Yimin Yuan

Reactive astrocytes inhibit the survival and differentiation of oligodendrocyte precursor cells by secreted TNF-α.

Axonal demyelination is a consistent pathological characteristic of spinal cord injury (SCI). Although an increased number of oligodendrocyte progenitor cells (OPCs) is observed in the injured spinal cord, they fail to convert into mature oligodendrocytes. However, little is known about the underlying mechanism. In our study, we identified a link between inhibition of OPC survival and differentiation and reactive astrocytes in glial scar that was mediated by tumor necrosis factor-α (TNF-α). Initially, both glial scar tissue and reactive astrocyte-conditioned medium were shown to inhibit OPC differentiation. Reverse transcriptase polymerase chain reaction (RT-PCR) and immunochemistry revealed that OPCs expressed type 1 TNF-α receptor (TNF-R1). When TNF-α or TNF-R1 was neutralized with antibody, the effect of reactive astrocyte-conditioned medium or recombinant TNF-α protein on OPC differentiation was markedly attenuated. In addition, reactive astrocyte-conditioned medium was also shown to induce OPC apoptosis. All these findings provide the first evidence that reactive astrocytes release TNF-α to inhibit OPC survival and prevent them from differentiating into mature oligodendrocytes, suggesting a mechanism for the failure of remyelination after SCI.

Triptolide promotes spinal cord repair by inhibiting astrogliosis and inflammation

Spinal cord injury (SCI) is a cause of major neurological disability, and no satisfactory treatment is currently available. Traumatic SCI directly damages the cell bodies and/or processes of neurons and triggers a series of endogenous processes, including neuroinflammatory response and reactive astrogliosis. In this study, we found that triptolide, one of the major active components of the traditional Chinese herb Tripterygium wilfordii Hook F, inhibited astrogliosis and inflammation and promoted spinal cord repair. Triptolide was shown to prevent astrocytes from reactive activation by blocking the JAK2/STAT3 pathway in vitro and in vivo. Furthermore, astrocytic gliosis and glial scar were greatly reduced in injured spinal cord treated with triptolide. Triptolide treatment was also shown to decrease the ED‐1 or CD11b‐positive inflammatory cells at the lesion site. Using neurofilament staining and anterograde tracing, a significantly greater number of regenerative axons were observed in the triptolide‐treated rats. Importantly, behavioral tests revealed that injured rats receiving triptolide had improved functional recovery as assessed by the Basso, Beattie, and Bresnahan open‐field scoring, grid‐walk, and foot‐print analysis. These results suggested that triptolide promoted axon regeneration and locomotor recovery by attenuating glial scaring and inflammation, and shed light on the potential therapeutic benefit for SCI.

Olfactory ensheathing cells: The primary innate immunocytes in the olfactory pathway to engulf apoptotic olfactory nerve debris

The olfactory system is an unusual tissue in which olfactory receptor neurons (ORNs) are continuously replaced throughout the life of mammals. Clearance of the apoptotic ORNs corpses is a fundamental process serving important functions in the regulation of olfactory nerve turnover and regeneration. However, little is known about the underlying mechanisms. Olfactory ensheathing cells (OECs) are a unique type of glial cells that wrap olfactory axons and support their continual regeneration from the olfactory epithelium to the bulb. In the present study, OECs were identified to exist in two different states, resting and reactive, in which resting OECs could be activated by LPS stimulation and functioned as phagocytes for cleaning apoptotic ORNs corpses. Confocal analysis revealed that dead ORNs debris were engulfed by OECs and co‐localized with lysosome associated membrane protein 1. Moreover, phosphatidylserine (PS) receptor was identified to express on OECs, which allowed OECs to recognize apoptotic ORNs by binding to PS. Importantly, engulfment of olfactory nerve debris by OECs was found in olfactory mucosa under normal turnover and was significantly increased in the animal model of olfactory bulbectomy, while little phagocytosis by Iba‐1‐positive microglia/macrophages was observed. Together, these results implicate OEC as a primary innate immunocyte in the olfactory pathway, and suggest a cellular and molecular mechanism by which ORNs corpses are removed during olfactory nerve turnover and regeneration.

Heterogeneous astrocytes: Active players in CNS.

Astrocytes, the predominant cell type that are broadly distributed in the brain and spinal cord, play key roles in maintaining homeostasis of the central nerve system (CNS) in physiological and pathological conditions. Increasing evidence indicates that astrocytes are a complex colony with heterogeneity on morphology, gene expression, function and many other aspects depending on their spatio-temporal distribution and activation level. In pathological conditions, astrocytes differentially respond to all kinds of insults, including injury and disease, and participate in the neuropathological process. Based on current studies, we here give an overview of the roles of heterogeneous astrocytes in CNS, especially in neuropathologies, which focuses on biological and functional diversity of astrocytes. We propose that a precise understanding of the heterogeneous astrocytes is critical to unlocking the secrets about pathogenesis and treatment of the mazy CNS.

Reactive Astrocytes in Glial Scar Attract Olfactory Ensheathing Cells Migration by Secreted TNF-α in Spinal Cord Lesion of Rat

Background After spinal cord injury (SCI), the formation of glial scar contributes to the failure of injured adult axons to regenerate past the lesion. Increasing evidence indicates that olfactory ensheathing cells (OECs) implanted into spinal cord are found to migrate into the lesion site and induce axons regeneration beyond glial scar and resumption of functions. However, little is known about the mechanisms of OECs migrating from injection site to glial scar/lesion site. Methods and Findings In the present study, we identified a link between OECs migration and reactive astrocytes in glial scar that was mediated by the tumor necrosis factor-α (TNF-α). Initially, the Boyden chamber migration assay showed that both glial scar tissue and reactive astrocyte-conditioned medium promoted OECs migration in vitro. Reactive astrocyte-derived TNF-α and its type 1 receptor TNFR1 expressed on OECs were identified to be responsible for the promoting effect on OECs migration. TNF-α-induced OECs migration was demonstrated depending on activation of the extracellular signal-regulated kinase (ERK) signaling cascades. Furthermore, TNF-α secreted by reactive astrocytes in glial scar was also showed to attract OECs migration in a spinal cord hemisection injury model of rat. Conclusions These findings showed that TNF-α was released by reactive astrocytes in glial scar and attracted OECs migration by interacting with TNFR1 expressed on OECs via regulation of ERK signaling. This migration-attracting effect of reactive astrocytes on OECs may suggest a mechanism for guiding OECs migration into glial scar, which is crucial for OECs-mediated axons regrowth beyond the spinal cord lesion site.

Olfactory ensheathing cells: attractant of neural progenitor migration to olfactory bulb.

Olfactory ensheathing cells (OECs) are the glial cells that derive from the olfactory placode, envelop olfactory axons in the course of migration from the olfactory epithelium to the olfactory bulb and reside primarily in the olfactory nerve layer. OECs transplantation as a promising experimental therapy for axonal injuries has been intensively studied; however, little is known about their roles in olfactory bulb development. In this study, we examined the effects of OECs on the migration of neural progenitors in rostral migratory stream (RMS). Initially, the neurosphere migration assay showed that OEC‐conditioned medium promoted progenitors to migrate from RMS neurospheres in a concentration dependent manner. Moreover, co‐culturing OECs nearby the RMS explants led to asymmetric migration of explants in different developing stages. However, OECs could influence the migration in a distance not further than 1.5 mm. Finally, slice assay that mimic the circumstance in vivo revealed that OECs had a chemoattractive activity on RMS neural progenitors. Together, these results demonstrate that OECs attract neural progenitors in RMS through the release of diffusible factors and it is likely that OECs mainly influence radial migration in the olfactory bulb but not tangential migration of the RMS invivo during development. This suggests a previously unknown function for OECs in olfactory development and a novel mechanism underlying the targeting of RMS cells.

Slit2 Regulates the Dispersal of Oligodendrocyte Precursor Cells via Fyn/RhoA Signaling

Background: Secreted by nervous system midline cells Slits regulate neurodevelopmental processes through binding to roundabout receptors (Robos). Results: Slit2 causes dispersal of oligodendrocyte precursor cells (OPCs) by inducing the association between Robo1 and Fyn. Conclusion: Robo1 interacts with Fyn to repel the migration of OPCs through RhoA activation. Significance: Learning how Slit/Robo signaling regulates OPC dispersal is crucial for understanding the distribution of OPCs during central nervous system development. Oligodendrocyte precursor cells (OPCs) are a unique type of glia that are responsible for the myelination of the central nervous system. OPC migration is important for myelin formation during central nervous system development and repair. However, the precise extracellular and intracellular mechanisms that regulate OPC migration remain elusive. Slits were reported to regulate neurodevelopmental processes such as migration, adhesion, axon guidance, and elongation through binding to roundabout receptors (Robos). However, the potential roles of Slits/Robos in oligodendrocytes remain unknown. In this study, Slit2 was found to be involved in regulating the dispersal of OPCs through the association between Robo1 and Fyn. Initially, we examined the expression of Robos in OPCs both in vitro and in vivo. Subsequently, the Boyden chamber assay showed that Slit2 could inhibit OPC migration. RoboN, a specific inhibitor of Robos, could significantly attenuate this effect. The effects were confirmed through the explant migration assay. Furthermore, treating OPCs with Slit2 protein deactivated Fyn and increased the level of activated RhoA-GTP. Finally, Fyn was found to form complexes with Robo1, but this association was decreased after Slit2 stimulation. Thus, we demonstrate for the first time that Slit2 regulates the dispersal of oligodendrocyte precursor cells through Fyn and RhoA signaling.

Ethyl pyruvate promotes spinal cord repair by ameliorating the glial microenvironment

BACKGROUND AND PURPOSE Spinal cord injury (SCI) triggers a series of endogenous processes, including neuroinflammation and reactive astrogliosis, which may contribute to the failure of neural regeneration and functional recovery. In the present study, the effect of ethyl pyruvate on spinal cord repair was explored.

Neuroprotective effects of nitidine against traumatic CNS injury via inhibiting microglia activation

Glial cell response to injury has been well documented in the pathogenesis after traumatic brain injury (TBI) and spinal cord injury (SCI). Although microglia, the resident macrophages in the central nervous system (CNS), are responsible for clearing debris and toxic substances, excessive activation of these cells will lead to exacerbated secondary damage by releasing a variety of inflammatory and cytotoxic mediators and ultimately influence the subsequent repair after CNS injury. In fact, inhibition of microgliosis represents a therapeutic strategy for CNS trauma. We here showed that nitidine, a benzophenanthridine alkaloid, restricted reactive microgliosis and promoted CNS repair after traumatic injury. Nitidine was shown to prevent cultured microglia from LPS-induced reactive activation by regulation of ERK and NF-κB signaling pathway. Furthermore, the nitidine-mediated inhibition of microgliosis was also shown in injured brain and spinal cord, which significantly increased neuronal survival and decreased neural tissue damage after injury. Importantly, behavioral analysis revealed that nitidine-treated mice with SCI had improved functional recovery as assessed by Basso Mouse Scale and swimming test. Together, these findings indicated that nitidine increased CNS tissue sparing and improved functional recovery by attenuating reactive microgliosis, suggestive of the potential therapeutic benefit for CNS injury.

Diffusible, membrane-bound, and extracellular matrix factors from olfactory ensheathing cells have different effects on the self-renewing and differentiating properties of neural stem cells

Transplantation of olfactory ensheathing cells (OECs) has been a promising strategy in enhancing central nervous system (CNS) regeneration. However, little is known about the effects of transplanted OECs on the self-renewal, neurogenesis, and oligodendrogenesis of neural stem cells (NSCs), which are known to play a very important role in the repair of damaged CNS tissue. In this study, we investigated the influence of diffusible, membrane-bound, and extracellular matrix factors from OECs on the self-renewal and differentiation properties of NSCs. We found that diffusible factors from cultured OECs promoted self-renewal, whereas the extracellular matrix molecules from OECs increased neurogenesis and oligodendrogenesis of NSCs. Furthermore, we demonstrated that directly coculturing OECs and NSCs inhibited not only self-renewal but also neurogenesis and oligodendrogenesis of NSCs. We propose three models for the interaction between transplanted OECs and endogenous NSCs. Our findings provide new insight into the ability of OECs to promote CNS repair and also indicate potential targets for manipulation of these cells to enhance their restorative ability.