Coaxing stem cells to repair the spinal cord

doi:10.1126/science.abe1661

GSTDTAP > 气候变化

DOI	10.1126/science.abe1661
	Coaxing stem cells to repair the spinal cord
	Catherina G. Becker; Thomas Becker
	2020-10-02
发表期刊	Science
出版年	2020
英文摘要	Spinal cord injuries destroy neurons, axonal processes, and oligodendrocytes that provide insulation and protection of axons by means of membrane wrappings, called myelin sheaths. None of these cellular structures are efficiently replaced after injury. This can lead to lifelong disabilities, including paralysis. Endogenous stem cells exist in the spinal cord, but after injury they produce mainly astrocytic scar tissue, no neurons, and very few oligodendrocytes ([ 1 ][1]). On page 73 of this issue, Llorens- Bobadilla et al. ([ 2 ][2]) show that by overexpressing a single factor in spinal stem cells, they can boost post-injury production of oligodendrocytes in mice. This leads to better remyelination of remaining axons that lost their myelin and to improved axonal impulse conduction in vivo. The study raises hope that endogenous stem cells in the injured spinal cord can be recruited to generate neural cell types in a more balanced way after injury to promote recovery of function. One of the problems with spinal cord injury is secondary cell death around an injury site that leads to the loss of not only neurons, but also oligodendrocytes and the myelin sheaths they produce. This in turn causes denuding of spared axons, which, bereft of their insulation and trophic support, function inefficiently and may ultimately degenerate. Llorens-Bobadilla et al. analyzed mouse ependymal cells (stem cells in the lining of the spinal cord central canal) to find that chromatin regions with binding motifs for the oligodendrocyte-determining transcription factors OLIG2 (oligodendrocyte transcription factor 2) and SOX10 were accessible even though the transcription factors were not expressed. This suggested a latent capacity of ependymal cells to generate oligodendrocytes. Indeed, inducing overexpression of OLIG2 in ependymal cells in vivo strongly increased the accessibility of OLIG2 binding sites and the production of oligodendrocytes from these cells after spinal injury. Neither promoter accessibility nor oligodendrocyte production increased without an injury, indicating that factors in addition to OLIG2 expression are necessary to realize the latent potential of ependymal cells for oligodendrocyte production. Injury induces ependymal cells to proliferate, which changes gene accessibility. Moreover, spinal injury induces inflammation ([ 3 ][3]) and attendant signaling molecules that may influence gene expression in ependymal cells, but these factors are largely unknown. The observed increase in oligodendrocyte numbers was substantial. High numbers of cells may have been reached because the progeny of ependymal cells comprises proliferative oligodendrocyte progenitors that can be considered transit-amplifying cells for oligodendrocytes. Even though oligodendrocyte production was boosted from less than 1% to more than one-third of ependymal progeny, the astrocytic scar, which also consists of cells derived from ependymal cells, was not depleted. The astrocytic scar has protective functions in wound healing ([ 4 ][4]), so it is important that any therapeutic approach does not compromise scar tissue. Together, these findings indicate that ependymal cells in the spinal cord can be reprogrammed for oligodendrocyte production after injury in mice. ![Figure][5] Induced protection Chromatin in adult ependymal cells in the mouse spinal cord is accessible to the transcription factor OLIG2 (oligodendrocyte transcription factor 2). After spinal cord injury, myelin is lost near the injury site and can be lost from spared axons. Overexpression of OLIG2 in ependymal cells in mice reprograms these stem cells to produce more oligodendrocytes, which form new myelin near the injury and improve axon conduction. GRAPHIC: KELLIE HOLOSKI/ SCIENCE Full differentiation of oligodendrocytes is a prerequisite for efficient impulse propagation in axons. One problem with naturally occurring remyelination is that new myelin sheaths are usually thinner than those that were originally present, compromising conduction velocity. It will be interesting to find out whether new myelin displays “full thickness” and is comparable to myelin that has arisen during development. It will also be interesting to determine whether new myelin persists for longer than the 3 months reported in this study to indicate permanent repair. Llorens-Bobadilla et al. found that induced myelin improved conductance velocity in a mouse model of spinal cord injury. The model is a contusion injury, which resembles the physical impact associated with injuries in humans. Conductance velocity in spared axons above the injury site was improved in OLIG2-overexpressing animals compared to injured controls, ostensibly because of improved myelination. Below the injury, no such effects were observed, likely because of the scarcity of spared axons. Consequently, recovery of function was not better in OLIG2-overexpressing animals. To bring about functional recovery, combinations with other treatments would be needed ([ 5 ][6]) because although oligodendrocytes can support axons, remyelination alone is insufficient to boost recovery ([ 6 ][7]). For example, axon growth can be enhanced by modulating intrinsic axon growth propensity ([ 7 ][8]) or the inhibitory environment ([ 8 ][9]). Moreover, transplanted neural stem cells can form new neurons that integrate and improve neuronal impulse conduction over an injury site ([ 9 ][10]). Electrical stimulation of spared fibers may also lead to more efficient myelination ([ 10 ][11]). In all approaches, newly grown axons could benefit from additional myelination capacity from induced oligodendrocytes. To realize the potential of ependymal cells in human spinal cord injuries, it will be necessary to determine whether similar stem cells exist near the human spinal cord central canal in sufficient numbers ([ 11 ][12]). The lumen of the central canal progressively disappears during childhood, but cells with stem cell potential can be isolated from the human spinal cord ([ 12 ][13]). It will be necessary to determine how similar these cells are to mouse ependymal cells and whether their chromatin is similarly poised to generate oligodendrocytes. From a therapeutic viewpoint, efficient means of inducing gene expression are needed. Viral delivery systems are under development that evade immune detection and can be switched off—an important safety feature to avoid unwanted proliferation of cells ([ 13 ][14]). Such strategies could be used to treat any demyelination after spinal injury or in demyelinating diseases, such as multiple sclerosis. Ependymal cells in the mouse spinal cord have a stem cell potential that sets them apart from other spinal cell types. For example, Llorens-Bobadilla et al. found that astrocytes did not produce oligodendrocytes after forced OLIG2 expression. What else could ependymal cells do? In rats, stem cells derived from whole spinal cord, including ependymal cells, formed neurons when transplanted into the hippocampus, a neurogenic region of the brain ([ 14 ][15]). In anamniotes (salamanders and fishes), spinal ependymal progenitor cells generate neurons after injury in situ ([ 12 ][13]). This indicates a potential for neurogenesis in spinal stem cells across vertebrates. It might be informative to determine the nature of the gene regulatory programs activated by anamniotes to produce neurons from ependymal cells in the spinal cord and whether these could be activated by gene therapy in nonregenerating mammals to contribute to repair after injury. 1. [↵][16]1. K. 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/298050
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Catherina G. Becker,Thomas Becker. Coaxing stem cells to repair the spinal cord[J]. Science,2020.
APA	Catherina G. Becker,&Thomas Becker.(2020).Coaxing stem cells to repair the spinal cord.Science.
MLA	Catherina G. Becker,et al."Coaxing stem cells to repair the spinal cord".Science (2020).