PMID- 15941905 OWN - NLM STAT- MEDLINE DCOM- 20051128 LR - 20210206 IS - 0006-4971 (Print) IS - 1528-0020 (Electronic) IS - 0006-4971 (Linking) VI - 106 IP - 7 DP - 2005 Oct 1 TI - Chemokine-induced recruitment of genetically modified bone marrow cells into the CNS of GM1-gangliosidosis mice corrects neuronal pathology. PG - 2259-68 AB - 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. FAU - Sano, Renata AU - Sano R AD - Department of Genetics and Tumor Cell Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA. FAU - Tessitore, Alessandra AU - Tessitore A FAU - Ingrassia, Angela AU - Ingrassia A FAU - d'Azzo, Alessandra AU - d'Azzo A LA - eng GR - CA 21765/CA/NCI NIH HHS/United States GR - R01-DK52025/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. DEP - 20050607 PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (CXCL12 protein, human) RN - 0 (Chemokine CCL3) RN - 0 (Chemokine CCL4) RN - 0 (Chemokine CXCL12) RN - 0 (Chemokines) RN - 0 (Chemokines, CXC) RN - 0 (Cxcl12 protein, mouse) RN - 0 (Macrophage Inflammatory Proteins) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 63231-63-0 (RNA) RN - EC 3.1.- (Ribonucleases) RN - EC 3.2.1.23 (beta-Galactosidase) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Apoptosis MH - Bone Marrow Cells/cytology/*metabolism MH - Brain/metabolism MH - Calcium/metabolism MH - Cell Movement MH - Cell Proliferation MH - Cell Transplantation MH - Central Nervous System/*metabolism MH - Chemokine CCL3 MH - Chemokine CCL4 MH - Chemokine CXCL12 MH - Chemokines/*metabolism MH - Chemokines, CXC/metabolism MH - Chromatography, Thin Layer MH - Down-Regulation MH - Endoplasmic Reticulum/metabolism MH - Enzyme-Linked Immunosorbent Assay MH - Gangliosidosis, GM1/genetics/*metabolism MH - Genetic Therapy/methods MH - Genetic Vectors MH - Green Fluorescent Proteins/metabolism MH - Humans MH - Immunohistochemistry MH - Inflammation MH - Lysosomes/enzymology MH - Macrophage Inflammatory Proteins/metabolism MH - Mice MH - Mice, Transgenic MH - Microscopy, Fluorescence MH - Neurodegenerative Diseases/pathology MH - Neurons/pathology MH - Protein Folding MH - RNA/chemistry MH - Reverse Transcriptase Polymerase Chain Reaction MH - Ribonucleases/metabolism MH - Time Factors MH - Up-Regulation MH - beta-Galactosidase/metabolism PMC - PMC1895262 EDAT- 2005/06/09 09:00 MHDA- 2005/12/13 09:00 PMCR- 2006/10/01 CRDT- 2005/06/09 09:00 PHST- 2005/06/09 09:00 [pubmed] PHST- 2005/12/13 09:00 [medline] PHST- 2005/06/09 09:00 [entrez] PHST- 2006/10/01 00:00 [pmc-release] AID - S0006-4971(20)67214-7 [pii] AID - 01062259 [pii] AID - 10.1182/blood-2005-03-1189 [doi] PST - ppublish SO - Blood. 2005 Oct 1;106(7):2259-68. doi: 10.1182/blood-2005-03-1189. Epub 2005 Jun 7.