Disease progression after bone marrow transplantation in a model of multiple sclerosis is associated with chronic microglial and glial progenitor response

Riccardo Cassiani-Ingoni, Paolo A. Muraro, Tim Magnus, Susan Reichert-Scrivner, Jens Schmidt, Jaebong Huh, Jacqueline A. Quandt, Andras Bratincsak, Tal Shahar, Fabrizio Eusebi, Lawrence (Larry) Sherman, Mark P. Mattson, Roland Martin, Mahendra S. Rao

    Research output: Contribution to journalArticle

    33 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)637-649
    Number of pages13
    JournalJournal of Neuropathology and Experimental Neurology
    Volume66
    Issue number7
    DOIs
    StatePublished - Jul 2007

    Fingerprint

    Bone Marrow Transplantation
    Neuroglia
    Multiple Sclerosis
    Disease Progression
    Autoimmune Experimental Encephalomyelitis
    Microglia
    Tissue Donors
    Astrocytes
    Recurrence
    Gliosis
    Demyelinating Diseases
    Green Fluorescent Proteins
    Developed Countries
    Bone Marrow Cells
    Nervous System
    Young Adult
    Immune System
    Chronic Disease
    Stem Cells
    Macrophages

    Keywords

    • Autoimmune disease
    • Bone marrow transplantation
    • CD44
    • Glial progenitor
    • Microglia
    • Olig2
    • Reactive astrocyte

    ASJC Scopus subject areas

    • Pathology and Forensic Medicine
    • Neuroscience(all)

    Cite this

    Disease progression after bone marrow transplantation in a model of multiple sclerosis is associated with chronic microglial and glial progenitor response. / Cassiani-Ingoni, Riccardo; Muraro, Paolo A.; Magnus, Tim; Reichert-Scrivner, Susan; Schmidt, Jens; Huh, Jaebong; Quandt, Jacqueline A.; Bratincsak, Andras; Shahar, Tal; Eusebi, Fabrizio; Sherman, Lawrence (Larry); Mattson, Mark P.; Martin, Roland; Rao, Mahendra S.

    In: Journal of Neuropathology and Experimental Neurology, Vol. 66, No. 7, 07.2007, p. 637-649.

    Research output: Contribution to journalArticle

    Cassiani-Ingoni, R, Muraro, PA, Magnus, T, Reichert-Scrivner, S, Schmidt, J, Huh, J, Quandt, JA, Bratincsak, A, Shahar, T, Eusebi, F, Sherman, LL, Mattson, MP, Martin, R & Rao, MS 2007, 'Disease progression after bone marrow transplantation in a model of multiple sclerosis is associated with chronic microglial and glial progenitor response', Journal of Neuropathology and Experimental Neurology, vol. 66, no. 7, pp. 637-649. https://doi.org/10.1097/nen.0b013e318093f3ef
    Cassiani-Ingoni, Riccardo ; Muraro, Paolo A. ; Magnus, Tim ; Reichert-Scrivner, Susan ; Schmidt, Jens ; Huh, Jaebong ; Quandt, Jacqueline A. ; Bratincsak, Andras ; Shahar, Tal ; Eusebi, Fabrizio ; Sherman, Lawrence (Larry) ; Mattson, Mark P. ; Martin, Roland ; Rao, Mahendra S. / Disease progression after bone marrow transplantation in a model of multiple sclerosis is associated with chronic microglial and glial progenitor response. In: Journal of Neuropathology and Experimental Neurology. 2007 ; Vol. 66, No. 7. pp. 637-649.
    @article{2cc8737efe6347d1b4413a6c3f726841,
    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.",
    keywords = "Autoimmune disease, Bone marrow transplantation, CD44, Glial progenitor, Microglia, Olig2, Reactive astrocyte",
    author = "Riccardo Cassiani-Ingoni and Muraro, {Paolo A.} and Tim Magnus and Susan Reichert-Scrivner and Jens Schmidt and Jaebong Huh and Quandt, {Jacqueline A.} and Andras Bratincsak and Tal Shahar and Fabrizio Eusebi and Sherman, {Lawrence (Larry)} and Mattson, {Mark P.} and Roland Martin and Rao, {Mahendra S.}",
    year = "2007",
    month = "7",
    doi = "10.1097/nen.0b013e318093f3ef",
    language = "English (US)",
    volume = "66",
    pages = "637--649",
    journal = "American Journal of Psychotherapy",
    issn = "0002-9564",
    publisher = "Lippincott Williams and Wilkins",
    number = "7",

    }

    TY - JOUR

    T1 - Disease progression after bone marrow transplantation in a model of multiple sclerosis is associated with chronic microglial and glial progenitor response

    AU - Cassiani-Ingoni, Riccardo

    AU - Muraro, Paolo A.

    AU - Magnus, Tim

    AU - Reichert-Scrivner, Susan

    AU - Schmidt, Jens

    AU - Huh, Jaebong

    AU - Quandt, Jacqueline A.

    AU - Bratincsak, Andras

    AU - Shahar, Tal

    AU - Eusebi, Fabrizio

    AU - Sherman, Lawrence (Larry)

    AU - Mattson, Mark P.

    AU - Martin, Roland

    AU - Rao, Mahendra S.

    PY - 2007/7

    Y1 - 2007/7

    N2 - 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.

    AB - 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.

    KW - Autoimmune disease

    KW - Bone marrow transplantation

    KW - CD44

    KW - Glial progenitor

    KW - Microglia

    KW - Olig2

    KW - Reactive astrocyte

    UR - http://www.scopus.com/inward/record.url?scp=34447331302&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=34447331302&partnerID=8YFLogxK

    U2 - 10.1097/nen.0b013e318093f3ef

    DO - 10.1097/nen.0b013e318093f3ef

    M3 - Article

    VL - 66

    SP - 637

    EP - 649

    JO - American Journal of Psychotherapy

    JF - American Journal of Psychotherapy

    SN - 0002-9564

    IS - 7

    ER -