title: Stem cell factor-activated bone marrow ameliorates amyotrophic lateral sclerosis by promoting protective microglial migration.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive disease associated with motor neuron death. Several experimental treatments, including cell therapy using hematopoietic or neuronal stem cells, have been tested in ALS animal models, but therapeutic benefits have been modest. Here we used a new therapeutic strategy, bone marrow transplantation (BMT) with stem cell factor (SCF)- or FMS-like tyrosine kinase 3 (flt3)-activated bone marrow (BM) cells for the treatment of hSOD1(G93A) transgenic mice. Motor function and survival showed greater improvement in the SCF group than in the group receiving BM cells that had not been activated (BMT alone group), although no improvement was shown in the flt3 group. In addition, larger numbers of BM-derived cells that expressed the microglia marker Iba1 migrated to the spinal cords of recipient mice compared with the BMT alone group. Moreover, after SCF activation, but not flt3 activation or no activation, the migrating microglia expressed glutamate transporter-1 (GLT-1). In spinal cords in the SCF group, inflammatory cytokines tumor necrosis factor-α and interleukin-1β were suppressed and the neuroprotective molecule insulin-like growth factor-1 increased relative to nontreatment hSOD1(G93A) transgenic mice. Therefore, SCF activation changed the character of the migrating donor BM cells, which resulted in neuroprotective effects. These studies have identified SCF-activated BM cells as a potential new therapeutic agent for the treatment of ALS.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Terashima
authors.forename: Hideto
authors.initials: H
authors.lastname: Kojima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Urabe
authors.forename: Isamu
authors.initials: I
authors.lastname: Yamakawa
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ogawa
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Kawai
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000502:physiology; D045442:Rotarod Performance Test; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D019089:Stem Cell Factor / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000627:therapeutic use; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D019089:Stem Cell Factor; D013482:Superoxide Dismutase; D051941:fms-Like Tyrosine Kinase 3; C491049:Aif1 protein, mouse; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C489787:MAP2 protein, rat; C109415:SOD1 G93A protein