This study was initiated due to an NIH "Facilities of Research--Spinal Cord Injury" contract to support independent replication of published studies that could be considered for a clinical trial in time. Minocycline has been shown to have neuroprotective effects in models of central nervous system injury, including in a contusive spinal cord injury (SCI) model at the thoracic level. Beneficial effects of minocycline treatment included a significant improvement in locomotor behavior and reduced histopathological changes [Lee, S.M., Yune, T.Y., Kim, S.J., Park, D.O.W., Lee, Y.K., Kim, Y.C., Oh, Y.J., Markelonis, G.J., Oh, T.H., 2003. Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. J Neurotrauma. 20, 1017-1027.] To verify these important observations, we repeated this study in our laboratory. The NYU (MASCIS) Impactor was used to produce a moderate cord lesion at the vertebral level T9-T10 (height 12.5 mm, weight 10 g), (n=45), followed by administration of minocycline, 90 mg/kg (group 1: minocycline IP, n=15; group 2: minocycline IV, n=15; group 3: vehicle IP, n=8; group 4: vehicle IV, n=7) immediately after surgery and followed by two more doses of 45 mg/kg/IP at 12 h and 24 h. Open field locomotion (BBB) and subscores were examined up to 6 weeks after SCI and cords were processed for quantitative histopathological analysis. Administration of minocycline after SCI did not lead to significant behavioral or histopathological improvement. Although positive effects with minocycline have been reported in several animal models of injury with different drug administration schemes, the use of minocycline following contusive SCI requires further investigation before clinical trials are implemented.

We previously showed that Nuclear Factor kappaB (NF-kappaB) inactivation in astrocytes leads to improved functional recovery following spinal cord injury (SCI). This correlated with reduced expression of pro-inflammatory mediators and chondroitin sulfate proteoglycans, and increased white matter preservation. Hence we hypothesized that inactivation of astrocytic NF-kappaB would create a more permissive environment for axonal sprouting and regeneration. We induced both contusive and complete transection SCI in GFAP-Inhibitor of kappaB-dominant negative (GFAP-IkappaBalpha-dn) and wild-type (WT) mice and performed retrograde [fluorogold (FG)] and anterograde [biotinylated dextran amine (BDA)] tracing 8 weeks after injury. Following contusive SCI, more FG-labeled cells were found in motor cortex, reticular formation, and raphe nuclei of transgenic mice. Spared and sprouting BDA-positive corticospinal axons were found caudal to the lesion in GFAP-IkappaBalpha-dn mice. Higher numbers of FG-labeled neurons were detected immediately rostral to the lesion in GFAP-IkappaBalpha-dn mice, accompanied by increased expression of synaptic and axonal growth-associated molecules. After transection, however, no FG-labeled neurons or BDA-filled axons were found rostral and caudal to the lesion, respectively, in either genotype. These data demonstrated that inhibiting astroglial NF-kappaB resulted in a growth-supporting terrain promoting sparing and sprouting, rather than regeneration, of supraspinal and propriospinal circuitries essential for locomotion, hence contributing to the improved functional recovery observed after SCI in GFAP-IkappaBalpha-dn mice.

This study was initiated due to an NIH "Facilities of Research--Spinal Cord Injury" contract to support independent replication of published studies that appear promising for eventual clinical testing. We repeated a study reporting the beneficial effects of recombinant human erythropoietin (rhEPO) treatment after spinal cord injury (SCI). Moderate thoracic SCI was produced by two methods: 1) compression due to placement of a modified aneurysm clip (20 g, 10 s) at the T3 spinal segment (n=45) [followed by administration of rhEPO 1000 IU/kg/IP in 1 or 3 doses (treatment groups)] and 2) contusion by means of the MASCIS impactor (n = 42) at spinal T9 (height 12.5 cm, weight 10 g) [followed by the administration of rhEPO 5000 IU/kg/IP for 7d or single dose (treatment groups)]. The use of rhEPO following moderate compressive or contusive injury of the thoracic spinal cord did not improve the locomotor behavior (BBB rating scale). Also, secondary changes (i.e. necrotic changes followed by cavitation) were not significantly improved with rhEPO therapy. With these results, although we cannot conclude that there will be no beneficial effect in different SCI models, we caution researchers that the use of rhEPO requires further investigation before implementing clinical trials.

The expression of myelination-associated genes (MGs) can be induced by cyclic adenosine monophosphate (cAMP) elevation in isolated Schwann cells (SCs). To further understand the effect of known SC mitogens in the regulation of SC differentiation, we studied the response of SCs isolated from adult nerves to combined cAMP, growth factors, including neuregulin, and serum. In adult SCs, the induction of MGs by cAMP coincided with the loss of genes expressed in non-myelin-forming SCs and with a change in cell morphology from a bipolar to an expanded epithelial-like shape. Prolonged treatment with high doses of cAMP-stimulating agents, as well as low cell density, was required for the induction of SC differentiation. Stimulation with serum, neuregulin alone, or other growth factors including PDGF, IGF and FGF, increased SC proliferation but did not induce the expression of MGs or the associated morphological change. Most importantly, when these factors were administered in combination with cAMP-stimulating agents, SC proliferation was synergistically increased without reducing the differentiating activity of cAMP. Even though the initiation of DNA synthesis and the induction of differentiation were mostly incompatible events in individual cells, SCs were able to differentiate under conditions that also supported active proliferation. Overall, the results indicate that in the absence of neurons, cAMP can trigger SC re-differentiation concurrently with, but independently of, growth factor signaling.

Regenerated cerebrospinal axons are considered to be involved in the spontaneous recovery of swimming ability following a spinal cord injury in adult zebrafish. We employed behavioral analysis, neuronal tracing, and immunocytochemistry to determine the exact temporal relationship between swimming ability and regenerated cerebrospinal axon number in adult zebrafish with a complete spinal cord transection. Between two and eight weeks post-lesion, swimming gradually improved to 44% of sham-injured zebrafish. Neurons within the reticular formation, magnocellular octaval nucleus, and nucleus of the medial longitudinal fascicle grew their axon across and at least four millimeters beyond the lesion. The largest increases in swimming ability and number of regenerated cerebrospinal axons were observed between two and four weeks post-lesion. Regression analyses revealed a significant correlation between swimming ability and the number of regenerated axons. Our results indicate the involvement of cerebrospinal axons in swimming recovery after spinal cord injury in adult zebrafish.

Adult zebrafish (Danio rerio) have a remarkable ability to restore function after an injury to the brain or spinal cord. The molecular and cellular mechanisms underlying this phenomenon are not fully understood. To enable investigation of these mechanisms we have developed an in vitro model system from the adult zebrafish brainstem, which can be maintained under serum-containing and serum-free conditions. While cultures are predominantly neuronal, they also contain glia and stem progenitor cells. Various stages of cellular differentiation are observed among both neuronal and non-neuronal populations. Quantitative morphological results revealed typical cellular growth over a two-week period. We argue that our novel brainstem culture model offers a powerful tool for the studies of axonal growth, neurogenesis, and regeneration in the adult zebrafish central nervous system.

Axon regeneration in the central nervous system is severely hampered, limiting functional recovery. This is in part because of endogenous axon regeneration inhibitors that accumulate at the injury site. Therapeutic targeting of these inhibitors and their receptors may facilitate axon outgrowth and enhance recovery. A rat model of spinal cord contusion injury was used to test the effects of two bacterial enzyme therapies that target independent axon regeneration inhibitors, sialidase (Vibrio cholerae) and chondroitinase ABC (ChABC, Proteus vulgaris). The two enzymes, individually and in combination, were infused for 2 weeks via implanted osmotic pumps to the site of a moderate thoracic spinal cord contusion injury. Sialidase was completely stable, whereas ChABC retained>30% of its activity in vivo over the 2 week infusion period. Immunohistochemistry revealed that infused sialidase acted robustly throughout the spinal cord gray and white matter, whereas ChABC activity was more intense superficially. Sialidase treatment alone resulted in improved behavioral and anatomical outcomes. Rats treated exclusively with sialidase showed significantly increased hindlimb motor function, evidenced by higher Basso Beattie and Bresnahan (BBB) and BBB subscores, and fewer stepping errors on a horizontal ladder. Sialidase-treated rats also had increased serotonergic axons caudal to the injury. ChABC treatment, in contrast, did not enhance functional recovery or alter axon numbers after moderate spinal cord contusion injury, and dampened the response of sialidase in the dual enzyme treatment group. We conclude that sialidase infusion enhanced recovery from spinal cord contusion injury, and that combining sialidase with ChABC failed to improve outcomes.

Schwann cells (SCs) are crucial for peripheral nerve development and regeneration; however, the intrinsic regulatory mechanisms governing postinjury responses are poorly understood. Activation and deacetylation of nuclear factor-κB (NF- κB) in SCs have been implicated as prerequisites for peripheral nerve myelination. Using GFAP-IκBα-dn mice in which NF- κB transcriptional activation is inhibited in SCs, we found no discernable differences in the quantity or structure of myelinated axons in adult facial nerves. Following crush injury, axonal regeneration was impaired at 31 days and significantly enhanced at 65 days in transgenic animals. Compact remyelination and Remak bundle organization were significantly compromised at 31 days and restored by 65 days post injury. Together, these data indicate that inhibition of NF-κB activation in SCs transiently delays axonal regeneration and compact remyelination. Manipulating the temporal activation of nuclear factor-κB in Schwann cells may offer new therapeutic avenues for PNS and CNS regeneration.

Freeze-dried poly(D,L-lactic acid) macroporous scaffold filled with a fibrin solution containing Schwann cells (SCs) lentivirally transduced to produce and secrete D15A, a bi-functional neurotrophin with brain-derived neurotrophic factor and neurotrophin-3 activity, and to express green fluorescent protein (GFP) were implanted in the completely transected adult rat thoracic spinal cord. Control rats were similarly injured and then implanted with scaffolds containing the fibrin solution with SCs lentivirally transduced to produce express GFP only or with the fibrin solution only. Transgene production and biological activity in vitro, SC survival within the scaffold in vitro and in vivo, scaffold integration, axonal regeneration and myelination, and hind limb motor function were analyzed at 1, 2, and 6 weeks after implantation. In vitro, lentivirally transduced SCs produced 87.5 ng/24 h/10(6) cells of D15A as measured by neurotrophin-3 activity in ELISA. The secreted D15A was biologically active as evidenced by its promotion of neurite outgrowth of dorsal root ganglion neurons in culture. In vitro, SCs expressing GFP were present in the scaffolds for up to 6 h, the end of a typical surgery session. Implantation of SC-seeded scaffolds caused modest loss of spinal nervous tissue. Reactive astrocytes and chondroitin sulfate glycosaminoglycans were present in spinal tissue adjacent to the scaffold. Vascularization of the scaffold was ongoing at 1 week post-implantation. There were no apparent differences in scaffold integration and blood vessel formation between groups. A decreasing number of implanted (GFP-positive) SCs were found within the scaffold during the first 3 days after implantation. Apoptosis was identified as one of the mechanisms of cell death. At 1 week and later time points after implantation, few of the implanted SCs were present in the scaffold. Neurofilament-positive axons were found in the scaffold. At 6 weeks post-grafting, myelinated axons were observed within and at the external surface of the scaffold. Axons did not grow from the scaffold into the caudal cord. All groups demonstrated a similar improvement of hind limb motor function. Our findings demonstrated that few seeded SCs survived in vivo, which could account for the modest axonal regeneration response into and across the scaffold. For the development of SC-seeded macroporous scaffolds that effectively promote axonal regeneration in the injured spinal cord, the survival and/or total number of SCs in the scaffold needs to be improved.

It was investigated whether the addition of basic fibroblast growth factor (FGF-2) enhances the efficacy of a Schwann cell (SC) bridge to repair the transected spinal cord by assessing tissue sparing and neuronal survival near the graft-cord interfaces, axonal regeneration and myelination in the graft, and behavioral recovery up to 12 weeks post-grafting. Experimental animals received a bridge of SCs within fibrin containing 1 microg of FGF-2; control animals received a SC implant without FGF-2. Sparing of tissue in a 2.5-mm-long segment near the graft-cord borders was 69% in the rostral and 52% in the caudal cord at 6 weeks post-grafting, not significantly different from the control group. With FGF-2, survival of NeuN-positive cells was increased in the rostral cord: 24.4%, 20.4%, and 17.2% of the number of positive cells in the uninjured cord compared to 13.5%, 9.1%, and 8.9% in controls at 3, 6, and 12 weeks post-grafting, respectively. Similarly, in the caudal cord, survival of NeuN-positive cells was increased with FGF-2: 19.3%, 16.8%, and 14.5% compared to 10.8%, 5.6%, and 6.1% in controls. The staining intensity of glial fibrillary acidic protein was significantly higher at the interfaces of both cord stumps at 3 weeks with SC/FGF-2 grafts; chondroitin sulfate proteoglycan (CS-56) staining was more intense in the rostral cord but only at 6 weeks. Blood vessels in the FGF-2 grafts were larger and less regular in shape than those in control grafts. Axonal growth into the bridge was not improved by the addition of FGF-2. Retrogradely traced neurons were not found rostral to the implant, indicating that axons had not grown a few mm into the caudal spinal tissue. Recovery of hind limb function was similar in both groups. Despite the neuroprotective effects of FGF-2, improved effects on axonal regeneration and functional recovery were not observed.

Chronic demyelination is a pathophysiologic component of compressive spinal cord injury (SCI) and a characteristic finding in demyelinating diseases including multiple sclerosis (MS). A better characterization of endogenous cells responsible for successful remyelination is essential for designing therapeutic strategies aimed at restoring functional myelin. The present study examined the spatiotemporal response of endogenous oligodendrocyte precursor cells (OPCs) following ethidium bromide (EB)-induced demyelination of the adult rat spinal cord. Beginning at 2 days post-EB injection (dpi), a robust mobilization of highly proliferative NG2(+) cells within the lesion was observed, none of which expressed the oligodendrocyte lineage-associated transcription factor Nkx2.2. At 7 dpi, a significant up-regulation of Nkx2.2 by OPCs within the lesion was observed, 90% of which coexpressed NG2 and virtually all of which coexpressed the bHLH transcription factor Olig2. Despite successful recruitment of Nkx2.2(+)/Olig2(+) OPCs within the lesion, demyelinated axons were not remyelinated by these OPCs in regions lacking astrocytes. Rather, Schwann cell remyelination predominated throughout the central core of the lesion, particularly around blood vessels. Oligodendrocyte remyelination was observed in the astrogliotic perimeter, suggesting a necessary role for astrocytes in oligodendrocyte maturation. In addition, reexpression of the radial glial antigen, RC-1, by reactive astrocytes and ependymal cells was observed following injury. However, these cells did not express the neural stem cell (NSC)-associated transcription factors Sox1 or Sox2, suggesting that the endogenous response is primarily mediated by glial progenitors. In vivo electrophysiology demonstrated a limited and unsustained functional recovery concurrent with endogenous remyelination following EB-induced lesions.

Schwann cell (SC) transplantation has been comprehensively studied as a strategy for spinal cord injury (SCI) repair. SCs are neuroprotective and promote axon regeneration and myelination. Nonetheless, substantial SC death occurs post-implantation, which limits therapeutic efficacy. The use of extracellular matrix (ECM)-derived matrices, such as Matrigel, supports transplanted SC survival and axon growth, resulting in improved motor function. Because appropriate matrices are needed for clinical translation, we test here the use of an acellular injectable peripheral nerve (iPN) matrix. Implantation of SCs in iPN into a contusion lesion did not alter immune cell infiltration compared to injury only controls. iPN implants were larger and contained twice as many SC-myelinated axons as Matrigel grafts. SC/iPN animals performed as well as the SC/Matrigel group in the BBB locomotor test, and made fewer errors on the grid walk at 4 weeks, equalizing at 8 weeks. The fact that this clinically relevant iPN matrix is immunologically tolerated and supports SC survival and axon growth within the graft offers a highly translational possibility for improving efficacy of SC treatment after SCI. To our knowledge, it is the first time that an injectable PN matrix is being evaluated to improve the efficacy of SC transplantation in SCI repair.

Crossed facilitatory interactions in the corticospinal pathway are impaired in humans with chronic incomplete spinal cord injury (SCI). The extent to which crossed facilitation is affected in muscles above and below the injury remains unknown. To address this question we tested 51 patients with neurological injuries between C2-T12 and 17 age-matched healthy controls. Using transcranial magnetic stimulation we elicited motor evoked potentials (MEPs) in the resting first dorsal interosseous, biceps brachii, and tibialis anterior muscles when the contralateral side remained at rest or performed 70% of maximal voluntary contraction (MVC) into index finger abduction, elbow flexion, and ankle dorsiflexion, respectively. By testing MEPs in muscles with motoneurons located at different spinal cord segments we were able to relate the neurological level of injury to be above, at, or below the location of the motoneurons of the muscle tested. We demonstrate that in patients the size of MEPs was increased to a similar extent as in controls in muscles above the injury during 70% of MVC compared to rest. MEPs remained unchanged in muscles at and within 5 segments below the injury during 70% of MVC compared to rest. However, in muscles beyond 5 segments below the injury the size of MEPs increased similar to controls and was aberrantly high, 2-fold above controls, in muscles distant (>15 segments) from the injury. These aberrantly large MEPs were accompanied by larger F-wave amplitudes compared to controls. Thus, our findings support the view that corticospinal degeneration does not spread rostral to the lesion, and highlights the potential of caudal regions distant from an injury to facilitate residual corticospinal output after SCI.

Methylprednisolone (MP) and interleukin-10 (IL-10) are tissue protective acutely after spinal cord injury (SCI); their combination offers additive protection (Takami et al., 2002a). Our study examined if acute administration of MP (30 mg/kg i.v. at 5 min, and 2 and 4 h after injury) and IL-10 (30 mg/kg i.p. at 30 min after injury) increases the efficacy of Schwann cell (SC) or SC plus olfactory ensheathing glia (SC/OEG) grafts transplanted into rat thoracic cord 1 week after contusive injury. Efficacy was determined by histology, anterograde and retrograde tracing, immunohistochemistry for gliosis and specific nerve fibers, and several behavioral tests. Administration of MP/IL-10 or SC or SC/OEG transplantation significantly increased the total volume of a 9-mm segment of cord encompassing the injury site at 12 weeks. The combination of either SC or SC/OEG transplantation with MP/IL-10 most significantly reduced cavitation. The individual treatments all significantly increased the volume of normal-appearing tissue compared to injury-only controls; however, significant decreases in the volume of normal-appearing tissue were seen when MP/IL-10 and cell grafts were combined compared to MP/IL-10 alone. SC/OEG grafts were effective in promoting serotonergic fiber growth into the graft and led to more reticulospinal fibers caudal to the graft; combination with MP/IL-10 did not further increase fiber number. Only the combination of MP/IL-10 with SC/OEG transplants significantly improved gross locomotor performance (BBB scores) over injury-only controls. MP/IL-10 given prior to SC-only transplants, however, worsened behavioral outcome. Because beneficial effects of MP/IL-10 were not always additive when combined with cell transplantation, we need to understand (1) how tissue protective agents may transform the milieu of the injured spinal cord to the benefit or detriment of later transplanted cells and (2) whether neuroprotectants need to be re-administered at the time of cell grafting or less invasive transplantation techniques employed to reduce damage to tissue spared by an earlier protection strategy.

This study was initiated due to an NIH "Facilities of Research-Spinal Cord Injury" contract to support independent replication of published studies. Transient blockage of the CD11d/CD18 integrin has been reported to reduce secondary neuronal damage as well as to improve functional recovery after spinal cord injury (SCI) in rats. The purpose of this study was to determine whether treatment with an anti-CD11d monoclonal antibody (mAb) would improve motor performance, reduce pain and histopathological damage in animals following clip-compression injury as reported. Adult male Wistar rats (250g) were anesthetized with isoflurane, and the T12 spinal cord exposed by T10 and T11 dorsal laminectomies followed by a 60s period of clip compression utilizing a 35g clip. Control animals received an isotype-matched irrelevant antibody (1B7) while the treated group received the anti-CD11d mAb (217L; 1.0mg/kg) systemically. Open-field locomotion and sensory function were assessed and animals were perfusion-fixed at twelve weeks after injury for quantitative histopathological analysis. As compared to 1B7, 217L treated animals showed an overall non-significant trend to better motor recovery. All animals showed chronic mechanical allodynia and anti-CD11d mAb treatment did not significantly prevent its development. Histopathological analysis demonstrated severe injury to gray and white matter after compression with a non-significant trend in anti-CD11d protection compared to control animals for preserved myelin. Although positive effects with the anti-CD11d mAb treatment have been reported after compressive SCI, it is suggested that this potential treatment requires further investigation before clinical trials in spinal cord injured patients are implemented.

Axons fail to regenerate in the injured spinal cord, limiting motor and autonomic recovery and contributing to long-term morbidity. Endogenous inhibitors, including those on residual myelin, contribute to regeneration failure. One inhibitor, myelin-associated glycoprotein (MAG), binds to sialoglycans and other receptors on axons. MAG inhibition of axon outgrowth in some neurons is reversed by treatment with sialidase, an enzyme that hydrolyzes sialic acids and eliminates MAG-sialoglycan binding. We delivered recombinant sialidase intrathecally to rats following a spinal cord contusive injury. Sialidase (or saline solution) was infused to the injury site continuously for 2 wk and then motor behavior, autonomic physiology, and anatomic outcomes were determined 3 wk later. Sialidase treatment significantly enhanced hindlimb motor function, improved bulbospinally mediated autonomic reflexes, and increased axon sprouting. These findings validate sialoglycans as therapeutic targets and sialidase as a candidate therapy for spinal cord injury.

An injury to the spinal cord causes long-lasting loss of nervous tissue because endogenous nervous tissue repair and regeneration at the site of injury is limited. We engineered an injectable nanofiber-hydrogel composite (NHC) with interfacial bonding to provide mechanical strength and porosity and examined its effect on repair and neural tissue regeneration in an adult rat model of spinal cord contusion. At 28 days after treatment with NHC, the width of the contused spinal cord segment was 2-fold larger than in controls. With NHC treatment, tissue in the injury had a 2-fold higher M2/M1 macrophage ratio, 5-fold higher blood vessel density, 2.6-fold higher immature neuron presence, 2.4-fold higher axon density, and a similar glial scar presence compared with controls. Spared nervous tissue volume in the contused segment and hind limb function was similar between groups. Our findings indicated that NHC provided mechanical support to the contused spinal cord and supported pro-regenerative macrophage polarization, angiogenesis, axon growth, and neurogenesis in the injured tissue without any exogenous factors or cells. These results motivate further optimization of the NHC and delivery protocol to fully translate the potential of the unique properties of the NHC for treating spinal cord injury.

There are conflicting reports on the impact of antidepressants on neural reactions for positive information. We thus hypothesized that there would be clinically important individual differences in neural reactivity to positive information during SSRI therapy. We further predicted that only those who responded to SSRIs would show increased amygdala reactivity to positive information following treatment to a level similar to that seen in healthy participants. Depressed individuals (n = 17) underwent fMRI during performance of a task involving rating the self-relevance of emotionally positive and negative cue words before and after receiving 12 weeks of SSRI therapy. At post-treatment, SSRI responders (n = 11) had increased amygdala activity in response to positive stimuli, and decreased activity in response to negative stimuli, compared to non-responders (n = 6). Results suggest that normalizing amygdala responses to salient information is a correlate of SSRI efficacy. Second line interventions that modulate amygdala activity, such as fMRI neurofeedback, may be beneficial in those who do not respond to SSRI medications.

A bone marrow-derived mesenchymal stromal cell (MSC) transplant and a bioengineered nanofiber-hydrogel composite (NHC) have been shown to stimulate nervous tissue repair in the contused spinal cord in rodent models. Here, these two modalities were combined to assess their repair effects in the contused spinal cord in adult rats. Cohorts of contused rats were treated with MSC in NHC (MSC-NHC), MSC in phosphate-buffered saline (MSC-PBS), NHC, or PBS injected into the contusion site at 3 days post-injury. One week after injury, there were significantly fewer CD68+ cells in the contusion with MSC-NHC and NHC, but not MSC-PBS. The reduction in CD86+ cells in the injury site with MSC-NHC was mainly attributed to NHC. One and eight weeks after injury, we found a greater CD206+/CD86+ cell ratio with MSC-NHC or NHC, but not MSC-PBS, indicating a shift from a pro-inflammatory towards an anti-inflammatory milieu in the injury site. Eight weeks after injury, the injury size was significantly reduced with MSC-NHC, NHC, and MSC-PBS. At this time, astrocyte, and axon presence in the injury site was greater with MSC-NHC compared with MSC-PBS. We did not find a significant effect of NHC on MSC transplant survival, and hind limb function was similar across all groups. However, we did find fewer macrophages at 1 week post-injury, more macrophages polarized towards a pro-regenerative phenotype at 1 and 8 weeks after injury, and reduced injury volume, more astrocytes, and more axons at 8 weeks after injury in rats with MSC-NHC and NHC alone compared with MSC-PBS; these findings were especially significant between rats with MSC-NHC and MSC-PBS. The data support further study in the use of an NHC-MSC combination transplant in the contused spinal cord.

Fibrotic scar formation contributes to the axon growth-inhibitory environment that forms following spinal cord injury (SCI). We recently demonstrated that depletion of hematogenous macrophages led to a reduction in fibrotic scar formation and increased axon growth after SCI. These changes were associated with decreased TNFSF13 (a proliferation inducing ligand (APRIL)) expression, but the role of APRIL in fibrotic scar formation after SCI has not been directly investigated. Thus, the goal of this study was to determine the role of APRIL in fibrotic scar formation after SCI.