exhibited augmented remyelination and neuron/oligodendrocyte repopulation compared to PBS- or GFP-NSC-treated mice. We inferred that the critical mechanism underlying enhanced effect of CCR5-transduced NSCs on EAE is the early migration of chemokine receptor-transduced NSCs into the inflamed foci. Such migration at an earlier stage of inflammation enables NSCs to exert more effective immunomodulation, to reduce the extent of early myelin/neuron damage by creating a less hostile environment for remyelinating cells, and possibly to participate in the remyelination/neural repopulation process. These features of BM-derived transduced NSCs, combined with their easy availability (the subject's own BM) and autologous properties, may lay the groundwork for an innovative approach to rapid and highly effective MS therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism*
  • Cell Differentiation / immunology
  • Chemotaxis, Leukocyte / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Immunohistochemistry
  • Immunomodulation
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Electron, Transmission
  • Neural Stem Cells / cytology
  • Neural Stem Cells / immunology
  • Neural Stem Cells / metabolism*
  • Receptors, CCR5 / immunology*
  • Receptors, CCR5 / metabolism
  • Transduction, Genetic

Substances

  • Receptors, CCR5