Transplanted neural precursor cells reduce brain inflammation to attenuate chronic experimental autoimmune encephalomyelitis

Abstract

Stem cell transplantation was introduced as a mean of cell replacement therapy, but the mechanism by which it confers clinical improvement in experimental models of neurological diseases is not clear. Here, we transplanted neural precursor cells (NPCs) into the ventricles of mice at day 6 after induction of chronic experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Transplanted cells migrated into white matter tracts and attenuated the clinical course of disease. NPC transplantation down-regulated the inflammatory brain process at the acute phase of disease, as indicated by a reduction in the number of perivascular infiltrates and of brain CD3+ T cells, an increase in the number and proportion of regulatory T cells and a reduction in the expression of ICAM-1 and LFA-1 in the brain. Demyelination and acute axonal injury in this model are considered to result mainly from the acute inflammatory process and correlate well with the chronic neurological residua. In consequence to inhibition of brain inflammation, precursor cell transplantation attenuated the primary demyelinating process and reduced the acute axonal injury. As a result, the size of demyelinated areas and extent of chronic axonal pathology were reduced in the transplanted brains. We suggest that the beneficial effect of transplanted NPCs in chronic EAE is mediated, in part, by decreasing brain inflammation and reducing tissue injury.

Introduction

Neural (stem) cell transplantation has been proposed as a means of cell replacement therapy for diseases of the central nervous system (CNS). Transplanted neural precursors of various origins improved the clinical outcome in experimental models of stroke (Veizovic et al., 2001), spinal cord trauma (McDonald et al., 1999) and multiple sclerosis (MS) (Pluchino et al., 2003). Although transplanted myelin-forming cells have remarkable remyelinating properties, resulting in restoration of electrophysiological nerve function (Milward et al., 1997), the mechanisms by which transplanted cells exert a beneficial clinical effect in chronic experimental autoimmune encephalomyelitis (EAE), the animal model of MS, are not clear. Cell-mediated immunity against myelin antigens, inducing demyelination and axonal injury, is a major factor in the pathogenesis of MS and EAE. In MS, the general failure of endogenous remyelination (Franklin, 2002) and inflammation-related axonal pathology (Kornek et al., 2000, Trapp et al., 1998) lead to accumulated neurological disability (Ferguson et al., 1997, Lovas et al., 2000). We have recently shown that neurosphere transplantation inhibited the clinical and pathological features of acute EAE, a model for disseminated brain inflammation with a minor demyelinating component (Einstein et al., 2003). We therefore hypothesized that the beneficial effects of transplanted cells in chronic EAE may be mediated, in part, by attenuation of the inflammatory brain process, leading to reduction in tissue injury. Here, we transplanted NPCs intracerebroventricularly (ICV) into C57Bl/6 mice with the MOG35–55 EAE model. In this model, the acute inflammation-mediated demyelination and axonal injury lead to a chronic clinical course of disability. We examined whether transplanted precursor cells inhibit the acute detrimental inflammatory brain process, leading to reduced demyelination and axonal injury and to improvement in the clinical outcome.