title: Chemokine-induced recruitment of genetically modified bone marrow cells into the CNS of GM1-gangliosidosis mice corrects neuronal pathology.
abstract: Bone marrow cells (BMCs) could correct some pathologic conditions of the central nervous system (CNS) if these cells would effectively repopulate the brain. One such condition is G(M1)-gangliosidosis, a neurodegenerative glycosphingolipidosis due to deficiency of lysosomal beta-galactosidase (beta-gal). In this disease, abnormal build up of G(M1)-ganglioside in the endoplasmic reticulum of brain cells results in calcium imbalance, induction of an unfolded protein response (UPR), and neuronal apoptosis. These processes are accompanied by the activation/proliferation of microglia and the production of inflammatory cytokines. Here we demonstrate that local neuroinflammation promotes the selective activation of chemokines, such as stromal-cell-derived factor 1 (SDF-1), macrophage inflammatory protein 1-alpha (MIP-1alpha), and MIP-1beta, which chemoattract genetically modified BMCs into the CNS. Mice that underwent bone marrow transplantation showed increased beta-gal activity in different brain regions and reduced lysosomal storage. Decreased production of chemokines and effectors of the UPR as well as restoration of neurologic functions accompanied this phenotypic reversion. Our results suggest that beta-gal-expressing bone marrow (BM)-derived cells selectively migrate to the CNS under a gradient of chemokines and become a source of correcting enzyme to deficient neurons. Thus, a disease condition such as G(M1)-gangliosidosis, which is characterized by neurodegeneration and neuroinflammation, may influence the response of the CNS to ex vivo gene therapy.
authors.affiliation: Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Renata
authors.initials: R
authors.lastname: Sano
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tessitore
authors.forename: Angela
authors.initials: A
authors.lastname: Ingrassia
authors.forename: Alessandra
authors.initials: A
authors.lastname: d'Azzo
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D017690:Cell Transplantation; D002490:Central Nervous System / Q000378:metabolism*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054377:Chemokine CXCL12; D018925:Chemokines / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism; D002855:Chromatography, Thin Layer; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D016537:Gangliosidosis, GM1 / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008247:Lysosomes / Q000201:enzymology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D019636:Neurodegenerative Diseases / Q000473:pathology; D009474:Neurons / Q000473:pathology; D017510:Protein Folding; D012313:RNA / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019402:Macrophage Inflammatory Proteins; D049452:Green Fluorescent Proteins; D012313:RNA; D012260:Ribonucleases; D001616:beta-Galactosidase; D002118:Calcium