Inhibition of RhoA-Subfamily GTPases Suppresses Schwann Cell Proliferation Through Regulating AKT Pathway Rather Than ROCK Pathway

Tan, Dandan; Wen, Jinkun; Li, Lixia; Wang, Xianghai; Qian, Changhui; Pan, Mengjie; Lai, Muhua; Deng, Junyao; Hu, Xiaofang; Zhang, Haowen; Guo, Jiasong

doi:10.3389/fncel.2018.00437

Cited by 20 publications

(13 citation statements)

References 43 publications

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“…Rho GTPases: small GTPases of the Rho (e.g., Cdc42, RhoA, Rac1) and Ras (RalA, RalB) families act as molecular switches, shuttling between activated GTP-bound and inactive GDP-bound states. Rho and Ras GTPases regulate cytoskeletal organization in Schwann cells to modulate critical events such as radial sorting during development (Benninger et al, 2007 ; Guo et al, 2013 ; Tan et al, 2018 ; Ommer et al, 2019 ). The chronic lack of Ral proteins in Schwann cells impairs radial sorting, resulting in the formation of unmyelinated or hypo-myelinated large-caliber axons, and abnormalities in the myelin sheath (Ommer et al, 2019 ).…”

Section: Schwann Cells: Understanding Development To Engineer Repairmentioning

confidence: 99%

Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury

Balakrishnan

Belfiore

Chu

et al. 2021

Front. Mol. Neurosci.

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Peripheral nerve injuries arising from trauma or disease can lead to sensory and motor deficits and neuropathic pain. Despite the purported ability of the peripheral nerve to self-repair, lifelong disability is common. New molecular and cellular insights have begun to reveal why the peripheral nerve has limited repair capacity. The peripheral nerve is primarily comprised of axons and Schwann cells, the supporting glial cells that produce myelin to facilitate the rapid conduction of electrical impulses. Schwann cells are required for successful nerve regeneration; they partially “de-differentiate” in response to injury, re-initiating the expression of developmental genes that support nerve repair. However, Schwann cell dysfunction, which occurs in chronic nerve injury, disease, and aging, limits their capacity to support endogenous repair, worsening patient outcomes. Cell replacement-based therapeutic approaches using exogenous Schwann cells could be curative, but not all Schwann cells have a “repair” phenotype, defined as the ability to promote axonal growth, maintain a proliferative phenotype, and remyelinate axons. Two cell replacement strategies are being championed for peripheral nerve repair: prospective isolation of “repair” Schwann cells for autologous cell transplants, which is hampered by supply challenges, and directed differentiation of pluripotent stem cells or lineage conversion of accessible somatic cells to induced Schwann cells, with the potential of “unlimited” supply. All approaches require a solid understanding of the molecular mechanisms guiding Schwann cell development and the repair phenotype, which we review herein. Together these studies provide essential context for current efforts to design glial cell-based therapies for peripheral nerve regeneration.

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Section: Schwann Cells: Understanding Development To Engineer Repairmentioning

confidence: 99%

Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury

Balakrishnan

Belfiore

Chu

et al. 2021

Front. Mol. Neurosci.

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“…Therefore, inhibitors of RhoA or ROCK are commonly utilized to promote peripheral nerve regeneration [ 6 , 7 ]. However, considering that the drugs used to treat the injured nerve may not just affect neurons but also impact on other cells, and a certain molecule might play diverse roles in different cell types [ 8 – 10 ]. Hence, we believe that revealing the role of RhoA in different cells is necessary.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, our team has found several surprising effects of RhoA on Schwann cells, such as RhoA knockdown depressing Schwann cell’s proliferation, migration, and myelination, and the typical downstream molecule ROCK does not contribute to some effects of RhoA on Schwann cells. For example, RhoA regulates Schwann cell’s differentiation through JNK pathway, while influencing its proliferation by regulating AKT pathway [ 8 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

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

Wen

et al. 2021

J Neuroinflammation

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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.

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“…However, it is also reported that active YAP/TAZ is not required for injury-induced SC proliferation in the early phase of nerve regeneration [ 24 ]. Furthermore, Y-27632 treatment does not alter SC proliferation rates because RhoA regulates SC proliferation through AKT rather than ROCK signaling [ 75 ]. When compared to our results, it is promising to transiently suppress ROCK or YAP/TAZ activity at the onset of nerve regeneration, which may help promote SC regenerative ability without impacting SC proliferation rates.…”

Section: Discussionmentioning

confidence: 99%

Cell Shape and Matrix Stiffness Impact Schwann Cell Plasticity via YAP/TAZ and Rho GTPases

Orkwis

Harris

2021

IJMS

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Schwann cells (SCs) are a highly plastic cell type capable of undergoing phenotypic changes following injury or disease. SCs are able to upregulate genes associated with nerve regeneration and ultimately achieve functional recovery. During the regeneration process, the extracellular matrix (ECM) and cell morphology play a cooperative, critical role in regulating SCs, and therefore highly impact nerve regeneration outcomes. However, the roles of the ECM and mechanotransduction relating to SC phenotype are largely unknown. Here, we describe the role that matrix stiffness and cell morphology play in SC phenotype specification via known mechanotransducers YAP/TAZ and RhoA. Using engineered microenvironments to precisely control ECM stiffness, cell shape, and cell spreading, we show that ECM stiffness and SC spreading downregulated SC regenerative associated proteins by the activation of RhoA and YAP/TAZ. Additionally, cell elongation promoted a distinct SC regenerative capacity by the upregulation of Rac1/MKK7/JNK, both necessary for the ECM and morphology changes found during nerve regeneration. These results confirm the role of ECM signaling in peripheral nerve regeneration as well as provide insight to the design of future biomaterials and cellular therapies for peripheral nerve regeneration.

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Inhibition of RhoA-Subfamily GTPases Suppresses Schwann Cell Proliferation Through Regulating AKT Pathway Rather Than ROCK Pathway

Cited by 20 publications

References 43 publications

Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury

Insights Into the Role and Potential of Schwann Cells for Peripheral Nerve Repair From Studies of Development and Injury

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

Cell Shape and Matrix Stiffness Impact Schwann Cell Plasticity via YAP/TAZ and Rho GTPases

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