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Cited by 164Neurogenesis and neuroplasticity mechanismsSpinal Cord Injury ResearchMultiple Sclerosis Research Studies

Chronic Oligodendrogenesis and Remyelination after Spinal Cord Injury in Mice and Rats

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Hesp, Zoe C., Goldstein, Evan A., Miranda, Carlos J., Kaspar, Brain K., McTigue, Dana M.·2015·The Journal of Neuroscience
DOI 10.1523/jneurosci.2568-14.2015PMC PMC4300327
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Abstract

Adult progenitor cells proliferate in the acutely injured spinal cord and their progeny differentiate into new oligodendrocytes (OLs) that remyelinate spared axons. Whether this endogenous repair continues beyond the first week postinjury (wpi), however, is unknown. Identifying the duration of this response is essential for guiding therapies targeting improved recovery from spinal cord injury (SCI) by enhancing OL survival and/or remyelination. Here, we used two PDGFRα-reporter mouse lines and rats injected with a GFP-retrovirus to assess progenitor fate through 80 d after injury. Surprisingly, new OLs were generated as late as 3 months after injury and their processes ensheathed axons near and distal to the lesion, colocalized with MBP, and abutted Caspr+ profiles, suggesting newly formed myelin. Semithin sections confirmed stereotypical thin OL remyelination and few bare axons at 10 wpi, indicating that demyelination is relatively rare. Astrocytes in chronic tissue expressed the pro-OL differentiation and survival factors CNTF and FGF-2. In addition, pSTAT3+ NG2 cells were present through at least 5 wpi, revealing active signaling of the Jak/STAT pathway in these cells. The progenitor cell fate genes Sox11, Hes5, Id2, Id4, BMP2, and BMP4 were dynamically regulated for at least 4 wpi. Collectively, these data verify that the chronically injured spinal cord is highly dynamic. Endogenous repair, including oligodendrogenesis and remyelination, continues for several months after SCI, potentially in response to growth factors and/or transcription factor changes. Identifying and understanding spontaneous repair processes such as these is important so that beneficial plasticity is not inadvertently interrupted and effort is not exerted to needlessly duplicate ongoing spontaneous repair.

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  • After SCI, remyelination does not begin until 2-3 weeks post-injury.

    “After SCI, remyelination does not begin until 2–3 weeks post-injury, therefore delayed tamoxifen treatment is required when using Cre mice to manipulate gene expression during this time frame [44].”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [44]

    The Discussion states that progenitors can remyelinate axons and that studies have shown this response occurs during the first two weeks after SCI. That contradicts the claim that remyelination does not begin until 2–3 weeks post-injury. The source’s page number is not available in our copy. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Tamoxifen given via oral gavage for 4 consecutive days is sufficient to induce Cre recombination in transgenic mice.

    “Tamoxifen was given via oral gavage for 4 consecutive days; this dosing regimen is sufficient to induce Cre recombination in transgenic mice [44]”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [44]

    The sections on generating PDGFRα-CreER:mT/mG and PDGFRα-ROSA mice report that four consecutive days of oral tamoxifen induced recombination in those transgenic lines. The copy does not specify oral gavage, so it does not establish that particular administration method. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • This significant increase in macrophage/microglia and NG2 cell proliferation is maintained for months post-injury.

    “This significant increase in macrophage/microglia and NG2 cell proliferation is maintained for months post-injury [2, 44]; therefore, it is not surprising that our data reveal ~25% of the NG2+ cells and CD68+ cells are EdU+ at 42pi.”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [44]

    The section 'OL progenitors proliferate for at least 4 weeks after SCI in rats' reports significantly increased NG2-cell proliferation at 1–4 weeks and levels 3–9 times above controls as late as 10 weeks, though it does not state that the later increase was statistically significant. The paper does not establish that macrophage/microglia proliferation remains increased for months; its cell-counting methods explicitly excluded macrophages from NG2-cell counts. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • After SCI, NG2 cell proliferation increases 50-fold as NG2 cells proliferate to replace NG2 cells and OLs lost from injury.

    “Less than 1% of glial cells divide in the uninjured rodent spinal cord [75]; however, after SCI, NG2 cell proliferation increases 50-fold as NG2 cells proliferate to replace NG2 cells and OLs lost from injury [44, 47].”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [44]

    The Introduction says SCI induces robust NG2-cell proliferation and that dividing NG2 cells give rise to new oligodendrocytes. The section ‘OL progenitors proliferate for at least 4 weeks after SCI in rats’ also reports new NG2 cells, but it does not substantiate a 50-fold increase: its stated figure is 3- to 9-fold above controls as late as 10 weeks after injury. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The Cre/lox system has been used in reporter mice to track oligodendrogenesis and myelin synthesis during development, after CNS demyelination, and after SCI.

    “The Cre/lox system been used in reporter mice to track oligodendrogenesis and myelin synthesis during development [45, 81], after CNS demyelination [82, 83], and after SCI [44, 84, 85].”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [44]

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Cited by

Sorted by citations

Authors
Hesp, Z. C., Goldstein, E. A., Miranda, C. J., Kaspar, B. K., & McTigue, D. M.
Affiliations
  • Nationwide Children's Hospital (US)
  • The Ohio State University (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2015-01-21
Volume
35
Issue
3
Pages
1274-1290
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.2568-14.2015
PMC
PMC4300327
OpenAlex
W1981030744
Cited by
164
References
8
Citations by year
2026: 7 · 2025: 9 · 2024: 11 · 2023: 11 · 2022: 19 · 2021: 13 · 2020: 15 · 2019: 20 · 2018: 15 · 2017: 19 · 2016: 15 · 2015: 10
FWCI
7.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Neurological Disorders and Stroke (R01NS059776, P30NS045758, NS059776)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
spinal cord injury, oligodendrogenesis, remyelination, oligodendrocytes, endogenous repair, progenitor cells, oligodendrocyte precursor cells, STAT3 signaling, BMP signaling, ciliary neurotrophic factor, FGF2, SOX11, Hes5, Id2, Id4, demyelination, axon ensheathment, myelination
MeSH terms
Animals, Cell Differentiation, Demyelinating Diseases, Female, Male, Nerve Regeneration, Oligodendroglia, Spinal Cord Injuries, Rats, Sprague-Dawley, Recovery of Function, Mice, Rats

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