title: Disease progression after bone marrow transplantation in a model of multiple sclerosis is associated with chronic microglial and glial progenitor response.
abstract: Multiple sclerosis (MS), the most common nontraumatic cause of neurologic disability in young adults in economically developed countries, is characterized by inflammation, gliosis, demyelination, and neuronal degeneration in the CNS. Bone marrow transplantation (BMT) can suppress inflammatory disease in a majority of patients with MS but retards clinical progression only in patients treated in the early stages of the disease. Here, we applied BMT in a mouse model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE), and investigated the kinetics of reconstitution of the immune system in the periphery and in the CNS using bone marrow cells isolated from syngeneic donors constitutively expressing green fluorescent protein. This approach allowed us to dissect the contribution of donor cells to the turnover of resident microglia and to the pathogenesis of observed disease relapses after BMT. BMT effectively blocked or delayed EAE development when mice were treated early in the course of the disease but was without effect in mice with chronic disease. We found that there is minimal overall replacement of host microglia with donor cells in the CNS and that newly transplanted cells do not appear to contribute to disease progression. In contrast, EAE relapses are accompanied by the robust activation of endogenous microglial and macroglial cells, which further involves the maturation of endogenous Olig2 glial progenitor cells into reactive astrocytes through the cytoplasmic translocation of Olig2 and the expression of CD44 on the cellular membrane. The observed maturation of large numbers of reactive astrocytes from glial progenitors and the chronic activation of host microglial cells have relevance for our understanding of the resident glial response to inflammatory injury in the CNS. Our data indicate that reactivation of a local inflammatory process after BMT is sustained predominantly by endogenous microglia/macrophages.
authors.affiliation: Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. cassianiingoni@gmail.com
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cassiani-Ingoni
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Muraro
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
authors.forename: Susan
authors.initials: S
authors.lastname: Reichert-Scrivner
authors.forename: Jens
authors.initials: J
authors.lastname: Schmidt
authors.forename: Jaebong
authors.initials: J
authors.lastname: Huh
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Quandt
authors.forename: Andras
authors.initials: A
authors.lastname: Bratincsak
authors.forename: Tal
authors.initials: T
authors.lastname: Shahar
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Eusebi
authors.forename: Larry S
authors.initials: LS
authors.lastname: Sherman
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
authors.forename: Mahendra S
authors.initials: MS
authors.lastname: Rao
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods*; D001921:Brain / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000473:pathology / Q000601:surgery; D005434:Flow Cytometry / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006023:Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000502:physiology*; D009103:Multiple Sclerosis / Q000473:pathology* / Q000601:surgery*; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D010446:Peptide Fragments; D013116:Spinal Cord / Q000473:pathology; D013234:Stem Cells / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D010446:Peptide Fragments; C512773:Olig2 protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55)