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Oligodendrocyte pathology following Traumatic Brain Injury: Experimental and clinical studies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Neurokirurgi)
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic brain injury (TBI) caused by traffic and fall accidents, sports-related injuries and violence commonly results in life-changing disabilities. Cognitive impairments following TBI may be due to disruption of axons, stretched by the acceleration/deceleration forces of the initial impact, and their surrounding myelin in neuronal networks. The primary injury, which also results in death to neuronal and glial cells, is followed by a cascade of secondary injury mechanisms including a complex inflammatory response that will exacerbate the white matter injury.

Axons are supported and protected by the ensheathing myelin, ensuring fast conduction velocity. Myelin is produced by oligodendrocytes (OLs), a cell type vulnerable to many of the molecular processes, including several inflammatory mediators, elicited by TBI. Since one OL extends processes to several axons, the protection of OLs is an important therapeutic target post-TBI.  During development, OLs mature from oligodendrocyte progenitor cells (OPCs), also present in the adult brain.

The aim of this thesis was to investigate white matter pathology, with a specific focus on the OL population, in experimental and clinical TBI. Since the inflammatory response may contribute to OL cell death and OPC proliferation, neutralization of interleukin-1β (IL-1β) was investigated.

The lateral and central fluid percussion injury models were used in mice and rats where memory, learning and complex behaviors were investigated by two functional tests. Brain tissue, surgically resected due to life-threatening brain swelling or hemorrhage, from TBI patients was also investigated. Axonal injury, myelin damage, microglia alterations and OPCs and OL cell death were investigated by immunohistochemical techniques. In focal and diffuse experimental TBI, OL cell death was observed in important white matter tracts. OL cell death was accompanied by myelin damage, axonal injury and presence of microglia as well as an increased number of OPCs in both the experimental and human setting. OPCs were found to proliferate in diffuse TBI in mice where both complex behavioral changes and impaired memory were observed. Neutralization of IL-1β normalized and improved these behavioral alterations and also lead to a preserved number of mature OLs although without influencing OPC proliferation.

The results provided in this thesis indicate that white matter pathology is a key component of the pathophysiology of TBI. The OPC proliferation may influence regeneration post-injury and might be an important future therapeutic targets for TBI. The present studies also suggest that treatment strategies targeting neuroinflammation may positively influence behavioral outcome and OL cell death in TBI.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , p. 76
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1311
Keywords [en]
Traumatic brain injury, oligodendrocytes, oligodendrocyte progenitor cells, interleukin 1-β, central fluid percussion injury
National Category
Natural Sciences
Research subject
Neurosurgery; Neurosurgery
Identifiers
URN: urn:nbn:se:uu:diva-316401ISBN: 978-91-554-9846-7 (print)OAI: oai:DiVA.org:uu-316401DiVA, id: diva2:1079047
Public defence
2017-05-05, Hedstrandsalen, Akademiska Sjukhuset, Uppsala, 09:00 (English)
Opponent
Supervisors
Note

(Faculty of Medicine)

Available from: 2017-04-11 Created: 2017-03-07 Last updated: 2017-04-21
List of papers
1. Myelin loss and oligodendrocyte pathology in white matter tracts following traumatic brain injury in the rat
Open this publication in new window or tab >>Myelin loss and oligodendrocyte pathology in white matter tracts following traumatic brain injury in the rat
2013 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 38, no 1, p. 2153-2165Article, review/survey (Refereed) Published
Abstract [en]

Axonal injury is an important contributor to the behavioral deficits observed following traumatic brain injury (TBI). Additionally, loss of myelin and/or oligodendrocytes can negatively influence signal transduction and axon integrity. Apoptotic oligodendrocytes, changes in the oligodendrocyte progenitor cell (OPC) population and loss of myelin were evaluated at 2, 7 and 21 days following TBI. We used the central fluid percussion injury model (n = 18 and three controls) and the lateral fluid percussion injury model (n = 15 and three controls). The external capsule, fimbriae and corpus callosum were analysed. With Luxol Fast Blue and RIP staining, myelin loss was observed in both models, in all evaluated regions and at all post-injury time points, as compared with sham-injured controls (P ≤ 0.05). Accumulation of β-amyloid precursor protein was observed in white matter tracts in both models in areas with preserved and reduced myelin staining. White matter microglial/macrophage activation, evaluated by isolectin B4 immunostaining, was marked at the early time points. In contrast, the glial scar, evaluated by glial fibrillary acidic protein staining, showed its highest intensity 21 days post-injury in both models. The number of apoptotic oligodendrocytes, detected by CC1/caspase-3 co-labeling, was increased in both models in all evaluated regions. Finally, the numbers of OPCs, evaluated with the markers Tcf4 and Olig2, were increased from day 2 (Olig2) or day 7 (Tcf4) post-injury (P ≤ 0.05). Our results indicate that TBI induces oligodendrocyte apoptosis and widespread myelin loss, followed by a concomitant increase in the number of OPCs. Prevention of myelin loss and oligodendrocyte death may represent novel therapeutic targets for TBI.

Keywords
apoptosis; central fluid percussion; lateral fluid percussion; myelin damage; Olig2; Tcf4
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-198321 (URN)10.1111/ejn.12179 (DOI)000321205000012 ()
Available from: 2013-04-11 Created: 2013-04-11 Last updated: 2017-12-06Bibliographically approved
2. Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1β
Open this publication in new window or tab >>Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1β
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2016 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 43, no 8, p. 1016-1033Article in journal (Refereed) Published
Abstract [en]

Widespread traumatic axonal injury (TAI) results in brain network dysfunction, which commonly leads to persisting cognitive and behavioural impairments following traumatic brain injury (TBI). TBI induces a complex neuroinflammatory response, frequently located at sites of axonal pathology. The role of the pro-inflammatory cytokine interleukin (IL)-1 has not been established in TAI. An IL-1-neutralizing or a control antibody was administered intraperitoneally at 30min following central fluid percussion injury (cFPI), a mouse model of widespread TAI. Mice subjected to moderate cFPI (n=41) were compared with sham-injured controls (n=20) and untreated, naive mice (n=9). The anti-IL-1 antibody reached the target brain regions in adequate therapeutic concentrations (up to similar to 30g/brain tissue) at 24h post-injury in both cFPI (n=5) and sham-injured (n=3) mice, with lower concentrations at 72h post-injury (up to similar to 18g/g brain tissue in three cFPI mice). Functional outcome was analysed with the multivariate concentric square field (MCSF) test at 2 and 9days post-injury, and the Morris water maze (MWM) at 14-21days post-injury. Following TAI, the IL-1-neutralizing antibody resulted in an improved behavioural outcome, including normalized behavioural profiles in the MCSF test. The performance in the MWM probe (memory) trial was improved, although not in the learning trials. The IL-1-neutralizing treatment did not influence cerebral ventricle size or the number of microglia/macrophages. These findings support the hypothesis that IL-1 is an important contributor to the processes causing complex cognitive and behavioural disturbances following TAI.

Keywords
axonal injury, behavioural outcome, central fluid percussion injury, interleukin-1, traumatic brain injury
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-297130 (URN)10.1111/ejn.13190 (DOI)000374645700004 ()27091435 (PubMedID)
Funder
Swedish Research Council
Available from: 2016-06-22 Created: 2016-06-21 Last updated: 2017-11-28Bibliographically approved
3. Human Traumatic Brain Injury Results in Oligodendrocyte Death and Increases the Number of Oligodendrocyte Progenitor Cells
Open this publication in new window or tab >>Human Traumatic Brain Injury Results in Oligodendrocyte Death and Increases the Number of Oligodendrocyte Progenitor Cells
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2016 (English)In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 75, no 6, p. 503-515Article in journal (Refereed) Published
Abstract [en]

Oligodendrocyte (OL) death may contribute to white matter pathology, a common cause of network dysfunction and persistent cognitive problems in patients with traumatic brain injury (TBI). Oligodendrocyte progenitor cells (OPCs) persist throughout the adult CNS and may replace dead OLs. OL death and OPCs were analyzed by immunohistochemistry of human brain tissue samples, surgically removed due to life-threatening contusions and/or focal brain swelling at 60.6 +/- 75 hours (range 4-192 hours) postinjury in 10 severe TBI patients (age 51.7 +/- 18.5 years). Control brain tissue was obtained postmortem from 5 age-matched patients without CNS disorders. TUNEL and CC1 co-labeling was used to analyze apoptotic OLs, which were increased in injured brain tissue (p < 0.05), without correlation with time from injury until surgery. The OPC markers Olig2, A2B5, NG2, and PDGFR-alpha were used. In contrast to the number of single-labeled Olig2, A2B5, NG2, and PDGFR-alpha-positive cells, numbers of Olig2 and A2B5 co-labeled cells were increased in TBI samples (p < 0.05); this was inversely correlated with time from injury to surgery (r = -0.8, p < 0.05). These results indicate that severe focal human TBI results in OL death and increases in OPCs postinjury, which may influence white matter function following TBI.

Keywords
Apoptosis, Human, Immunohistochemistry, Oligodendrocyte, Oligodendrocyte progenitor cells, Traumatic brain injury
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-299587 (URN)10.1093/jnen/nlw025 (DOI)000377665000003 ()27105664 (PubMedID)
Available from: 2016-07-22 Created: 2016-07-22 Last updated: 2017-11-28Bibliographically approved
4. Diffuse traumatic brain injury in the mouse induces a transient proliferation of oligodendrocyte progenitor cells in injured white matter tracts
Open this publication in new window or tab >>Diffuse traumatic brain injury in the mouse induces a transient proliferation of oligodendrocyte progenitor cells in injured white matter tracts
2017 (English)In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 35, no 2, p. 251-263Article in journal (Refereed) Published
Abstract [en]

Background: Injury to the white matter may lead to impaired neuronal signaling and is commonly observed following traumatic brain injury (TBI). Although endogenous repair of TBI-induced white matter pathology is limited, oligodendrocyte progenitor cells (OPCs) may be stimulated to proliferate and regenerate functionally myelinating oligodendrocytes. Even though OPCs are present throughout the adult brain, little is known about their proliferative activity following axonal injury caused by TBI.

Objective: We hypothesized that central fluid percussion injury (cFPI) in mice, a TBI model causing wide-spread axonal injury, results in OPC proliferation.

Methods: Proliferation of OPCs was evaluated in 27 cFPI mice using 5-ethynyl-2-deoxyuridine (EdU) labeling and a cell proliferation assay at 2 (n=9), 7 (n = 8) and 21 (n = 10) days post injury (dpi). Sham-injured mice (n = 14) were used as controls. OPC proliferation was quantified by immunohistochemistry using the OPC markers NG2 and Olig2 in several white matter loci including the corpus callosum, external capsule, fimbriae, the internal capsule and cerebral peduncle.

Results: The number of EdU/DAPI/Olig2-positive cells were increased in the cFPI group compared to sham-injured animals at 7 days post-injury (dpi; p≤0.05) in the majority of white matter regions. The OPC proliferation had subsided by 21 dpi. The number of EdU/DAPI/NG2 cells was also increase at 7 dpi in the external capsule and fimbriae.

Conclusion: These results suggest that traumatic axonal injury in the mouse induces a transient proliferative response of residing OPCs. These proliferating OPCs may replace dead oligodendrocytes and contribute to remyelination, which needs evaluation in future studies.

Keywords
traumatic brain injury, proliferation, axonal injury, EdU, oligodendrocyte progenitor cell, white matter, myelin, central fluid percussion injury
National Category
Neurology
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-316586 (URN)10.3233/RNN-160675 (DOI)000398131700009 ()27768001 (PubMedID)
Funder
The Swedish Brain FoundationSwedish Research Council
Available from: 2017-03-03 Created: 2017-03-03 Last updated: 2018-09-04Bibliographically approved
5. Reduced loss of mature Oligodendrocytes following Diffuse Traumatic Brain Injury in the mouse by Neutralization of Interleukin-1β
Open this publication in new window or tab >>Reduced loss of mature Oligodendrocytes following Diffuse Traumatic Brain Injury in the mouse by Neutralization of Interleukin-1β
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Abstract

Background: Traumatic brain injury (TBI) leads to several secondary consequences impairing patient outcome. Injury to the components of the white matter, the oligodendrocyte population, myelin and axons, associate with post-injury cognitive deficits. Oligodendrocytes (OLs), the myelin-producing cell, are highly vulnerable post-TBI. Lost OLs may be replaced by proliferating oligodendrocyte progenitor cells (OPCs). A complex inflammatory response is also initiated following TBI, which is an important therapeutic target in TBI. The cytokine, interleukin-1β (IL-1β), is a key mediator of the inflammatory response. When neutralized following experimental TBI, behavioral and histological outcome is improved by unknown mechanisms.

Methods: The central fluid percussion injury (cFPI) and sham injury was used in mice at three survival end-points; 2, 7 and 14 days post-injury. Mice were, at 30 min post-injury, randomly administered a neutralizing IL-1β antibody or a control antibody.  OPC proliferation (5-ethynyl 2´- deoxyuridine (EdU)/Olig 2 co-labeling) and mature OL cell death was evaluated in injured white matter tracts. In situ hybridization for Olig2 transcripts in EdU positive cells and microglia ramification was also evaluated.

Results: Attenuated cell death, indicated by cleaved caspase-3 expression, and OL cell loss was observed in brain-injured animals treated with the IL-1β neutralizing antibody without influencing proliferation of OPCs, the number of Olig2 transcript or the ramification of microglia. 

 

Conclusion: Although OPC proliferation was not influenced, IL-1β neutralization reduced oligodendrocyte cell death in diffuse TBI which may partly explain the beneficial outcome observed using this anti-inflammatory treatment.   

 

Keywords
Oligodendrocyte progenitor cell, central fluid percussion injury, microglia, Olig2, IL-1β
National Category
Neurology
Research subject
Neuroscience; Neurosurgery
Identifiers
urn:nbn:se:uu:diva-316727 (URN)
Available from: 2017-03-06 Created: 2017-03-06 Last updated: 2017-03-07

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