Rat models of complete and partial injuries are the most frequently used models for analysis of the cellular and molecular processes of nerve regeneration and axon sprouting. Studies of nerve ...regeneration and axon sprouting after complete and partial nerve injuries, respectively, are reviewed. Special consideration is made of the peripheral nerves chosen for the studies and the outcome measures that were utilized in the studies. The studies have made important contributions to our knowledge of the degenerative and regenerative processes that occur after the peripheral nerve injuries, why functional recovery is frequently compromised after delayed surgery, the positive effects of neurotrophic factors on nerve regeneration after delayed nerve repair or after insertion of autografts between transected nerve, and how axon regeneration may be accelerated by brief periods of electrical stimulation and/or by administration of androgens.
RNA-binding proteins Lin28a/b regulate cellular growth and tissue regeneration. Here, we investigated the role of Lin28 in the control of axon regeneration in postmitotic neurons. We find that ...Lin28a/b are both necessary and sufficient for supporting axon regeneration in mature sensory neurons through their regulatory partners, let-7 microRNAs (miRNAs). More importantly, overexpression of Lin28a in mature retinal ganglion cells (RGCs) produces robust and sustained optic nerve regeneration. Additionally, combined overexpression of Lin28a and downregulation of Pten in RGCs act additively to promote optic nerve regeneration, potentially by reducing the backward turning of regenerating RGC axons. Our findings not only reveal a vital role of Lin28 signaling in regulating mammalian axon regeneration but also identify a signaling pathway that can promote axon regeneration in the central nervous system (CNS).
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•Upregulation of Lin28a/b is necessary and sufficient for sensory axon regeneration•let-7 microRNAs act downstream of Lin28a/b in regulating sensory axon regeneration•Upregulation of Lin28a in RGCs induces robust and sustained optic nerve regeneration•Lin28a overexpression and Pten knockdown have additive effect on axon regeneration
Axon regeneration in the mammalian CNS is a challenge. Wang et al. show that the Lin28/let-7 axis plays an important role in governing mammalian axon regeneration in the peripheral nervous system. More importantly, overexpression of Lin28a induces robust and sustained axon regeneration in the CNS.
Peripheral nerve injury (PNI) is a major burden to society with limited therapeutic options, and novel biomaterials have great potential for shifting the current paradigm of treatment. With a rising ...prevalence of chronic illnesses such as diabetes mellitus (DM), treatment of PNI is further complicated, and only few studies have proposed therapies suitable for peripheral nerve regeneration in DM. To provide a supportive environment to restore structure and/or function of nerves in DM, we developed a novel thermo-sensitive heparin-poloxamer (HP) hydrogel co-delivered with basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) in diabetic rats with sciatic nerve crush injury. The delivery vehicle not only had a good affinity for large amounts of growth factors (GFs), but also controlled their release in a steady fashion, preventing degradation in vitro. In vivo, compared with HP hydrogel alone or direct GFs administration, GFs-HP hydrogel treatment is more effective at facilitating Schwann cell (SC) proliferation, leading to an increased expression of nerve associated structural proteins, enhanced axonal regeneration and remyelination, and improved recovery of motor function (all p < 0.05). Our mechanistic investigation also revealed that these neuroprotective and neuroregenerative effects of the GFs-HP hydrogel may be associated with activations of phosphatidylinositol 3 kinase and protein kinase B (PI3K/Akt), janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways. Our work provides a promising therapy option for peripheral nerve regeneration in patients with DM.
Tissue repair after spinal cord injury requires the mobilization of immune and glial cells to form a protective barrier that seals the wound and facilitates debris clearing, inflammatory containment ...and matrix compaction. This process involves corralling, wherein phagocytic immune cells become confined to the necrotic core, which is surrounded by an astrocytic border. Here we elucidate a temporally distinct gene signature in injury-activated microglia and macrophages (IAMs) that engages axon guidance pathways. Plexin-B2 is upregulated in IAMs and is required for motor sensory recovery after spinal cord injury. Plexin-B2 deletion in myeloid cells impairs corralling, leading to diffuse tissue damage, inflammatory spillover and hampered axon regeneration. Corralling begins early and requires Plexin-B2 in both microglia and macrophages. Mechanistically, Plexin-B2 promotes microglia motility, steers IAMs away from colliding cells and facilitates matrix compaction. Our data therefore establish Plexin-B2 as an important link that integrates biochemical cues and physical interactions of IAMs with the injury microenvironment during wound healing.
Interleukin-4 (IL-4) has garnered interest as a cytokine that mediates regeneration across multiple tissues including peripheral nerve. Within nerve, we previously showed endogenous IL-4 was critical ...to regeneration across nerve gaps. Here, we determined a generalizable role of IL-4 in nerve injury and regeneration. In wild-type (WT) mice receiving a sciatic nerve crush, IL-4 expressing cells preferentially accumulated within the injured nerve compared to affected sites proximal, such as dorsal root ganglia (DRGs), or distal muscle. Immunohistochemistry and flow cytometry confirmed that eosinophils (CD45+, CD11b+, CD64−, Siglec-F+) were sources of IL-4 expression. Examination of targets for IL-4 within nerve revealed macrophages, as well as subsets of neurons expressed IL-4R, while Schwann cells expressed limited IL-4R. Dorsal root ganglia cultures were exposed to IL-4 and demonstrated an increased proportion of neurons that extended axons compared to cultures without IL-4 (control), as well as longer myelinated axons compared to cultures without IL-4. The role of endogenous IL-4 during nerve injury and regeneration in vivo was assessed following a sciatic nerve crush using IL-4 knockout (KO) mice. Loss of IL-4 affected macrophage accumulation within injured nerve compared to WT mice, as well as shifted macrophage phenotype towards a CD206- phenotype with altered gene expression. Furthermore, this loss of IL-4 delayed initial axon regeneration from the injury crush site and subsequently delayed functional recovery and re-innervation of neuromuscular junctions compared to wild-type mice. Given the role of endogenous IL-4 in nerve regeneration, exogenous IL-4 was administered daily to WT mice following a nerve crush to examine regeneration. Daily IL-4 administration increased early axonal extension and CD206+ macrophage accumulation but did not alter functional recovery compared to untreated mice. Our data demonstrate IL-4 promotes nerve regeneration and recovery after injury.
•Eosinophils are a source of IL-4 within injured nerve.•Loss of IL-4 impeded axonal regeneration and functional recovery.•Macrophages alter their phenotype in the absence of IL-4.•Neurons enhance their axonal extension and myelination in the presence of IL-4.•Exogenous IL-4 promotes axonal regeneration and alters macrophage phenotype.
Peripheral nerve injury (PNI), causing loss of sensory and motor function, is a complex and challenging disease in the clinic due to the restricted regeneration capacity. Nerve guidance conduits ...(NGCs) have become a promising substitute for peripheral nerve regeneration, but their efficacy is often limited. Here, inspired by the physiological structures of peripheral nerves, we present a conductive topological scaffold for nerve repair by modifying
butterfly wing with reduced graphene oxide (rGO) nanosheets and methacrylated gelatin (GelMA) hydrogel encapsulated brain-derived neurotrophic factor (BDNF). Benefiting from the biocompatibility of GelMA hydrogel, the conductivity of rGO and parallel nanoridge structures of wing scales, PC12 cells, and neural stem cells grown on the modified wing have an increased neurite length with guided cellular orientation. In addition, the NGCs are successfully obtained by manually rolling up the scaffolds and exhibited great performance in repairing 10 mm sciatic nerve defects in rats, and we believe that the NGCs can be applied in reparing longer nerve defects in the future by further optimization. We also demonstrate the feasibility of electrically conductive NGCs based on the rGO/BDNF/GelMA-integrated
butterfly wing as functional nerve regeneration conduits, which may have potential value for application in repairing peripheral nerve injuries.
A favorable microenvironment plays an important role in nerve regeneration. Extracellular matrix (ECM) derived from cultured cells or natural tissues can facilitate nerve regeneration in the presence ...of various microenvironmental cues, including biochemical, spatial, and biomechanical factors. This study, through proteomics and three-dimensional image analysis, determines that the components and spatial organization of the ECM secreted by bone marrow mesenchymal cells (BMSCs) are more similar to acellular nerves than those of the ECMs derived from Schwann cells (SCs), skin-derived precursor Schwann cells (SKP–SCs), or fibroblasts (FBs). ECM-modified nerve grafts (ECM-NGs) are engineered by co-cultivating BMSCs, SCs, FBs, SKP-SCs with well-designed nerve grafts used to bridge nerve defects. BMSC-ECM-NGs exhibit the most promising nerve repair properties based on the histology, neurophysiology, and behavioral analyses. The regeneration microenvironment formed by the ECM-NGs is also characterized by proteomics, and the advantages of BMSC-ECM-NGs are evidenced by the enhanced expression of factors related to neural regeneration and reduced immune response. Together, these findings indicate that BMSC-derived ECMs create a more superior microenvironment for nerve regeneration than that by the other ECMs and may, therefore, represent a potential alternative for the clinical repair of peripheral nerve defects.
Axon regeneration failure accounts for permanent functional deficits following CNS injury in adult mammals. However, the underlying mechanisms remain elusive. In analyzing axon regeneration in ...different mutant mouse lines, we discovered that deletion of suppressor of cytokine signaling 3 (
SOCS3) in adult retinal ganglion cells (RGCs) promotes robust regeneration of injured optic nerve axons. This regeneration-promoting effect is efficiently blocked in
SOCS3-gp130 double-knockout mice, suggesting that
SOCS3 deletion promotes axon regeneration via a gp130-dependent pathway. Consistently, a transient upregulation of ciliary neurotrophic factor (CNTF) was observed within the retina following optic nerve injury. Intravitreal application of CNTF further enhances axon regeneration from
SOCS3-deleted RGCs. Together, our results suggest that compromised responsiveness to injury-induced growth factors in mature neurons contributes significantly to regeneration failure. Thus, developing strategies to modulate negative signaling regulators may be an efficient strategy of promoting axon regeneration after CNS injury.
Peripheral nerve injury (PNI) is a serious clinical health problem caused by the damage of peripheral nerves which results in neurological deficits and permanent disability. There are several factors ...that may cause PNI such as localized damage (car accident, trauma, electrical injury) and outbreak of the systemic diseases (autoimmune or diabetes). While various diagnostic procedures including X-ray, magnetic resonance imaging (MRI), as well as other type of examinations such as electromyography or nerve conduction studies have been efficiently developed, a full recovery in patients with PNI is in many cases deficient or incomplete. This is the reason why additional therapeutic strategies should be explored to favor a complete rehabilitation in order to get appropriate nerve injury regeneration. The use of biomaterials acting as scaffolds opens an interesting approach in regenerative medicine and tissue engineering applications due to their ability to guide the growth of new tissues, adhesion and proliferation of cells including the expression of bioactive signals. This review discusses the preparation and therapeutic strategies describing in vitro and in vivo experiments using graphene-based materials in the context of PNI and their ability to promote nerve tissue regeneration.
•Peripheral nerve injuries result in neurological deficits and permanent disability.•A full recovery in patients with peripheral nerve injury is in many cases deficient or incomplete.•Graphene and its derivatives can be used for the preparation of scaffolds for neural tissue engineering.•The presence of graphene or derivatives in hybrid materials influences both cell adhesion and cell proliferation.
Injured peripheral nerves regenerate their lost axons but functional recovery in humans is frequently disappointing. This is so particularly when injuries require regeneration over long distances ...and/or over long time periods. Fat replacement of chronically denervated muscles, a commonly accepted explanation, does not account for poor functional recovery. Rather, the basis for the poor nerve regeneration is the transient expression of growth-associated genes that accounts for declining regenerative capacity of neurons and the regenerative support of Schwann cells over time. Brief low-frequency electrical stimulation accelerates motor and sensory axon outgrowth across injury sites that, even after delayed surgical repair of injured nerves in animal models and patients, enhances nerve regeneration and target reinnervation. The stimulation elevates neuronal cyclic adenosine monophosphate and, in turn, the expression of neurotrophic factors and other growth-associated genes, including cytoskeletal proteins. Electrical stimulation of denervated muscles immediately after nerve transection and surgical repair also accelerates muscle reinnervation but, at this time, how the daily requirement of long-duration electrical pulses can be delivered to muscles remains a practical issue prior to translation to patients. Finally, the technique of inserting autologous nerve grafts that bridge between a donor nerve and an adjacent recipient denervated nerve stump significantly improves nerve regeneration after delayed nerve repair, the donor nerves sustaining the capacity of the denervated Schwann cells to support nerve regeneration. These reviewed methods to promote nerve regeneration and, in turn, to enhance functional recovery after nerve injury and surgical repair are sufficiently promising for early translation to the clinic.
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