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1.
Brain ; 140(2): 399-413, 2017 02.
Article in English | MEDLINE | ID: mdl-28007993

ABSTRACT

Astrocytes are key players in the pathology of multiple sclerosis and can assume beneficial and detrimental roles during lesion development. The triggers and timing of the different astroglial responses in acute lesions remain unclear. Astrocytes in acute multiple sclerosis lesions have been shown previously to contain myelin debris, although its significance has not been examined. We hypothesized that myelin phagocytosis by astrocytes is an early event during lesion formation and leads to astroglial immune responses. We examined multiple sclerosis lesions and other central nervous system pathologies with prominent myelin injury, namely, progressive multifocal leukoencephalopathy, metachromatic leukodystrophy and subacute infarct. In all conditions, we found that myelin debris was present in most astrocytes at sites of acute myelin breakdown, indicating that astroglial myelin phagocytosis is an early and prominent feature. Functionally, myelin debris was taken up by astrocytes through receptor-mediated endocytosis and resulted in astroglial NF-κB activation and secretion of chemokines. These in vitro results in rats were validated in human disease where myelin-positive hypertrophic astrocytes showed increased nuclear localization of NF-κB and elevated chemokine expression compared to myelin-negative, reactive astrocytes. Thus, our data suggest that myelin uptake is an early response of astrocytes in diseases with prominent myelin injury that results in recruitment of immune cells. This first line response of astrocytes to myelin injury may exert beneficial or detrimental effects on the lesion pathology, depending on the inflammatory context. Modulating this response might be of therapeutic relevance in multiple sclerosis and other demyelinating conditions.


Subject(s)
Astrocytes/metabolism , Demyelinating Autoimmune Diseases, CNS/pathology , Myelin Sheath/metabolism , Myelin Sheath/pathology , Phagocytosis/physiology , Adult , Aged , Animals , Animals, Newborn , Astrocytes/pathology , Cell Proliferation/drug effects , Cells, Cultured , Child, Preschool , Culture , Cytokines/metabolism , Endocytosis/drug effects , Endocytosis/physiology , Female , Humans , Hydrazones/pharmacology , Macrophages/metabolism , Macrophages/pathology , Male , Middle Aged , Rats , Rats, Sprague-Dawley , Stroke/pathology , Time Factors , Transforming Growth Factor beta/pharmacology
2.
Exp Neurol ; 255: 113-26, 2014 May.
Article in English | MEDLINE | ID: mdl-24631375

ABSTRACT

Spinal cord injury (SCI) evokes rapid deleterious and reparative glial reactions. Understanding the triggers for these responses is necessary for designing strategies to maximize repair. This study examined lesion formation and glial responses to vascular disruption and hemorrhage, a prominent feature of acute SCI. The specific role of hemorrhage is difficult to evaluate in trauma-induced lesions, because mechanical injury initiates many downstream responses. To isolate vascular disruption from trauma-induced effects, we created a novel and reproducible model of collagenase-induced intraspinal hemorrhage (ISH) and compared glial reactions between unilateral ISH and a hemi-contusion injury. Similar to contusion injuries, ISH lesions caused loss of myelin and axons and became filled with iron-laden macrophages. We hypothesized that intraspinal hemorrhage would also initiate reparative cellular responses including NG2+ oligodendrocyte progenitor cell (OPC) proliferation and oligodendrocyte genesis. Indeed, ISH induced OPC proliferation within 1d post-injury (dpi), which continued throughout the first week and resulted in a sustained elevation of NG2+ OPCs. ISH also caused oligodendrocyte loss within 4h that was sustained through 3d post-ISH. However, oligodendrogenesis, as determined by bromo-deoxyuridine (BrdU) positive oligodendrocytes, restored oligodendrocyte numbers by 7dpi, revealing that proliferating OPCs differentiated into new oligodendrocytes after ISH. The signaling molecules pERK1/2 and pSTAT3 were robustly increased acutely after ISH, with pSTAT3 being expressed in a portion of OPCs, suggesting that activators of this signaling cascade may initiate OPC responses. Aside from subtle differences in timing of OPC responses, changes in ISH tissue closely mimicked those in hemi-contusion tissue. These results are important for elucidating the contribution of hemorrhage to lesion formation and endogenous cell-mediated repair, and will provide the foundation for future studies geared toward identifying the role of specific blood components on injury and repair mechanisms. This understanding may provide new clinical targets for SCI and other devastating conditions such as intracerebral hemorrhage.


Subject(s)
Antigens/metabolism , Hemorrhage/pathology , Neural Stem Cells/pathology , Oligodendroglia/pathology , Proteoglycans/metabolism , Spinal Cord Diseases/pathology , Spinal Cord Injuries/pathology , Animals , Axons/metabolism , Axons/pathology , Cell Count , Cell Differentiation/physiology , Female , Hemorrhage/etiology , Hemorrhage/metabolism , Neural Stem Cells/metabolism , Oligodendroglia/metabolism , Rats , Rats, Sprague-Dawley , Spinal Cord Diseases/etiology , Spinal Cord Diseases/metabolism , Spinal Cord Injuries/complications , Spinal Cord Injuries/metabolism
3.
Neurotherapeutics ; 8(2): 262-73, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21404073

ABSTRACT

Oligodendrocytes (OLs) are particularly susceptible to the toxicity of the acute lesion environment after spinal cord injury (SCI). They undergo both necrosis and apoptosis acutely, with apoptosis continuing at chronic time points. Loss of OLs causes demyelination and impairs axon function and survival. In parallel, a rapid and protracted OL progenitor cell proliferative response occurs, especially at the lesion borders. Proliferating and migrating OL progenitor cells differentiate into myelinating OLs, which remyelinate demyelinated axons starting at 2 weeks post-injury. The progression of OL lineage cells into mature OLs in the adult after injury recapitulates development to some degree, owing to the plethora of factors within the injury milieu. Although robust, this endogenous oligogenic response is insufficient against OL loss and demyelination. First, in this review we analyze the major spatial-temporal mechanisms of OL loss, replacement, and myelination, with the purpose of highlighting potential areas of intervention after SCI. We then discuss studies on OL protection and replacement. Growth factors have been used both to boost the endogenous progenitor response, and in conjunction with progenitor transplantation to facilitate survival and OL fate. Considerable progress has been made with embryonic stem cell-derived cells and adult neural progenitor cells. For therapies targeting oligogenesis to be successful, endogenous responses and the effects of the acute and chronic lesion environment on OL lineage cells must be understood in detail, and in relation, the optimal therapeutic window for such strategies must also be determined.


Subject(s)
Oligodendroglia/pathology , Spinal Cord Injuries/pathology , Animals , Cell Differentiation/physiology , Demyelinating Diseases/pathology , Humans , Nerve Regeneration/physiology , Stem Cells/cytology , Stem Cells/metabolism
4.
Stem Cell Res Ther ; 2(1): 7, 2011 Feb 14.
Article in English | MEDLINE | ID: mdl-21345248

ABSTRACT

Endogenous cell proliferation and gliogenesis have been extensively documented in spinal cord injury, particularly in terms of proliferating oligodendrocyte progenitor cells. Despite the characterization of different proliferating cell types in the intact and injured spinal cord, the exact sources of new glial cells have remained elusive. Most studies on cell fate within the spinal cord have focused on following the progeny of one specific population of dividing cells, thus making it difficult to understand the relative contributions of each mitotic cell population to the formation of new glia after spinal cord injury. A recent study from the Frisen laboratory is the first to quantitatively and qualitatively characterize the response of ependymal cells, oligodendrocyte progenitors, and astrocytes in parallel by using transgenic reporter mice corresponding to each cell type. The investigators characterize the distribution and phenotype of progeny, along with the quantitative contributions of each progenitor type to newly formed cells. Their findings provide valuable insight into the endogenous cell replacement response to spinal cord injury, thus paving the way for advances in modulating specific populations of progenitor cells with the goal of promoting structural and functional recovery after spinal cord injury.


Subject(s)
Spinal Cord Injuries/therapy , Stem Cells/cytology , Animals , Antigens/genetics , Antigens/metabolism , Cell Proliferation , Oligodendroglia/cytology , Promoter Regions, Genetic , Proteoglycans/genetics , Proteoglycans/metabolism , Stem Cell Transplantation , Stem Cells/metabolism
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