Chemokine-induced recruitment of genetically modified bone marrow cells into the CNS of GM1-gangliosidosis mice corrects neuronal pathology

Abstract

IntroductionChemokines comprise a family of about 50 small protein ligands that together with their cognate receptors control leukocyte trafficking during immune surveillance and inflammatory-cell recruitment during host defense. [1][2][3] Besides their known function in the immune system, these molecules have also been implicated in the maintenance of central nervous system (CNS) homeostasis and as a mediator of neuroinflammation. [4][5][6][7][8] Two types of interactions primarily control the activity of chemokines in the CNS. The first involves chemokine immobilization by glycosaminoglycans (GAGs), which play a role in the formation of chemokine gradients and trigger localization of leukocyte subpopulations to the site of infection or injury, present at the endothelial surface and the extracellular matrix. 9,10 The other interaction entails the tight binding of chemokines to their G-protein-coupled receptors on the surface of leukocytes; this binding activates integrins and promotes their adhesion to the endothelium, followed by their penetration across the endothelial layer into the CNS perivascular space. [11][12][13][14][15] In the CNS, chemokines are expressed constitutively at low or negligible levels in astrocytes and microglia, but their expression is rapidly induced by neuroinflammatory conditions [16][17][18] and is mediated by several proinflammatory cytokines (eg, tumor necrosis factor ␣ [TNF-␣], interferon ␥ [IFN-␥], and tumor growth factor ␤1 [TGF-␤1]). [19][20][21][22] CNS inflammation occurs in several neurodegenerative conditions, including those associated with a lysosomal storage disease (LSD), [23][24] and is likely responsible for the recruitment of monocytes and macrophages from peripheral blood. In the murine model of the LSD, G M2 -gangliosidosis recruitment of macrophages into the CNS is mediated by the chemokine macrophage inflammatory protein 1-␣ (MIP-1␣) and has been implicated in the pathogenesis of this disease. 25 Genetic defects that alter ␤-galactosidase (␤-gal) activity in humans have a devastating effect on the CNS and result in the neurodegenerative LSD G M1 -gangliosidosis. 26 The clinical phenotypes of this disease demonstrate a continuum of severity: (1) Infantile G M1 -gangliosidosis progresses rapidly; developmental arrest occurs soon after birth; and symptoms include profound neurologic deterioration, psychomotor retardation, visceromegaly, and cardiac involvement. Death due to infection or cardiac failure occurs normally within the second year of life. (2) Late-infantile/ juvenile G M1 -gangliosidosis includes little or no systemic organ involvement, but neurologic problems, ataxia, and seizures develop generally soon after the onset of the symptoms. (3) Chronic G M1 -gangliosidosis manifests as slow, progressive dementia, Parkinsonian features, and extrapyramidal signs. At the cellular level, G M1 -gangliosidosis affects primarily neurons, which become distended and fill with membranous cytoplasmic bodies, but astrocytes and microglia also appear vacuolated. Abnormal...

Gene therapy for the neurological manifestations in lysosomal storage disorders

“…Subsequent studies using more effi cient lentiviral-based vectors that transduced a greater number of the donor hematopoietic stem cells and that resulted in the secretion of higher levels of the enzyme (i.e., arylsulfatase A) completely prevented the development of neuropathology and behavioral abnormalities in mice ( 141,151 ). Similar encouraging results were obtained in mouse models of other LSDs including MPS I, MPS IIIA, globoid cell leukodystrophy, and GM1 gangliosidosis ( 142,(152)(153)(154)(155). In addition to the correction of the neurological disease, transplantation of gene-modifi ed donor cells also provided an additional benefi t of addressing the visceral components of the disease.…”

Invasion of Hematopoietic Cells into the Brain of Amyloid Precursor Protein Transgenic Mice

“…Therefore, it remains to be evaluated whether these cells are causal, contributory, or sequels of the disease process. However, the fact that they invade and associate with the amyloid plaques, together with their easy accessibility and genetic manipulation, makes them interesting as a therapeutic vehicle for targeted intervention (Priller et al, 2001), which recently has been demonstrated successfully for a lysosomal storage disease (Sano et al, 2005). Harnessed with an amyloid-degrading enzyme or an immune modulator, autologous bone marrow-derived cells may offer a potent, targeted therapeutic strategy of clearing amyloid deposition and/or reducing amyloid-associated neurodegeneration.…”

CXCR4 signaling in the regulation of stem cell migration and development

“…It has even been demonstrated that CXCR4 expressing mesenchymal stem cells can enter the brain following stroke (Hill et al, 2004) or under other circumstances (Sano et al, 2005). Indeed, a population of CXCR4 expressing cells that also express neuronal markers such as nestin, have been observed in the BM and are mobilized into the blood in response to stroke .…”