Axonal regeneration effects of Wnt3a-secreting fibroblast transplantation in spinal cord-injured rats

Suh, Hyung Il; Min, Joongkee; Choi, Kyung Hyo; Kim, Seong Who; Kim, Ki Soo; Jeon, Sang Ryong

doi:10.1007/s00701-011-0945-1

Cited by 58 publications

(43 citation statements)

References 34 publications

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“…While some axons are likely absent due to the loss of neurogenesis at the injury site, the magnitude of the effect we observe suggests that axons from more distant surviving neurons may fail to regrow as well. Along with other studies (Park et al, 2013; Suh et al, 2011), our data suggest that Wnt/ß-catenin signaling may promote axon regrowth either directly, or through induction of secondary pathways in radial glia.…”

Section: Resultssupporting

confidence: 87%

Wnt/ß-catenin signaling is required for radial glial neurogenesis following spinal cord injury

Briona

Poulain

Mosimann

et al. 2015

Developmental Biology

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Spinal cord injury results in permanent sensorimotor loss in mammals, in part due to a lack of injury-induced neurogenesis. The regeneration of neurons depends upon resident neural progenitors, which in zebrafish persist throughout the central nervous system as radial glia. However the molecular mechanisms regulating spinal cord progenitors remain uncharacterized. Wnt/ß-catenin signaling is necessary for the regenerative response of multiple tissues in zebrafish as well as other vertebrates, but it is not known whether the pathway has a role in spinal cord regeneration. Here we show that spinal radial glia exhibit Wnt/ß-catenin activity as they undergo neurogenesis following transection. We then use Cre-mediated lineage tracing to label the progeny of radial glia and show that Wnt/ß-catenin signaling is required for progenitors to differentiate into neurons. Finally, we show that axonal regrowth after injury also requires Wnt/ß-catenin signaling, suggesting coordinated roles for the pathway in functional recovery. Our data thus establish Wnt/ß-catenin pathway activation as a necessary step in spinal cord regeneration.

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Section: Resultssupporting

confidence: 87%

Wnt/ß-catenin signaling is required for radial glial neurogenesis following spinal cord injury

Briona

Poulain

Mosimann

et al. 2015

Developmental Biology

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“…82,83 After SCI, Wnt5a is induced in reactive astrocytes surrounding the damaged area, and corticospinal axonal growth is inhibited by noncanonical activation of the Ryk receptor in both mice 28 and rats. 20 Consistently, inhibition of noncanonical Ryk activation using Ab 20,28 or, alternatively, activation of canonical Wnt signaling using either lithium, 84,85 exogenous Wnt3a administration, 79 or transplantation of Wnt3a-secreting fibroblasts 86 improves locomotor recovery by promoting axonal regeneration after SCI. In our study, we observed detectable levels of Wnt5a at the nonlesioned and all of the times we analyzed postinjury, and we observed an increase in the expression of Ryk during late time points.…”

Section: Discussionmentioning

confidence: 92%

Wnts Are Expressed in the Spinal Cord of Adult Mice and Are Differentially Induced after Injury

González-Fernández

Fernández-Martos

Shields

et al. 2014

Journal of Neurotrauma

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The Wnt family of proteins plays key roles during central nervous system development and has been involved in several neuropathologies during adulthood, including spinal cord injury (SCI). However, Wnts expression knowledge is relatively limited during adult stages. Here, we sought to define the Wnt family expression pattern after SCI in adult mice by using quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Under physiological conditions, the messenger RNAs (mRNAs) of most Wnt ligands, inhibitors, receptors, and coreceptors are constitutively expressed in healthy adult mice. After dorsal hemisection, we found significant time-dependent variations, with a prominent upregulation of Wnt inhibitory factor 1 (Wif1). IHC against Frizzled (Fz) 1 and Fz4, as representatives of late and acute upregulated receptors, showed a differential expression in the uninjured spinal cord of Fz1 by neurons and oligodendrocytes and Fz4 by astrocytes. After injury, both receptors were maintained in the same type of cells. Finally, by using BATgal reporter mice, our results revealed active b-catenin signaling in neurons of the dorsal horn and cells of the central canal of uninjured spinal cords, besides a lack of additional SCI-induced activation.In conclusion, we demonstrate Wnt expression in the adult spinal cord of mice that is modulated by SCI, which differs from that previously described in rats. Further, Fz receptors are differentially expressed by neurons and glial cells, suggestive for cell-specific patterns and thus diverse physiological roles. Further studies will help toward in-depth characterization of the role of all Wnt factors and receptors described and eventually allow for the design of novel therapies.

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“…The Wnt protein specifically binds to the N-terminal cysteine-rich region of the Frizzled (Fz) receptor and functions through the classical Wnt/β-catenin pathway as well as non-classical Wnt/PCP or Wnt/Ca pathway (2,34,35). Studies have shown that Wnt signaling abnormalities might be related to axonal injury after aplastic failure and the occurrence of certain mental diseases (36–38). In a chronic pain model induced by multiple sclerosis, Wnt expression was upregulated in the spinal dorsal horn, which caused disease progression (39).…”

Section: Discussionmentioning

confidence: 99%

Effect of Wnt signaling pathway on pathogenesis and intervention of neuropathic pain

Zhao

Yang

2018

Exp Ther Med

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Neuropathic pain (NP) is a common clinical chronic pain with very complex mechanisms. This study explored the function of activated Wnt signaling pathway in NP. A rat model of chronic constriction injury (CCI) was established. Different doses of IWP-2, a Wnt signal inhibitor, were intrathecally injected to observe the behavior indicators at different time-points, including the pain induced by mechanical stimulation and thermal stimulation. The mRNA and protein levels of Wnt-3a, Frizzled 4 and β-catenin in lumbar (L) 4–6 dorsal root ganglion (DRG) of rats in each group, as well as synaptic plasticity-related molecules in DRG region of rats were detected by RT-PCR and western blotting, respectively. Compared with Sham group and Naive group, paw withdrawal thermal latency and paw withdrawal mechanical threshold were significantly decreased after CCI, while synaptic plasticity was increased (P<0.05). Besides, activation of Wnt/β-catenin signaling pathway was observed in rats with CCI. We found that intrathecal injection of IWP-2 effectively relieved the pain behavior and reduced the synaptic plasticity in rats with neuropathic pain after CCI, suggesting that the inactivated Wnt/β-catenin signaling pathway might be the major mechanism responsible for this effect. Our data demonstrated that intrathecal injection of IWP-2 ameliorated neuropathic pain in CCI rats by inhibiting the Wnt/β-catenin pathway.

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Axonal regeneration effects of Wnt3a-secreting fibroblast transplantation in spinal cord-injured rats

Cited by 58 publications

References 34 publications

Wnt/ß-catenin signaling is required for radial glial neurogenesis following spinal cord injury

Wnt/ß-catenin signaling is required for radial glial neurogenesis following spinal cord injury

Wnts Are Expressed in the Spinal Cord of Adult Mice and Are Differentially Induced after Injury

Effect of Wnt signaling pathway on pathogenesis and intervention of neuropathic pain

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