Role of microtubule dynamics in Wallerian degeneration and nerve regeneration after peripheral nerve injury

Liu, Jingmin; Li, Lixia; Zou, Ying; Fu, Lanya; Ma, Xiaokun; Zhang, Haowen; Xu, Yizhou; Xu, Jikai; Zhang, Jiaqi; Li, Mi; Hu, Xiaofang; Li, Zhenlin; Wang, Xianghai; Sun, Hao; Zheng, Hui; Zhu, Lixin; Guo, Jiasong

doi:10.4103/1673-5374.320997

Cited by 17 publications

(9 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Then, TEM results confirmed that ES promotes the disintegration of myelin sheaths and axons as well as debris removal. In addition, RNA‐seq results showed that ES may activate the microtubule system and autophagy‐related signaling pathways, which have been shown to play critical roles in WD (Liu et al, 2022). We speculate that this is one reason why ES accelerates the clearance of myelin debris, and this issue warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Electrical stimulation accelerates Wallerian degeneration and promotes nerve regeneration after sciatic nerve injury

Zhang

et al. 2022

Glia

View full text Add to dashboard Cite

Following peripheral nerve injury (PNI), Wallerian degeneration (WD) in the distal stump can generate a microenvironment favorable for nerve regeneration. Brief low‐frequency electrical stimulation (ES) is an effective treatment for PNI, but the mechanism underlying its effect on WD remains unclear. Therefore, we hypothesized that ES could enhance nerve regeneration by accelerating WD. To verify this hypothesis, we used a rat model of sciatic nerve transection and provided ES at the distal stump of the injured nerve. The injured nerve was then evaluated after 1, 4, 7, 14 and 21 days post injury (dpi). The results showed that ES significantly promoted the degeneration and clearance of axons and myelin, and the dedifferentiation of Schwann cells. It upregulated the expression of BDNF and NGF and increased the number of monocytes and macrophages. Through transcriptome sequencing, we systematically investigated the effect of ES on the molecular processes involved in WD at 4 dpi. Evaluation of nerves bridged using silicone tubing after transection showed that ES accelerated early axonal and vascular regeneration while delaying gastrocnemius atrophy. These results demonstrate that ES promotes nerve regeneration by accelerating WD and upregulating the expression of neurotrophic factors.

show abstract

Section: Discussionmentioning

confidence: 99%

Electrical stimulation accelerates Wallerian degeneration and promotes nerve regeneration after sciatic nerve injury

Zhang

et al. 2022

Glia

View full text Add to dashboard Cite

show abstract

“…Adult mice (8 weeks, regardless of sex) were anesthetized with an intraperitoneal injection of 12 mg/mL tribromoethanol (180 mg/kg body weight), and then the right sciatic nerve was bluntly exposed. A crush injury at 0.3 cm distal to the sciatic notch was performed using a fine, smooth and straight hemostat (#EMZ-125-Z, Ermei, China) for 2 min, which established a sciatic nerve crush injury model [ 23 ]. A sciatic nerve transection injury model was established through a transection at 0.3 cm distal to the sciatic notch.…”

Section: Methodsmentioning

confidence: 99%

Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice

Wen

et al. 2021

J Neuroinflammation

Self Cite

View full text Add to dashboard Cite

Background Plenty of macrophages are recruited to the injured nerve to play key roles in the immunoreaction and engulf the debris of degenerated axons and myelin during Wallerian degeneration, thus creating a conducive microenvironment for nerve regeneration. Recently, drugs targeting the RhoA pathway have been widely used to promote peripheral axonal regeneration. However, the role of RhoA in macrophage during Wallerian degeneration and nerve regeneration after peripheral nerve injury is still unknown. Herein, we come up with the hypothesis that RhoA might influence Wallerian degeneration and nerve regeneration by affecting the migration and phagocytosis of macrophages after peripheral nerve injury. Methods Immunohistochemistry, Western blotting, H&E staining, and electrophysiology were performed to access the Wallerian degeneration and axonal regeneration after sciatic nerve transection and crush injury in the LyzCre+/−; RhoAflox/flox (cKO) mice or Lyz2Cre+/− (Cre) mice, regardless of sex. Macrophages’ migration and phagocytosis were detected in the injured nerves and the cultured macrophages. Moreover, the expression and potential roles of ROCK and MLCK were also evaluated in the cultured macrophages. Results 1. RhoA was specifically knocked out in macrophages of the cKO mice; 2. The segmentation of axons and myelin, the axonal regeneration, and nerve conduction in the injured nerve were significantly impeded while the myoatrophy was more severe in the cKO mice compared with those in Cre mice; 3. RhoA knockout attenuated the migration and phagocytosis of macrophages in vivo and in vitro; 4. ROCK and MLCK were downregulated in the cKO macrophages while inhibition of ROCK and MLCK could weaken the migration and phagocytosis of macrophages. Conclusions Our findings suggest that RhoA depletion in macrophages exerts a detrimental effect on Wallerian degeneration and nerve regeneration, which is most likely due to the impaired migration and phagocytosis of macrophages resulted from disrupted RhoA/ROCK/MLCK pathway. Since previous research has proved RhoA inhibition in neurons was favoring for axonal regeneration, the present study reminds us of that the cellular specificity of RhoA-targeted drugs is needed to be considered in the future application for treating peripheral nerve injury.

show abstract

“…An ex vivo PNI model was developed with a nerve explant culture to mimic the progress of Wallerian degeneration, as previously reported (Liu et al, 2022; Zou et al, 2022). Briefly, 10 days after the last tamoxifen injection, the sciatic nerves of adult icKO or Cre ERT2 mice were dissected and cut into 0.5 cm segments, then incubated in the Schwann cell culture medium (as described below).…”

Section: Methodsmentioning

confidence: 99%

Schwann cell‐specific RhoA knockout accelerates peripheral nerve regeneration via promoting Schwann cell dedifferentiation

Liu

et al. 2023

Glia

Self Cite

View full text Add to dashboard Cite

Our previous studies indicated that RhoA knockdown or inhibition could alleviate the proliferation, migration, and differentiation of Schwann cells. However, the role of RhoA in Schwann cells during nerve injury and repair is still unknown. Herein, we developed two lines of Schwann cells conditional RhoA knockout (cKO) mice by breeding RhoAflox/flox mice with PlpCre‐ERT2 or DhhCre mice. Our results indicate that RhoA cKO in Schwann cells accelerates axonal regrowth and remyelination after sciatic nerve injury, which enhances the recovery of nerve conduction and hindlimb gait, and alleviates the amyotrophy in gastrocnemius muscle. Mechanistic studies in both in vivo and in vitro models revealed that RhoA cKO could facilitate Schwann cell dedifferentiation via JNK pathway. Schwann cell dedifferentiation subsequently promotes Wallerian degeneration by enhancing phagocytosis and myelinophagy, as well as stimulating the production of neurotrophins (NT‐3, NGF, BDNF, and GDNF). These findings shed light on the role of RhoA in Schwann cells during nerve injury and repair, indicating that cell type‐specific RhoA targeting could serve as a promising molecular therapeutic strategy for peripheral nerve injury.

show abstract

Role of microtubule dynamics in Wallerian degeneration and nerve regeneration after peripheral nerve injury

Cited by 17 publications

References 60 publications

Electrical stimulation accelerates Wallerian degeneration and promotes nerve regeneration after sciatic nerve injury

Electrical stimulation accelerates Wallerian degeneration and promotes nerve regeneration after sciatic nerve injury

Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice

Schwann cell‐specific RhoA knockout accelerates peripheral nerve regeneration via promoting Schwann cell dedifferentiation

Contact Info

Product

Resources

About