Neural Stem/Progenitor Cells from the Adult Human Spinal Cord Are Multipotent and Self-Renewing and Differentiate after Transplantation

Mothe, Andrea J.; Zahir, Tasneem; Santaguida, Carlo; Cook, Douglas J.; Tator, Charles H.

doi:10.1371/journal.pone.0027079

Cited by 78 publications

(79 citation statements)

References 69 publications

(103 reference statements)

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“…Therefore the larger size of the stage 50 nuclei could indicate the presence of more lax chromatin and a greater tendency for cell division compared to cells in stage 66 froglets, where the nuclei are smaller and pyknotic. Our observations in froglets are very much like those reported in rodent and primate spinal cords, where Sox2 + cells are present in the adult spinal cord, but are poorly activated in response to SCI (Bylund et al., 2003; Sandberg et al, 2005; Mizuseki et al, 1998; Rogers et al, 2009; Mothe et al, 2011). Intriguingly, we found that the levels of Sox2 and Sox3 mRNA do not decrease during metamorphosis suggesting that the protein levels are regulated through a post-transcriptional mechanism.…”

Section: Discussionsupporting

confidence: 86%

Regeneration of Xenopus laevis spinal cord requires Sox2/3 expressing cells

Muñoz¹,

Edwards-Faret²,

Moreno³

et al. 2015

Developmental Biology

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Spinal cord regeneration is very inefficient in humans, causing paraplegia and quadriplegia. Studying model organisms that can regenerate the spinal cord in response to injury could be useful for understanding the cellular and molecular mechanisms that explain why this process fails in humans. Here, we use Xenopus laevis as a model organism to study spinal cord repair. Histological and functional analyses showed that larvae at pre-metamorphic stages restore anatomical continuity of the spinal cord and recover swimming after complete spinal cord transection. These regenerative capabilities decrease with onset of metamorphosis. The ability to study regenerative and non-regenerative stages in Xenopus laevis makes it a unique model system to study regeneration. We studied the response of Sox2/3 expressing cells to spinal cord injury and their function in the regenerative process. We found that cells expressing Sox2 and/or Sox3 are present in the ventricular zone of regenerative animals and decrease in non-regenerative froglets. Bromodeoxyuridine (BrdU) experiments and in vivo time-lapse imaging studies using green fluorescent protein (GFP) expression driven by the Sox3 promoter showed a rapid, transient and massive proliferation of Sox2/3+ cells in response to injury in the regenerative stages. The in vivo imaging also demonstrated that Sox2/3+ neural progenitor cells generate neurons in response to injury. In contrast, these cells showed a delayed and very limited response in non-regenerative froglets. Sox2 knockdown and overexpression of a dominant negative form of Sox2 disrupts locomotor and anatomical-histological recovery. We also found that neurogenesis markers increase in response to injury in regenerative but not in non-regenerative animals. We conclude that Sox2 is necessary for spinal cord regeneration and suggest a model whereby spinal cord injury activates proliferation of Sox2/3 expressing cells and their differentiation into neurons, a mechanism that is lost in non-regenerative froglets.

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Section: Discussionsupporting

confidence: 86%

Regeneration of Xenopus laevis spinal cord requires Sox2/3 expressing cells

Muñoz¹,

Edwards-Faret²,

Moreno³

et al. 2015

Developmental Biology

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“…Cells removed from the ependymal regions of spinal cords from fresh autopsy tissue (organ transplant donors) differentiated into neurons and glia in vitro, 17,18 suggesting both a multipotent and a self-renewing capacity. Neurospheres formed from these cells expressed high levels of nestin, a marker of neural progenitor cells, and SOX2, a marker of neural stem cells, and displayed a morphology with long nestin-positive processes radially emanating from the neurospheres 18 in a manner reminiscent of tanycyte morphology.…”

Section: Discussionmentioning

confidence: 99%

“…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. 17,18 One of the common markers for progenitor cells, nestin, is increased in the ependyma of human spinal cords from patients with multiple sclerosis, 19 amyotrophic lateral sclerosis (ALS), and spinal tumors, 20 and in hydrocephalic infants. 21 There are discrepancies in the reported antigenicity, development, location, and response of cells purported to be NPC in the spinal cord injury.…”

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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“…Recently, we demonstrated that selfrenewing multipotent NSPCs can be passaged from the adult human spinal cord of organ transplant donors and that these cells differentiate into both neurons and glia following transplantation into rats with SCI (70). Stem cells isolated from the human fetal brain were transplanted into NOD/SCID mice with SCI, and the grafted cells expressed neural differentiation markers and improved recovery (71,72).…”

Section: Figurementioning

confidence: 99%