Ethics and accountability for clinical trials.

In May 2023, a disclaimer posted on ClinicalTrials.gov dismisses accountability for the accuracy of registered information. For spinal cord injury, inconsistencies in intervention classification, phase designation, and lack of study protocols and results threaten the integrity of the database and put users at risk. An investment in what the resource should be rather than what it is not will give it the authority commensurate with the requirements for its regulatory use and informed decision-making for prospective trial participants.

Ketogenesis controls mitochondrial gene expression and rescues mitochondrial bioenergetics after cervical spinal cord injury in rats.

A better understanding of the secondary injury mechanisms that occur after traumatic spinal cord injury (SCI) is essential for the development of novel neuroprotective strategies linked to the restoration of metabolic deficits. We and others have shown that Ketogenic diet (KD), a high fat, moderate in proteins and low in carbohydrates is neuroprotective and improves behavioural outcomes in rats with acute SCI. Ketones are alternative fuels for mitochondrial ATP generation, and can modulate signaling pathways via targeting specific receptors. Here, we demonstrate that ad libitum administration of KD for 7 days after SCI rescued mitochondrial respiratory capacity, increased parameters of mitochondrial biogenesis, affected the regulation of mitochondrial-related genes, and activated the NRF2-dependent antioxidant pathway. This study demonstrates that KD improves post-SCI metabolism by rescuing mitochondrial function and supports the potential of KD for treatment of acute SCI in humans.

Diversity of Reactive Astrogliosis in CNS Pathology: Heterogeneity or Plasticity?

Astrocytes are essential for the development and homeostatic maintenance of the central nervous system (CNS). They are also critical players in the CNS injury response during which they undergo a process referred to as "reactive astrogliosis." Diversity in astrocyte morphology and gene expression, as revealed by transcriptional analysis, is well-recognized and has been reported in several CNS pathologies, including ischemic stroke, CNS demyelination, and traumatic injury. This diversity appears unique to the specific pathology, with significant variance across temporal, topographical, age, and sex-specific variables. Despite this, there is limited functional data corroborating this diversity. Furthermore, as reactive astrocytes display significant environmental-dependent plasticity and fate-mapping data on astrocyte subsets in the adult CNS is limited, it remains unclear whether this diversity represents heterogeneity or plasticity. As astrocytes are important for neuronal survival and CNS function post-injury, establishing to what extent this diversity reflects distinct established heterogeneous astrocyte subpopulations vs. environmentally dependent plasticity within established astrocyte subsets will be critical for guiding therapeutic development. To that end, we review the current state of knowledge on astrocyte diversity in the context of three representative CNS pathologies: ischemic stroke, demyelination, and traumatic injury, with the goal of identifying key limitations in our current knowledge and suggesting future areas of research needed to address them. We suggest that the majority of identified astrocyte diversity in CNS pathologies to date represents plasticity in response to dynamically changing post-injury environments as opposed to heterogeneity, an important consideration for the understanding of disease pathogenesis and the development of therapeutic interventions.

Temporal Progression of Acute Spinal Cord Injury Mechanisms in a Rat Model: Contusion, Dislocation, and Distraction.

Traumatic spinal cord injuries (SCIs) occur due to different spinal column injury patterns, including burst fracture, dislocation, and flexion-distraction. Pre-clinical studies modeling different SCI mechanisms have shown distinct histological differences between these injuries both acutely (3 h and less) and chronically (8 weeks), but there remains a temporal gap. Different rates of injury progression at specific regions of the spinal cord may provide insight into the pathologies that are initiated by specific SCI mechanisms. Therefore, the objective of this study was to evaluate the temporal progression of injury at specific tracts within the white matter, for time-points of 3 h, 24 h, and 7 days, for three distinct SCI mechanisms. In this study, 96 male Sprague Dawley rats underwent one of three SCI mechanisms: contusion, dislocation, or distraction. Animals were sacrificed at one of three times post-injury: 3 h, 24 h, or 7 days. Histological analysis using eriochrome cyanide and immunostaining for MBP, SMI-312, neurofilament-H (NF-H), and ß-III tubulin were used to characterize white matter sparing and axon and myelinated axon counts. The regions analyzed were the gracile fasciculus, cuneate fasciculus, dorsal corticospinal tract, and ventrolateral white matter. Contusion, dislocation, and distraction SCIs demonstrated distinct damage patterns that progressed differently over time. Myelinated axon counts were significantly reduced after dislocation and contusion injuries in most locations and time-points analyzed (compared with sham). This indicates early myelin damage often within 3 h. Myelinated axon counts after distraction dropped early and did not demonstrate any significant progression over the next 7 days. Important differences in white matter degeneration were identified between injury types, with distraction injuries showing the least variability across time-points These findings and the observation that white matter injury occurs early, and in many cases, without much dynamic change, highlight the importance of injury type in SCI research-both clinically and pre-clinically.

Ketogenic regimens for acute neurotraumatic events.

Dietary modification would be the most translatable, cost-efficient, and, likely, the safest approach available that can reduce the reliance on pharmaceutical treatments for treating acute or chronic neurological disorders. A wide variety of evidence suggests that the ketogenic diet (KD) could have beneficial effects in acute traumatic events, such as spinal cord injury and traumatic brain injury. Review of existing human and animal studies revealed that KD can improve motor neuro-recovery, gray matter sparing, pain thresholds, and neuroinflammation and decrease depression. Although the exact mechanism by which the KD provides neuroprotection is not fully understood, its effects on cellular energetics, mitochondria function and inflammation are likely to have a role.

Transplantation of Skin Precursor-Derived Schwann Cells Yields Better Locomotor Outcomes and Reduces Bladder Pathology in Rats with Chronic Spinal Cord Injury.

Cell transplantation for spinal cord injury (SCI) has largely been studied in sub-acute settings within 1-2 weeks of injury. In contrast, here we transplanted skin-derived precursors differentiated into Schwann cells (SKP-SCs) into the contused rat spinal cord 8 weeks post-injury (wpi). Twenty-one weeks later (29 wpi), SKP-SCs were found to have survived transplantation, integrated with host tissue, and mitigated the formation of a dense glial scar. Furthermore, transplanted SKP-SCs filled much of the lesion sites and greatly enhanced the presence of endogenous SCs, which myelinated thousands of sprouting/spared host axons in and around the injury site. In addition, SKP-SC transplantation improved locomotor outcomes and decreased pathological thickening of bladder wall. To date, functional improvements have very rarely been observed with cell transplantation beyond the sub-acute stage of injury. Hence, these findings indicate that skin-derived SCs are a promising candidate cell type for the treatment of chronic SCI.

Neuroprotective effects of a ketogenic diet in combination with exogenous ketone salts following acute spinal cord injury.

We have previously shown that induction of ketosis by ketogenic diet (KD) conveyed neuroprotection following spinal cord injury in rodent models, however, clinical translation may be limited by the slow raise of ketone levels when applying KD in the acute post-injury period. Thus we investigated the use of exogenous ketone supplementation (ketone sodium, KS) combined with ketogenic diet as a means rapidly inducing a metabolic state of ketosis following spinal cord injury in adult rats. In uninjured rats, ketone levels increased more rapidly than those in rats with KD alone and peaked at higher levels than we previously demonstrated for the KD in models of spinal cord injury. However, ketone levels in KD + KS treated rats with SCI did not exceed the previously observed levels in rats treated with KD alone. We still demonstrated neuroprotective effects of KD + KS treatment that extend our previous neuroprotective observations with KD only. The results showed increased neuronal and axonal sparing in the dorsal corticospinal tract. Also, better performance of forelimb motor abilities were observed on the Montoya staircase (for testing food pellets reaching) at 4 and 6 weeks post-injury and rearing in a cylinder (for testing forelimb usage) at 6 and 8 weeks post-injury. Taken together, the findings of this study add to the growing body of work demonstrating the potential benefits of inducing ketosis following neurotrauma. Ketone salt combined with a ketogenic diet gavage in rats with acute spinal cord injury can rapidly increase ketone body levels in the blood and promote motor function recovery. This study was approved by the Animal Care Committee of the University of British Columbia (protocol No. A14-350) on August 31, 2015.

Correction to: Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.

The article Niacin­mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system, written by Khalil S. Rawji, Adam M.H. Young, Tanay Ghosh, Nathan J. Michaels, Reza Mirzaei, Janson Kappen, Kathleen L. Kolehmainen, Nima Alaeiilkhchi, Brian Lozinski, Manoj K. Mishra, Annie Pu, Weiwen Tang, Salma Zein, Deepak K. Kaushik, Michael B. Keough, Jason R. Plemel, Fiona Calvert, Andrew J. Knights, Daniel J. Gaffney, Wolfram Tetzlaff, Robin J. M. Franklin and V. Wee Yong, was originally published electronically on the publisher's internet.

HDAC inhibition leads to age-dependent opposite regenerative effect upon PTEN deletion in rubrospinal axons after SCI.

Epigenetic changes associated with aging have been linked to functional and cognitive deficits in the adult CNS. Histone acetylation is involved in the control of the transcription of plasticity and regeneration-associated genes. The intrinsic axon growth capacity in the CNS is negatively regulated by phosphatase and tensin homolog (Pten). Inhibition of Pten is an effective method to stimulate axon growth following an injury to the optic nerve, corticospinal tract (CST), and rubrospinal tract (RST). Our laboratory has previously demonstrated that the deletion of Pten in aged animals diminishes the regenerative capacity in rubrospinal neurons. We hypothesize that changes in the chromatin structure might contribute to this age-associated decline. Here, we assessed whether Trichostatin A (TSA), a histone deacetylases (HDACs) inhibitor, reverses the decline in regeneration in aged Ptenf/f mice. We demonstrate that HDAC inhibition induces changes in the expression of GAP43 in both young and aged Ptenf/f mice. The regenerative capacity of the RST did not improve significantly in young mice, neither their motor function on the horizontal ladder or cylinder test after TSA treatment for 7 days. Interestingly, TSA treatment in the aged mice worsened their motor function deficits, suggesting that the systemic treatment with TSA might have an overall adverse effect on motor recovery after SCI in aged animals.

A Cervical Spinal Cord Hemi-Contusion Injury Model Based on Displacement Control in Non-Human Primates (Macaca fascicularis).

Non-human primate (NHP) spinal cord injury (SCI) models can be informative in the evaluation of treatments that show promise in rodent models prior to translation to humans. In the present study, we aimed to establish a cervical spinal hemi-contusion model with controlled displacement and evaluate the abnormalities in behavior, electrophysiology, histology, and magnetic resonance imaging. Twelve adult NHPs were divided into an SCI group (n = 8, 24 and 48 weeks) and a control group (n = 4). An impactor (Φ = 4 mm) was driven to compress the left C5 cord at 800 mm/sec. The contusion displacement and peak force was 4.08 ± 0.17 mm and 19.8 ± 4.6 N. The behavioral assessment showed a consistent dysfunction below the wrist and spontaneous recovery of limb function after injury. Lesion length and lesion area at the epicenter based on T2 hyperintensity were 5.68 ± 0.47 mm and 5.99 ± 0.24 mm2 at 24 weeks post-injury (wpi), and 5.29 ± 0.17 mm and 5.95 ± 0.24 mm2 at 48 wpi. The spared spinal cord area immuno-positive for glial fibrillary acidic protein was significantly reduced, while the staining intensity increased at 24 wpi and 48 wpi, compared with the sham group. Ipsilateral somatosensory and motor evoked potentials were dynamic, increasing in latency and decreasing in amplitude compared with pre-operative values or the contralateral values, and correlated to varying degrees with behavioral outcomes. A shift in size-frequency distribution of sensory neurons of the dorsal root ganglia (DRG) was consistent with a loss of large-diameter cells. The present study demonstrated that the NHP SCI model resulted in consistent unilateral limb dysfunction and potential plasticity in the face of loss of spinal cord and DRG tissue.

Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.

Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor CD36 of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of CD36 in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates CD36 expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9-12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis.

Effect of Velocity and Duration of Residual Compression in a Rat Dislocation Spinal Cord Injury Model.

Early decompression of the traumatically injured and persistently compressed spinal cord is intuitively beneficial for neurological outcome. Despite considerable pre-clinical evidence of a neurological benefit to early decompression, the effect of early surgical decompression in clinical spinal cord injury (SCI) remains less clear. The discrepancy between pre-clinical and clinical results may be due to differences between the biomechanical variables used in pre-clinical animal models and the biomechanical conditions occurring in clinical injuries. These pre-clinical variables include region of spinal cord, velocity of impact, and injury mechanism. In this study, the effect of velocity and duration of residual compression on injury severity were evaluated using a novel, rodent model of cervical dislocation SCI. Fifty-two male Sprague-Dawley rats were included in five groups: two timings of decompression (24 min, 240 min), two velocities (10 mm/sec, 500 mm/sec), and a sham group. All injuries involved a 1.45-mm dorsal dislocation of the C6 vertebra relative to C5 with subsequent residual compression of 0.8 mm. Animals were evaluated for motor function using the Martinez open field, grip strength, and grooming tests for 6 weeks post-injury. Immunohistochemistry and histology following sacrifice were conducted with counts for NeuN- and choline acetyltransferase (ChAT)-positive neurons, and length of cavitation. Behavioral testing and histological analysis revealed that injuries induced by the high velocity were consistently more severe than those induced by the low velocity, with behavioral correlations ranging between 0.46 and 0.58 (p < 0.05). Longer duration of residual compression did not produce significantly more severe injuries as measured by functional tests and histology. These findings demonstrate that the velocity of the initial traumatic impact may be a more important factor than duration of residual compression in determining SCI severity in a dislocation model of SCI.

FAIR SCI Ahead: The Evolution of the Open Data Commons for Pre-Clinical Spinal Cord Injury Research.

Over the last 5 years, multiple stakeholders in the field of spinal cord injury (SCI) research have initiated efforts to promote publications standards and enable sharing of experimental data. In 2016, the National Institutes of Health/National Institute of Neurological Disorders and Stroke hosted representatives from the SCI community to streamline these efforts and discuss the future of data sharing in the field according to the FAIR (Findable, Accessible, Interoperable and Reusable) data stewardship principles. As a next step, a multi-stakeholder group hosted a 2017 symposium in Washington, DC entitled "FAIR SCI Ahead: the Evolution of the Open Data Commons for Spinal Cord Injury research." The goal of this meeting was to receive feedback from the community regarding infrastructure, policies, and organization of a community-governed Open Data Commons (ODC) for pre-clinical SCI research. Here, we summarize the policy outcomes of this meeting and report on progress implementing these policies in the form of a digital ecosystem: the Open Data Commons for Spinal Cord Injury (ODC-SCI.org). ODC-SCI enables data management, harmonization, and controlled sharing of data in a manner consistent with the well-established norms of scholarly publication. Specifically, ODC-SCI is organized around virtual "laboratories" with the ability to share data within each of three distinct data-sharing spaces: within the laboratory, across verified laboratories, or publicly under a creative commons license (CC-BY 4.0) with a digital object identifier that enables data citation. The ODC-SCI implements FAIR data sharing and enables pooled data-driven discovery while crediting the generators of valuable SCI data.

The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury.

Oligodendrocyte progenitor cells (OPCs) are the most proliferative and dispersed population of progenitor cells in the adult central nervous system, which allows these cells to rapidly respond to damage. Oligodendrocytes and myelin are lost after traumatic spinal cord injury (SCI), compromising efficient conduction and, potentially, the long-term health of axons. In response, OPCs proliferate and then differentiate into new oligodendrocytes and Schwann cells to remyelinate axons. This culminates in highly efficient remyelination following experimental SCI in which nearly all intact demyelinated axons are remyelinated in rodent models. However, myelin regeneration comprises only one role of OPCs following SCI. OPCs contribute to scar formation after SCI and restrict the regeneration of injured axons. Moreover, OPCs alter their gene expression following demyelination, express cytokines and perpetuate the immune response. Here, we review the functional contribution of myelin regeneration and other recently uncovered roles of OPCs and their progeny to repair following SCI.

Skilled reaching deterioration contralateral to cervical hemicontusion in rats is reversed by pregabalin treatment conditional upon its early administration.

INTRODUCTION: Gabapentinoids are first-line treatments for painful traumatic and nontraumatic central nervous system disorders. Evidence from a large human study suggests that early use of gabapentinoids after spinal cord injury improves motor scores. The underlying mechanism is unknown. OBJECTIVES: We sought to examine the effects of early pregabalin (PGB, a gabapentinoid) treatment on performance in a fine motor task (skilled reaching) after cervical hemicontusion. We also asked whether early PGB administration affected PGB responsiveness later on. METHODS: Rats received C4/5 cervical hemicontusions. Injury severities ranged from 80 to 150 kdyn. We monitored evidence of skin irritation (peri-incisional and elsewhere) and quantified food pellet retrieval using the Montoya staircase test. Behaviours were assessed in rats receiving early (for 3 weeks from injury induction) and/or late (resuming or beginning at week 8) PGB treatment in animals with 150-kdyn injuries. RESULTS: Contralateral skilled reaching waned in control animals with 150-kdyn injuries. This was prevented in animals, which received early PGB as long as treatment continued. Deterioration of skilled reaching was reversed by later (week 8) PGB only in animals that had received early treatment. Ipsilateral reaching impairment was not improved by PGB. Relief of skin irritation verified early PGB efficacy. CONCLUSION: Hemicontusive spinal cord injury produces a contralateral motor phenotype evocative of on-going neuropathic pain. Early PGB preserves sensitivity to subsequent PGB treatment, indicating that motor function is impaired by neuropathic pain and can be improved indirectly by early PGB administration. Direct effects of PGB on motor circuitry cannot be excluded but are not supported by our data.

KIF2A characterization after spinal cord injury.

Axons in the central nervous system (CNS) typically fail to regenerate after injury. This failure is multi-factorial and caused in part by disruption of the axonal cytoskeleton. The cytoskeleton, in particular microtubules (MT), plays a critical role in axonal transport and axon growth during development. In this regard, members of the kinesin superfamily of proteins (KIFs) regulate the extension of primary axons toward their targets and control the growth of collateral branches. KIF2A negatively regulates axon growth through MT depolymerization. Using three different injury models to induce SCI in adult rats, we examined the temporal and cellular expression of KIF2A in the injured spinal cord. We observed a progressive increase of KIF2A expression with maximal levels at 10 days to 8 weeks post-injury as determined by Western blot analysis. KIF2A immunoreactivity was present in axons, spinal neurons and mature oligodendrocytes adjacent to the injury site. Results from the present study suggest that KIF2A at the injured axonal tips may contribute to neurite outgrowth inhibition after injury, and that its increased expression in inhibitory spinal neurons adjacent to the injury site might contribute to an intrinsic wiring-control mechanism associated with neuropathic pain. Further studies will determine whether KIF2A may be a potential target for the development of regeneration-promoting or pain-preventing therapies.

Development of a traumatic cervical dislocation spinal cord injury model with residual compression in the rat.

BACKGROUND: Preclinical spinal cord injury models do not represent the wide range of biomechanical factors seen in human injuries, such as spinal level, injury mechanism, velocity of spinal cord impact, and residual compression. These factors may be responsible for differences observed between experimental and clinical study results, especially related to the controversial issue of timing of surgical decompression. NEW METHOD: Somatosensory Evoked Potentials were used to: a) characterize residual compression depths in a dislocation model, and b) evaluate the physiological effect of whether or not the spinal cord was decompressed following the initial injury, prior to the application of residual compression. Modifications to vertebral clamps and the development of a novel surgical frame allowed us to conduct surgical and injury procedures in a controlled manner without the risk of additional damage to the spinal cord. Behavioural outcomes were evaluated following varying dislocation displacements, in addition to the survivability of 4 h of residual compression following a traumatic injury. RESULTS: Residual compression immediately following the initial dislocation demonstrated significantly different electrophysiological response compared to when the residual compression was delayed. COMPARISON WITH EXISTING METHOD: There are currently no other residual compression models that utilize a dislocation injury mechanism. Many residual compression studies have demonstrated the effectiveness of early decompression, however the compression of the spinal cord is often not representative of clinical traumatic injuries. Preclinical studies typically model residual compression using a sustained force through quasi-static application, when human injuries often occur at high velocities, followed by a sustained displacement occlusion of the spinal canal. CONCLUSIONS: This study has validated several novel procedural approaches and injury parameters, and provided critical details to implement in the development of a traumatic cervical dislocation SCI model with residual compression.

Basic biomechanics of spinal cord injury - How injuries happen in people and how animal models have informed our understanding.

The wide variability, or heterogeneity, in human spinal cord injury is due partially to biomechanical factors. This review summarizes our current knowledge surrounding the patterns of human spinal column injury and the biomechanical factors affecting injury. The biomechanics of human spinal injury is studied most frequently with human cadaveric models and the features of the two most common injury patterns, burst fracture and fracture dislocation, are outlined. The biology of spinal cord injury is typically studied with animal models and the effects of the most relevant biomechanical factors - injury mechanism, injury velocity, and residual compression, are described. Tissue damage patterns and behavioural outcomes following dislocation or distraction injury mechanisms differ from the more commonly used contusion mechanism. The velocity of injury affects spinal cord damage, principally in the white matter. Ongoing, or residual compression after the initial impact does affect spinal cord damage, but few models exist that replicate the clinical scenario. Future research should focus on the effects of these biomechanical factors in different preclinical animal models as recent data suggests that treatment outcomes may vary between models.

Diffusion tensor imaging shows mechanism-specific differences in injury pattern and progression in rat models of acute spinal cord injury.

We investigate the ability of diffusion tensor imaging (DTI) to distinguish between three experimental rat models of spinal cord injury mechanism - contusion, dislocation, and distraction. Ex vivo DTI scans were performed on cord specimens that were preserved at different time points of the acute injury (3 hr, 24 hr, and 7 days post-injury) across all three injury mechanisms. White matter was classified as abnormal if their DTI metric was substantially different from regional values measured from a set of uninjured controls, thus allowing generation of binary "white matter damage maps" which categorizes each pixel in the DTI image as "normal" or "damaged". Damage classification was most robust using thresholds in the longitudinal diffusivity, which supports previous studies that show that longitudinal diffusivity is the most robust DTI metric in depicting damage in SCI. Furthermore, the spatial damage patterns from all subjects in the same group were consolidated into a "damage occurrence ratio map", which illustrates an average damage shape that characterizes the injury mechanism. Our analysis has yielded a dataset which highlights the differences in injury pattern due to the initial mode of mechanical injury. For example, contusion produced an initial injury that emanated radially outward from the central canal, with subsequent damage along the caudal corticospinal tract and rostral gracile fasciculus; dislocation injuries showed a high level of involvement in the lateral and ventral white matter which became less apparent by 7 days post-injury, and distraction injuries were found to be less focal and more distributed rostrocaudally. This work represents a first step in adopting the use of the primary injury mechanism as a clinical prognostic factor in SCI, which may help to inform the trialing of existing neuroprotective treatment candidates, the development of new therapies as well as personalize the management of SCI for the individual patient.

Factors Within the Endoneurial Microenvironment Act to Suppress Tumorigenesis of MPNST.

Background: Deciphering avenues to adequately control malignancies in the peripheral nerve will reduce the need for current, largely-ineffective, standards of care which includes the use of invasive, nerve-damaging, resection surgery. By avoiding the need for en bloc resection surgery, the likelihood of retained function or efficient nerve regeneration following the control of tumor growth is greater, which has several implications for long-term health and well-being of cancer survivors. Nerve tumors can arise as malignant peripheral nerve sheath tumors (MPNST) that result in a highly-aggressive form of soft tissue sarcoma. Although the precise cause of MPNST remains unknown, studies suggest that dysregulation of Schwann cells, mediated by the microenvironment, plays a key role in tumor progression. This study aimed to further characterize the role of local microenvironment on tumor progression, with an emphasis on identifying factors within tumor suppressive environments that have potential for therapeutic application. Methods: We created GFP-tagged adult induced tumorigenic Schwann cell lines (iSCs) and transplanted them into various in vivo microenvironments. We used immunohistochemistry to document the response of iSCs and performed proteomics analysis to identify local factors that might modulate divergent iSC behaviors. Results: Following transplant into the skin, spinal cord or epineurial compartment of the nerve, iSCs formed tumors closely resembling MPNST. In contrast, transplantation into the endoneurial compartment of the nerve significantly suppressed iSC proliferation. Proteomics analysis revealed a battery of factors enriched within the endoneurial compartment, of which one growth factor of interest, ciliary neurotrophic factor (CNTF) was capable of preventing iSCs proliferation in vitro. Conclusions: This dataset describes a novel approach for identifying biologically relevant therapeutic targets, such as CNTF, and highlights the complex relationship that tumor cells have with their local microenvironment. This study has significant implications for the development of future therapeutic strategies to fight MPNSTs, and, consequently, improve peripheral nerve regeneration and nerve function.