Spinal Cord Injury Reveals Multilineage Differentiation of Ependymal Cells

Meletis, Konstantinos; Barnabé-Heider, Fanie; Carlén, Marie; Evergren, Emma; Tomilin, N.V.; Shupliakov, Oleg; Frisén, Jonas

doi:10.1371/journal.pbio.0060182

Cited by 576 publications

(870 citation statements)

References 64 publications

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“…MicroRNA studies also suggest that SOX9 is gliogenic, promoting neural stem cells to adopt an astrocyte or oligodendrocyte fate (Cheng et al, 2009). Following injury, neural stem cells proliferate and differentiate almost exclusively into astrocytes (Johansson et al, 1999;Meletis et al, 2008) that generate scar, but not into neurons (Johansson et al, 1999). These results are consistent with the hypothesis that, in neural stem cells, SOX9 expression promotes a glial rather than a neuronal cell fate and that, in Sox9 conditional knock-outs, neural stem cells activated by the injury may adopt a neuronal as opposed to a glial fate.…”

Section: Discussionmentioning

confidence: 99%

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

McKillop

Dragan

Schedl

et al. 2012

Glia

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Chondroitin sulfate proteoglycans (CSPGs) found in perineuronal nets and in the glial scar after spinal cord injury have been shown to inhibit axonal growth and plasticity. Since we have previously identified SOX9 as a transcription factor that upregulates the expression of a battery of genes associated with glial scar formation in primary astrocyte cultures, we predicted that conditional Sox9 ablation would result in reduced CSPG expression after spinal cord injury and that this would lead to increased neuroplasticity and improved locomotor recovery. Control and Sox9 conditional knock-out mice were subject to a 70 kdyne contusion spinal cord injury at thoracic level 9. One week after injury, Sox9 conditional knock-out mice expressed reduced levels of CSPG biosynthetic enzymes (Xt-1 and C4st), CSPG core proteins (brevican, neurocan, and aggrecan), collagens 2a1 and 4a1, and Gfap, a marker of astrocyte activation, in the injured spinal cord compared with controls. These changes in gene expression were accompanied by improved hind limb function and locomotor recovery as evaluated by the Basso Mouse Scale (BMS) and rodent activity boxes. Histological assessments confirmed reduced CSPG deposition and collagenous scarring at the lesion of Sox9 conditional knock-out mice, and demonstrated increased neurofilament-positive fibers in the lesion penumbra and increased serotonin immunoreactivity caudal to the site of injury. These results suggest that SOX9 inhibition is a potential strategy for the treatment of SCI.

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Section: Discussionmentioning

confidence: 99%

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

McKillop

Dragan

Schedl

et al. 2012

Glia

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“…New neurons are continuously generated in the anterior subventricular zone (SVZ) of adult rodents, from which they migrate via the rostral migratory stream to the olfactory bulb [19][20][21][22][23], and in the subgranular zone of the hippocampal dentate gyrus of both adult rodents [24][25][26][27] and humans [6,28]. The subependymal cell layer of the ventricles [29] and spinal cord [30] contains stem cells that give rise to both neurons and glia. Multi-potential precursors are abundant in many regions of the adult brain parenchyma [31][32][33][34].…”

Section: Glial Progenitor Cells In the Adult Central Nervous Systemmentioning

confidence: 99%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.

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“…Cells taken from these regions can be cultured to form neurospheres and, under the right conditions, differentiate into mature astrocytes, oligodendrocytes, and neurons. [3][4][5][6][7][8][9] Proliferation can be stimulated by epidermal growth factor (EGF) with basic fibroblast growth factor (bFGF), 6,10 or by injury. 7,11 Proliferation of ependymal cells in the normal uninjured rat spinal cord is limited, but appears to follow a rostrocaudal axis with a higher proliferation of cells in the more caudal regions of the spinal cord.…”

Section: Introductionmentioning

confidence: 99%

“…12 Dividing cells express markers of mature astrocytes or oligodendrocytes, but remain in situ rather than migrating to the surrounding tissue. 13 After spinal cord injury in the rat, NPCs proliferate and differentiate into glial cells but not neurons, 5,14,15 and can migrate toward an injury site. 11,14,16 Endogenous NPC present in the adult human spinal cord have been isolated from fresh autopsy tissue, cultured, and shown to differentiate into neurons and glial cells in vitro.…”

Section: Introductionmentioning

confidence: 99%

Nestin-Positive Ependymal Cells Are Increased in the Human Spinal Cord after Traumatic Central Nervous System Injury

Cawsey

Duflou

Weickert

et al. 2015

Journal of Neurotrauma

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Endogenous neural progenitor cell niches have been identified in adult mammalian brain and spinal cord. Few studies have examined human spinal cord tissue for a neural progenitor cell response in disease or after injury. Here, we have compared cervical spinal cord sections from 14 individuals who died as a result of nontraumatic causes (controls) with 27 who died from injury with evidence of trauma to the central nervous system. Nestin immunoreactivity was used as a marker of neural progenitor cell response. There were significant increases in the percentage of ependymal cells that were nestin positive between controls and trauma cases. When sections from lumbar and thoracic spinal cord were available, nestin positivity was seen at all three spinal levels, suggesting that nestin reactivity is not simply a localized reaction to injury. There was a positive correlation between the percentage of ependymal cells that were nestin positive and post-injury survival time but not for age, postmortem delay, or glial fibrillary acidic protein (GFAP) immunoreactivity. No doublelabelled nestin and GFAP cells were identified in the ependymal, subependymal, or parenchymal regions of the spinal cord. We need to further characterize this subset of ependymal cells to determine their role after injury, whether they are a population of neural progenitor cells with the potential for proliferation, migration, and differentiation for spinal cord repair, or whether they have other roles more in line with hypothalamic tanycytes, which they closely resemble.

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Spinal Cord Injury Reveals Multilineage Differentiation of Ependymal Cells

Cited by 576 publications

References 64 publications

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

Cell Therapy for Multiple Sclerosis

Nestin-Positive Ependymal Cells Are Increased in the Human Spinal Cord after Traumatic Central Nervous System Injury

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