Astrocytic reprogramming combined with rehabilitation strategy improves recovery from spinal cord injury

Yang, Tuo; Xing, Lingyan; Yu, Wei; Cai, Yunyun; Cui, Shusen; Chen, Gang

doi:10.1096/fj.202001657rr

Cited by 34 publications

(33 citation statements)

References 73 publications

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“…To observe axonal growth or regeneration, we traced corticospinal tract and propriospinal axons based on a previously published protocol. 30 As shown in Figure 3C, the virus-traced injured axons stopped at the rostral terminal of the injured site in the control group, and jumbled neurites (labeled with $) were observed at the injured site. L-leucine treated mice exhibited significantly increase in number of axons, direct access to the injured site (white arrows with a short tail), and axonal sprouting (white arrows with a long tail) from the contralateral neurons.…”

Section: L-leucine Promoted Functional Recovery and Axon Re-growth After Spinal Cord Injurymentioning

confidence: 83%

“…As shown in Figure 3A, the BMS score revealed that L‐leucine supplementation improved the functional recovery of mice with SCI, and on the 7th and 10th day, the BMS scores showed significant increases compared with those of mice treated with saline injection ( P = .0177 and P = .0424, respectively). To observe axonal growth or regeneration, we traced corticospinal tract and propriospinal axons based on a previously published protocol 30 . As shown in Figure 3C, the virus‐traced injured axons stopped at the rostral terminal of the injured site in the control group, and jumbled neurites (labeled with $) were observed at the injured site.…”

Section: Resultsmentioning

confidence: 99%

“…The tracing procedure of propriospinal neurons was performed as described in a previous study 30 . After anesthesia, T8 laminectomy was performed without touching the spinal cord.…”

Section: Methodsmentioning

confidence: 99%

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L‐leucine promotes axonal outgrowth and regeneration via mTOR activation

Teng

Lin

et al. 2021

FASEB j.

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Discovering safe and effective drugs that promote neuron regeneration is an essential strategy for the recovery of central nervous system injuries. In this study, we found that L-leucine, an essential amino acid obtained from both supplements and food sources, could dramatically boost axonal outgrowth and regeneration. First, the effects of L-leucine on neurons were evaluated by cell apoptosis, survival, and death assays, and the results showed no changes in these processes after treatment. By live cell imaging, L-leucine was found to remarkably increase axonal length and growth velocity after axotomy. We also verified that L-leucine enhanced p-mTOR/p-S6K activation in neurons by testing with an mTOR inhibitor, rapamycin. Thereafter, we investigated the effects of L-leucine on the spinal cord injury in vivo. A mouse model of spinal cord hemi-section was established, and L-leucine was administered by tail intravenous injection. Basso mouse scale values revealed that L-leucine could improve functional recovery after injury. It was also notable that L-leucine treatment promoted axon growth across chondroitin sulfate proteoglycan (CSPG) areas.Furthermore, we used CSPGs as inhibitory environmental cues and clarified that L-leucine significantly enhanced axonal outgrowth and regeneration by promoting p-mTOR and p-S6K activation. Therefore, our study is the first to report that L-leucine promotes axonal regeneration in vitro and in vivo and could be candidate drug for axonal re-growth and nervous functional recovery.

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Section: L-leucine Promoted Functional Recovery and Axon Re-growth After Spinal Cord Injurymentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

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L‐leucine promotes axonal outgrowth and regeneration via mTOR activation

Teng

Lin

et al. 2021

FASEB j.

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“…Myt1l has been implicated in neuronal reprogramming either alone or in combination with the transcription factors ascl1 and bcl2 (Vierbuchen, Ostermeier, Pang, Kokubu, Sudhof, and Wernig 2010; Liang, Tan, Wang, Tao, Huang, Ma, Fukunaga, Huang, and Han 2018). Neuronal reprogramming has been applied to generate neurons in many diseases and pathological states, including spinal cord regeneration, Parkinson’s Disease, and Alzheimer’s Disease (Yang, Xing, Yu, cai, Cui, and Chen 2020; Guo, Zhang, Wu, Chen, Wang, and Chen 2014; Qian, Kang, Hu, Zhang, Liang, Meng, Zhang, Xue, Maimon, Dowdy, Devaraj, Zhou, Mobley, Cleveland, and Fu 2020). Therefore, it might be interesting to explore the role of Myt1 in neuronal reprogramming, which may offer new insight into neuronal regeneration.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity and molecular programming of progenitors for motor neurons and oligodendrocytes

Xing

Chai

Wang

et al. 2021

Preprint

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The pMN domain is a restricted domain in the ventral spinal cords, defined by the expression of olig2 gene. The fate determination of pMN progenitors is highly temporally and spatially regulated, with motor neurons and oligodendrocyte progenitor cells (OPCs) developing sequentially. Insight into the heterogeneity and molecular programs of pMN progenitors is currently lacking. With the zebrafish model, we identified multiple states of neural progenitors using single-cell sequencing: proliferating progenitors, common progenitors for both motor neurons and OPCs, and restricted precursors for either motor neurons or OPCs. We found specific molecular programs for neural progenitor fate transition, and manipulations of representative genes in the motor neuron or OPC lineage confirmed their critical role in cell fate determination. The transcription factor NPAS3 is necessary for the development of the OPC lineage and can interact with many known genes associated with schizophrenia. Deciphering progenitor heterogeneity and molecular mechanisms for these transitions will elucidate the formation of complex neuron-glia networks in the central nervous system during development, and understand the basis of neurodevelopmental disorders.

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“…As we described previously [20], the mice were deeply anesthetized with iso urane, and their ascending aortas were perfused rst with PBS and then with 4% paraformaldehyde. After perfusion, the L4-L6 spinal cord segments were collected and then post xed overnight.…”

Section: Immuno Uorescence Assaymentioning

confidence: 99%

Maresin 1 promotes nerve regeneration and alleviates neuropathic pain after nerve injury

Wei¹,

Chen²,

Su³

et al. 2021

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Background: Peripheral nerve injury (PNI) is a public health concern that results in sensory and motor disorders as well as neuropathic pain and secondary lesions. Currently, effective treatments for PNI are still limited. For example, while nerve growth factor (NGF) is widely used in the treatment of PNI to promote nerve regeneration, it also induces pain. Maresin 1 (MaR1) is an anti-inflammatory and proresolving mediator that has the potential to regenerate tissue. We determined whether MaR1 is able to promote nerve regeneration as well as alleviating neuropathic pain, and to be considered as a putative therapeutic agent for treating PNI.Methods: PNI models were constructed with eight-week-old adult male ICR mice and treated with NGF, MaR1 or saline by local application, intrathecal injection or intraplantar injection. Behavioral analysis and muscle atrophy test were assessed after treatment. Immunofluorescence assay was performed to examine the expression of ATF-3, GFAP, IBA1, and NF200. The expression transcript levels of inflammatory factors IL1β, IL-6, and TNF-α were detected by quantitative real-time RT-PCR. AKT, ERK, mTOR, PI3K, phosphorylated AKT, phosphorylated ERK, phosphorylated mTOR, and phosphorylated PI3K levels were examined by western blot analysis. Whole-cell patch-clamp recordings were executed to detect transient receptor potential vanilloid 1 (TRPV1) currents.Results: MaR1 demonstrated a more robust ability to promote sensory and motor function recovery in mice after sciatic nerve crush injury than NGF. Immunohistochemistry analyses showed that the administration of MaR1 to mice with nerve crush injury reduced the number of damaged DRG neurons, promoted injured nerve regeneration and inhibited gastrocnemius muscle atrophy. Western blot analysis of ND7/23 cells cultured with MaR1 revealed that MaR1 regulated neurite outgrowth through the PI3K-AKT-mTOR signaling pathway. Moreover, MaR1 dose-dependently attenuated the mechanical allodynia and thermal hyperalgesia induced by nerve injury. Consistent with the analgesic effect, MaR1 inhibited capsaicin-elicited TRPV1 currents, repressed the nerve injury-induced activation of spinal microglia and astrocytes and reduced the production of proinflammatory cytokines in the spinal cord dorsal horn in PNI mice.Conclusions: Application of MaR1 to PNI mice significantly promoted nerve regeneration and alleviated neuropathic pain, suggesting that MaR1 is a promising therapeutic agent for PNI.

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Astrocytic reprogramming combined with rehabilitation strategy improves recovery from spinal cord injury

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 34 publications

References 73 publications

L‐leucine promotes axonal outgrowth and regeneration via mTOR activation

L‐leucine promotes axonal outgrowth and regeneration via mTOR activation

Heterogeneity and molecular programming of progenitors for motor neurons and oligodendrocytes

Maresin 1 promotes nerve regeneration and alleviates neuropathic pain after nerve injury

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