c-Fos is necessary for HGF-mediated gene regulation and cell migration in Schwann cells

Ko, Kyeong Ryang; Lee, Jung-Hun; Nho, Boram; Kim, Sun‐Young

doi:10.1016/j.bbrc.2018.08.054

Cited by 14 publications

(20 citation statements)

References 16 publications

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“…Screening with receptor specific inhibitors in sciatic nerve explants to identify signals regulating Gab2 phosphorylation, Shin et al found that crizotinib, a selective c‐Met inhibitor, suppressed the tyrosine phosphorylation of Gab2, indicating that HGF regulates Gab2 phosphorylation in Schwann cells (Shin et al, 2017). HGF treatment not only induced tyrosine phosphorylation of Gab2 but also induced c‐Met phosphorylation, ERK and AKT activation in Schwann cells (Ko, Lee, Lee, et al, 2018; Ko, Lee, Nho, & Kim, 2018; Shin et al, 2017). HGF treatment also increased the level of cJun expression in Schwann cells and promoted Schwann cell migration (Ko, Lee, Lee, et al, 2018; Ko, Lee, Nho, & Kim, 2018; Shin et al, 2017).…”

Section: Signals Promoting Schwann Cell Migration Toward the Middle Omentioning

confidence: 99%

“…HGF treatment not only induced tyrosine phosphorylation of Gab2 but also induced c‐Met phosphorylation, ERK and AKT activation in Schwann cells (Ko, Lee, Lee, et al, 2018; Ko, Lee, Nho, & Kim, 2018; Shin et al, 2017). HGF treatment also increased the level of cJun expression in Schwann cells and promoted Schwann cell migration (Ko, Lee, Lee, et al, 2018; Ko, Lee, Nho, & Kim, 2018; Shin et al, 2017). Exogenous application of HGF around the injury site enhanced peripheral nerve regeneration while treatment with a c‐Met inhibitor (PHA‐665752) following injury inhibited peripheral nerve regeneration (Ko, Lee, Lee, et al, 2018).…”

Section: Signals Promoting Schwann Cell Migration Toward the Middle Omentioning

confidence: 99%

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Migrating Schwann cells direct axon regeneration within the peripheral nerve bridge

Parkinson²,

Dun

2020

Glia

153

117

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Schwann cells within the peripheral nervous system possess a remarkable regenerative potential. Current research shows that peripheral nerve-associated Schwann cells possess the capacity to promote repair of multiple tissues including peripheral nerve gap bridging, skin wound healing, digit tip repair as well as tooth regeneration. One of the key features of the specialized repair Schwann cells is that they become highly motile. They not only migrate into the area of damaged tissue and become a key component of regenerating tissue but also secrete signaling molecules to attract macrophages, support neuronal survival, promote axonal regrowth, activate local mesenchymal stem cells, and interact with other cell types. Currently, the importance of migratory Schwann cells in tissue regeneration is most evident in the case of a peripheral nerve transection injury. Following nerve transection, Schwann cells from both proximal and distal nerve stumps migrate into the nerve bridge and form Schwann cell cords to guide axon regeneration. The formation of Schwann cell cords in the nerve bridge is key to successful peripheral nerve repair following transection injury. In this review, we first examine nerve bridge formation and the behavior of Schwann cell migration in the nerve bridge, and then discuss how migrating Schwann cells direct regenerating axons into the distal nerve. We also review the current understanding of signals that could activate Schwann cell migration and signals that Schwann cells utilize to direct axon regeneration. Understanding the molecular mechanism of Schwann cell migration could potentially offer new therapeutic strategies for peripheral nerve repair.

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Section: Signals Promoting Schwann Cell Migration Toward the Middle Omentioning

confidence: 99%

Section: Signals Promoting Schwann Cell Migration Toward the Middle Omentioning

confidence: 99%

Migrating Schwann cells direct axon regeneration within the peripheral nerve bridge

Parkinson²,

Dun

2020

Glia

153

117

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“…The prolonged effects long after disappearance of the plasmid suggests that VM202 treatment may change the course of disease progression. For example, in animal models, HGF produced from intramuscularly injected VM202 interacts with the c‐Met receptor present on Schwann cells or sensory neurons via ERK or AP‐1 signaling pathways, respectively, to promote axon outgrowth 19,43 . Current therapies are palliative and do not target the mechanisms underlying painful DPN.…”

Section: Discussionmentioning

confidence: 99%

“…For example, in animal models, HGF produced from intramuscularly injected VM202 interacts with the c-Met receptor present on Schwann cells or sensory neurons via ERK or AP-1 signaling pathways, respectively, to promote axon outgrowth. 19,43 Current therapies are palliative and do not target the mechanisms underlying painful DPN. Thus, the availability of a potential therapy that changes pain-generating circuits and/or regenerates damaged nerves would fundamentally change approaches to painful DPN.…”

Section: Efficacymentioning

confidence: 99%

Gene therapy for diabetic peripheral neuropathy: A randomized, placebo‐controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor

Kessler

Shaibani

Sang

et al. 2021

Clinical Translational Sci

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VM202 is a plasmid DNA encoding two isoforms of hepatocyte growth factor (HGF). A previous phase II study in subjects with painful diabetic peripheral neuropathy (DPN) showed significant reductions in pain. A phase III study was conducted to evaluate the safety and efficacy of VM202 in DPN. The trial was conducted in two parts, one for 9 months (DPN 3‐1) with 500 subjects (VM202: 336 subjects; and placebo: 164) and a preplanned subset of 101 subjects (VM202: 65 subjects; and placebo: 36) with a noninterventional extension to 12 months (DPN 3‐1b). VM202 or placebo was administered to calf muscles on days 0 and 14, and on days 90 and 104. The primary end point in DPN 3‐1 was change from baseline in the mean 24‐h Numerical Rating Scale (NRS) pain score. In DPN 3‐1b, the primary end point was safety, whereas the secondary efficacy end point was change in the mean pain score. VM202 was well‐tolerated in both studies without significant adverse events. VM202 failed to meet its efficacy end points in DPN 3‐1. In DPN 3‐1b, however, VM202 showed significant and clinically meaningful pain reduction versus placebo. Pain reduction in DPN 3‐1b was even greater in subjects not receiving gabapentin or pregabalin, confirming an observation noted in the phase II study. In DPN 3‐1b, symptomatic relief was maintained for 8 months after the last injection suggesting that VM202 treatment might change disease progression. Despite the perplexing discrepancy between the two studies, the safety and long‐lasting pain‐relieving effects of VM202 observed in DPN 3‐1b warrant another rigorous phase III study. WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Current therapies for painful diabetic peripheral neuropathy (DPN) are palliative and do not target the underlying mechanisms. Moreover, symptomatic relief is often limited with existing neuropathic pain drugs. Thus, there is a great medical need for safer and effective treatments for DPN. WHAT QUESTION DID THIS STUDY ADDRESS? Can nonviral gene delivery of hepatocyte growth factor reduce pain in patients with DPN and potentially modify progression of the disorder? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Nonviral gene therapy can be used safely and practically to treat DPN. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? As the first gene medicine to enter advanced clinical trials for the treatment of DPN, this study provides the proof of concept of an entirely new potential approach to the disorder.

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“…FOS is a kind of immediate early gene, which is upregulated by hypoxia in a very short time [ 4 ], and it is responsible for the transcription of some late-response genes and cell damage. It is considered that the degree of cell damage is positively correlated to the expression level of FOS [ 5 ]. Acute hypoxia is also accompanied with the decrease of pH in the extracellular fluid due to the glycolysis enhancement.…”

Section: Introductionmentioning

confidence: 99%

Antagonistic Effects of Tetramethylpyrazine on Hypoxic Respiratory Depression in Rats

Gao

Liu

2020

Evidence-Based Complementary and Alternative Medicine

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Objective. Tetramethylpyrazine (TMP) is an alkaloid extracted from the root and stem of the traditional Chinese herbal medicine called Chuanxiong. The present study aims to study the effects of TMP on hypoxic respiratory depression in rats. Materials and methods. The effects of TMP on respiratory responses of rats induced by hypoxia were observed by diaphragm electromyogram (EMG) recording. The effects of TMP on the protein expression of FOS and acid sensing ion channel1a (ASIC1a) in the brainstem induced by hypoxia were investigated by immunohistochemistry. Results. The respiration of rats was first excited and then depressed during hypoxia treatment, while TMP pretreatment could significantly antagonize the respiratory depression induced by hypoxia P < 0.01 . Hypoxia obviously induced the protein expression of FOS P < 0.01 and ASIC1a P < 0.05 in the brainstem, which can be also significantly inhibited by TMP pretreatment. Conclusions. TMP has protective effects on hypoxic respiratory depression, and the mechanisms might be concerned with its downregulation of FOS and ASIC1a in the brainstem induced by hypoxia.

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c-Fos is necessary for HGF-mediated gene regulation and cell migration in Schwann cells

Cited by 14 publications

References 16 publications

Migrating Schwann cells direct axon regeneration within the peripheral nerve bridge

Migrating Schwann cells direct axon regeneration within the peripheral nerve bridge

Gene therapy for diabetic peripheral neuropathy: A randomized, placebo‐controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor

Antagonistic Effects of Tetramethylpyrazine on Hypoxic Respiratory Depression in Rats

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