No abstract

Recently, we showed that Schwann cells transfer ribosomes to injured axons. Here, we demonstrate that Schwann cells transfer ribosomes to regenerating axons in vivo. For this, we used lentiviral vector-mediated expression of ribosomal protein L4 and eGFP to label ribosomes in Schwann cells. Two approaches were followed. First, we transduced Schwann cells in vivo in the distal trunk of the sciatic nerve after a nerve crush. Seven days after the crush, 12% of regenerating axons contained fluorescent ribosomes. Second, we transduced Schwann cells in vitro that were subsequently injected into an acellular nerve graft that was inserted into the sciatic nerve. Fluorescent ribosomes were detected in regenerating axons up to 8 weeks after graft insertion. Together, these data indicate that regenerating axons receive ribosomes from Schwann cells and, furthermore, that Schwann cells may support local axonal protein synthesis by transferring protein synthetic machinery and mRNAs to these axons.

Peripheral nerve injury remains a major cause of morbidity in trauma patients. Despite advances in microsurgical techniques and improved understanding of nerve regeneration, obtaining satisfactory outcomes after peripheral nerve injury remains a difficult clinical problem. There is a growing body of evidence in preclinical animal studies demonstrating the supportive role of stem cells in peripheral nerve regeneration after injury. The characteristics of both mesoderm‐derived and ectoderm‐derived stem cell types and their role in peripheral nerve regeneration are discussed, specifically focusing on the presentation of both foundational laboratory studies and translational applications. The current state of clinical translation is presented, with an emphasis on both ethical considerations of using stems cells in humans and current governmental regulatory policies. Current advancements in cell‐based therapies represent a promising future with regard to supporting nerve regeneration and achieving significant functional recovery after debilitating nerve injuries.

In this review article, the authors offer their perspective on nerve surgery for nerve injury, with a focus on recent evolution of management and the current surgical management. The authors provide a brief historical perspective to lay the foundations of the modern understanding of clinical nerve injury and its evolving management, especially over the last century. The shift from evaluation of the nerve injury using macroscopic techniques of exploration and external neurolysis to microscopic interrogation, interfascicular dissection, and internal neurolysis along with the use of intraoperative electrophysiology were important advances of the past 50 years. By the late 20th century, the advent and popularization of interfascicular nerve grafting techniques heralded a major advance in nerve reconstruction and allowed good outcomes to be achieved in a large percentage of nerve injury repair cases. In the past 2 decades, there has been a paradigm shift in surgical nerve repair, wherein surgeons are not only directing the repair at the injury zone, but also are deliberately performing distal-targeted nerve transfers as a preferred alternative in an attempt to restore function. The peripheral rewiring approach allows the surgeon to convert a very proximal injury with long regeneration distances and (often) uncertain outcomes to a distal injury and repair with a greater potential of regenerative success and functional recovery. Nerve transfers, originally performed as a salvage procedure for severe brachial plexus avulsion injuries, are now routinely done for various less severe brachial plexus injuries and many other proximal nerve injuries, with reliably good to even excellent results. The outcomes from nerve transfers for select clinical nerve injury are emphasized in this review. Extension of the rewiring paradigm with nerve transfers for CNS lesions such as spinal cord injury and stroke are showing great potential and promise. Cortical reeducation is required for success, and an emerging field of rehabilitation and restorative neurosciences is evident, which couples a nerve transfer procedure to robotically controlled limbs and mind-machine interfacing. The future for peripheral nerve repair has never been more exciting.

Skin-derived precursor Schwann cell (SKPSC) therapy has been identified as a potentially beneficial treatment for peripheral nerve injuries. One hypothesised mechanism by which SKPSCs enhance recovery is via the modulation of macrophages. In the present study, we investigated the immunomodulatory properties of adult rat SKPSCs, and demonstrated that these cells expressed a battery of cytokines, including interferon-γ (IFN-γ), interleukin (IL)-1β, and, most abundantly, IL-6. Whereas macrophages exposed to depleted or fibroblast-conditioned medium secreted minimal amounts of tumor necrosis factor-α (TNF-α), in the presence of SKPSC-conditioned medium, macrophages secreted > 500 pg/mL TNF-α. Following the transplantation of SKPSCs into injured rat sciatic nerves, we observed an SKPSC density-dependent increase in the number of macrophages (Pearson's r = 0.66) and an SKPSC density-dependent decrease in myelin debris (Pearson's r = -0.68). To determine the effect of IL-6 in a proinflammatory context, macrophage cultures were primed with either lipopolysaccharide (LPS)/IFN-γ/IL-1β or LPS/IFN-γ/IL-1β + IL-6, and this showed a 212% and 301% increase in the number of inducible nitric oxide synthase (iNOS)-positive proinflammatory macrophages respectively. In contrast to neurons exposed to conditioned medium from unprimed macrophages, neurons treated with conditioned medium from proinflammatory-primed macrophages showed a 13-26% reduction in neurite outgrowth. Anti-IL-6 antibody combined with SKPSC transplant therapy following nerve injury did not alter macrophage numbers or debris clearance, but instead reduced iNOS expression as compared with SKPSC + IgG-treated rats. SKPSC + anti-IL-6 treatment also resulted in a two-fold increase in gastrocnemius compound muscle action potential amplitudes as compared with SKPSC + IgG treatment. Understanding the mechanisms underlying immunomodulatory aspects of SKPSC therapy and developing approaches to manipulate these responses are important for advancing Schwann cell-based therapies.

While damaged peripheral nerves demonstrate some potential to regenerate, complete functional recovery remains infrequent, owing to a functional loss of supportive Schwann cells distal to the injury. An emerging solution to improve upon this intrinsic regenerative capacity is to supplement injured nerves with stem cells derived from various tissues. While many of these strategies have proven successful in animal models, few studies have examined the behavior of transplanted stem cells in vivo, including whether they survive and differentiate. In previous work, we demonstrated that cells derived from neonatal rodent dermis (skin-derived precursor cells, or SKPs) could improve regenerative parameters when transplanted distal to both acute and chronic nerve injuries in Lewis rats. The aim of this work was to track the fate of these cells in various nerve injury paradigms and determine the response of these cells to a known glial growth factor. Here, we report that SKPs survive, respond to local cues, differentiate into myelinating Schwann cells, and avoid complete clearance by the host's immune defenses for a minimum of 10weeks. Moreover, the ultimate fate of SKPs in vivo depends on the nerve environment into which they are injected and can be modified by inclusion of heregulin-1β.

Acute spinal cord injury (SCI) is devastating for patients and their caretakers and has an annual incidence of 20–50 per million people. Following initial assessment with appropriate physical examination and imaging, patients who are deemed surgical candidates should undergo decompression with stabilization. Earlier intervention can improve neurological recovery in the post-operative period while allowing earlier mobilization. Optimized medical management is paramount to improve outcomes. Emerging strategies for managing SCI in the acute period stem from an evolving understanding of the pathophysiology of the injury. General areas of focus include ischemia prevention, reduction of secondary injury due to inflammation, modulation of the cytotoxic and immune response, and promotion of cellular regeneration. In this article, we review established, emerging, and novel experimental therapies. Continued translational research on these methods will improve the feasibility of bench-to-bedside innovations in treating patients with acute SCI.

SKP-SCs are robustly capable of myelination. They improve the recovery of a focal tibial nerve demyelination model by myelinating a measured percentage of axons.