title: Therapeutic effects of normal cells on ABCD1 deficient cells in vitro and hematopoietic cell transplantation in the X-ALD mouse model.
abstract: Bone marrow transplantation (BMT) is accepted as an efficient therapy for X-linked adrenoleukodystrophy (ALD). To clarify the mechanisms of this treatment, we examined the effects of hematopoietic cell transplantation (HCT) in an ATP-binding cassette, subfamily D, member 1 (ABCD1) knock out mice and co-culture of ALD patient fibroblasts with normal cells. We treated ABCD1 knock out mice with HCT using lacZ-transgenic mice as donors, which enabled us to detect donor-derived cells. We also examined the effects of co-culturing a normal microglia cell line (N9) with ALD fibroblasts. beta-Galactosidase (beta-GAL) activity was higher in spleen, lung and kidney than in liver, brain and spinal cord of the recipient ABCD1 knock out mice. HCT reduced the accumulation of very long chain fatty acid (VLCFA) in those tissues. The reduction of the VLCFA ratio was significant in spleen and lung; tissues with higher beta-GAL activity. ABCD1 was detectable in spleen from HCT mice. Co-culture of ALD fibroblasts with normal fibroblast cells reduced VLCFA accumulation in ALD cells. This effect was not observed when the cells were co-cultured while separated by a filter membrane. Our data suggest that supplying normal cells for ABCD1 knockout mouse by HCT corrects metabolic abnormalities in ALD tissues through a cell-mediated process. The correction requires direct cell-to-cell contact for recovering normal cell function.
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamada
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ohyagi
authors.forename: Nobue
authors.initials: N
authors.lastname: Shinnoh
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Manabu
authors.initials: M
authors.lastname: Osoegawa
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ochi
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Kira
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Furuya
mesh_terms: D000326:Adrenoleukodystrophy / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D001773:Blood Cells / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D016026:Bone Marrow Transplantation; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques / Q000379:methods; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007763:Lac Operon; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013154:Spleen / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C515482:CCL22 protein, human; C515483:Ccl22 protein, mouse; D054422:Chemokine CCL22; D019742:Chemokines, CC; D005227:Fatty Acids; D016023:Integrins; D001616:beta-Galactosidase