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Impaired oligodendrogenesis in the white matter of aged mice following diffuse traumatic brain injury

Michalettos, Georgios LU ; Clausen, Fredrik LU ; Özen, Ilknur LU ; Ruscher, Karsten LU and Marklund, Niklas LU orcid (2024) In GLIA
Abstract

Senescence is a negative prognostic factor for outcome and recovery following traumatic brain injury (TBI). TBI-induced white matter injury may be partially due to oligodendrocyte demise. We hypothesized that the regenerative capacity of oligodendrocyte precursor cells (OPCs) declines with age. To test this hypothesis, the regenerative capability of OPCs in young [(10 weeks ±2 (SD)] and aged [(62 weeks ±10 (SD)] mice was studied in mice subjected to central fluid percussion injury (cFPI), a TBI model causing widespread white matter injury. Proliferating OPCs were assessed by immunohistochemistry for the proliferating cell nuclear antigen (PCNA) marker and labeled by 5-ethynyl-2′-deoxyuridine (EdU) administered daily through... (More)

Senescence is a negative prognostic factor for outcome and recovery following traumatic brain injury (TBI). TBI-induced white matter injury may be partially due to oligodendrocyte demise. We hypothesized that the regenerative capacity of oligodendrocyte precursor cells (OPCs) declines with age. To test this hypothesis, the regenerative capability of OPCs in young [(10 weeks ±2 (SD)] and aged [(62 weeks ±10 (SD)] mice was studied in mice subjected to central fluid percussion injury (cFPI), a TBI model causing widespread white matter injury. Proliferating OPCs were assessed by immunohistochemistry for the proliferating cell nuclear antigen (PCNA) marker and labeled by 5-ethynyl-2′-deoxyuridine (EdU) administered daily through intraperitoneal injections (50 mg/kg) from day 2 to day 6 after cFPI. Proliferating OPCs were quantified in the corpus callosum and external capsule on day 2 and 7 post-injury (dpi). The number of PCNA/Olig2-positive and EdU/Olig2-positive cells were increased at 2dpi (p <.01) and 7dpi (p <.01), respectively, in young mice subjected to cFPI, changes not observed in aged mice. Proliferating Olig2+/Nestin+ cells were less common (p <.05) in the white matter of brain-injured aged mice, without difference in proliferating Olig2+/PDGFRα+ cells, indicating a diminished proliferation of progenitors with different spatial origin. Following TBI, co-staining for EdU/CC1/Olig2 revealed a reduced number of newly generated mature oligodendrocytes in the white matter of aged mice when compared to the young, brain-injured mice (p <.05). We observed an age-related decline of oligodendrogenesis following experimental TBI that may contribute to the worse outcome of elderly patients following TBI.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
aging, axonal injury, fluid percussion, oligodendrocyte progenitor cells, proliferation, traumatic brain injury, white matter
in
GLIA
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:38180164
  • scopus:85181529890
ISSN
0894-1491
DOI
10.1002/glia.24499
language
English
LU publication?
yes
id
498dd904-48f7-407a-bfd2-8a042326d2c6
date added to LUP
2024-02-06 12:03:47
date last changed
2024-04-22 19:08:18
@article{498dd904-48f7-407a-bfd2-8a042326d2c6,
  abstract     = {{<p>Senescence is a negative prognostic factor for outcome and recovery following traumatic brain injury (TBI). TBI-induced white matter injury may be partially due to oligodendrocyte demise. We hypothesized that the regenerative capacity of oligodendrocyte precursor cells (OPCs) declines with age. To test this hypothesis, the regenerative capability of OPCs in young [(10 weeks ±2 (SD)] and aged [(62 weeks ±10 (SD)] mice was studied in mice subjected to central fluid percussion injury (cFPI), a TBI model causing widespread white matter injury. Proliferating OPCs were assessed by immunohistochemistry for the proliferating cell nuclear antigen (PCNA) marker and labeled by 5-ethynyl-2′-deoxyuridine (EdU) administered daily through intraperitoneal injections (50 mg/kg) from day 2 to day 6 after cFPI. Proliferating OPCs were quantified in the corpus callosum and external capsule on day 2 and 7 post-injury (dpi). The number of PCNA/Olig2-positive and EdU/Olig2-positive cells were increased at 2dpi (p &lt;.01) and 7dpi (p &lt;.01), respectively, in young mice subjected to cFPI, changes not observed in aged mice. Proliferating Olig2+/Nestin+ cells were less common (p &lt;.05) in the white matter of brain-injured aged mice, without difference in proliferating Olig2+/PDGFRα+ cells, indicating a diminished proliferation of progenitors with different spatial origin. Following TBI, co-staining for EdU/CC1/Olig2 revealed a reduced number of newly generated mature oligodendrocytes in the white matter of aged mice when compared to the young, brain-injured mice (p &lt;.05). We observed an age-related decline of oligodendrogenesis following experimental TBI that may contribute to the worse outcome of elderly patients following TBI.</p>}},
  author       = {{Michalettos, Georgios and Clausen, Fredrik and Özen, Ilknur and Ruscher, Karsten and Marklund, Niklas}},
  issn         = {{0894-1491}},
  keywords     = {{aging; axonal injury; fluid percussion; oligodendrocyte progenitor cells; proliferation; traumatic brain injury; white matter}},
  language     = {{eng}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{GLIA}},
  title        = {{Impaired oligodendrogenesis in the white matter of aged mice following diffuse traumatic brain injury}},
  url          = {{http://dx.doi.org/10.1002/glia.24499}},
  doi          = {{10.1002/glia.24499}},
  year         = {{2024}},
}