Repair Of Central Nervous System Injuries Research Articles

From Physiology to Pathology of Astrocytes: Highlighting Their Potential as Therapeutic Targets for CNS Injury.

In the mammalian central nervous system (CNS), astrocytes are the ubiquitous glial cells that have complex morphological and molecular characteristics. These fascinating cells play essential neurosupportive and homeostatic roles in the healthy CNS and undergo morphological, molecular, and functional changes to adopt so-called 'reactive' states in response to CNS injury or disease. In recent years, interest in astrocyte research has increased dramatically and some new biological features and roles of astrocytes in physiological and pathological conditions have been discovered thanks to technological advances. Here, we will review and discuss the well-established and emerging astroglial biology and functions, with emphasis on their potential as therapeutic targets for CNS injury, including traumatic and ischemic injury. This review article will highlight the importance of astrocytes in the neuropathological process and repair of CNS injury.

Conductive 3D Ti3C2Tx MXene-Matrigel hydrogels promote proliferation and neuronal differentiation of neural stem cells

Neural stem cells (NSCs) transplantation has great potential in the field of central nervous system injury repair, but the limited differentiation efficiency of transplanted NSCs often affects the therapeutic effect. In this paper, we present a stable three-dimensional (3D) conductive hydrogel prepared by cross-linking MXenes to Matrigel hydrogel. Benefiting from 3D microporous network structure of hydrogel, the conductive hydrogel can provide an extracellular matrix-like substrate for NSCs growth. Moreover, with the addition of Ti3C2Tx MXenes, the composite has excellent electrical conductivity and biocompatibility. It is demonstrated that MXene-Matrigel hydrogels can effectively promote the proliferation and differentiation of NSCs. These findings provide experimental evidence for understanding the regulatory role of conductive hydrogels on NSCs and provides new strategies for neural tissue engineering.

Proteoglycans and glycosaminoglycans in central nervous system injury.

The brain and spinal cord constitute the central nervous system (CNS), which when injured, can be exceedingly devastating. The mechanistic roles of proteoglycans (PGs) and their glycosaminoglycan (GAG) side chains in such injuries have been extensively studied. CNS injury immediately alters endothelial and extracellular matrix (ECM) PGs and GAGs. Subsequently, these alterations contribute to acute injury, postinjury fibrosis, and postinjury repair. These effects are central to the pathophysiology of CNS injury. This review focuses on the importance of PGs and GAGs in multiple forms of injury including traumatic brain injury, spinal cord injury, and stroke. We highlight the causes and consequences of degradation of the PG and GAG-enriched endothelial glycocalyx in early injury and discuss the pleiotropic roles of PGs in neuroinflammation. We subsequently evaluate the dualistic effects of PGs on recovery: both PG/GAG-mediated inhibition and facilitation of repair. We then report promising therapeutic strategies that may prove effective for repair of CNS injury including PG receptor inhibition, delivery of endogenous, pro-repair PGs and GAGs, and direct degradation of pathological GAGs. Finally, we discuss the importance of two PG- and GAG-containing ECM structures (synapses and perineuronal nets) in CNS injury and recovery.

Semi-Interpenetrating Polymer Network of Hyaluronan and Chitosan Self-Healing Hydrogels for Central Nervous System Repair.

The repair of the central nervous system (CNS) is a major challenge because of the difficulty for neurons or axons to regenerate after damages. Injectable hydrogels have been developed to deliver drugs or cells for neural repair, but these hydrogels usually require conditional stimuli or additional catalysts to control the gelling process. Self-healing hydrogels, which can be injected locally to fill tissue defects after stable gelation, are attractive candidates for CNS treatment. In the current study, the self-healing hydrogel with a semi-interpenetrating polymer network (SIPN) was prepared by incorporation of hyaluronan (HA) into the chitosan-based self-healing hydrogel. The addition of HA allowed the hydrogel to pass through a narrow needle much more easily. As the HA content increased, the hydrogel showed a more packed nanostructure and a more porous microstructure verified by coherent small-angle X-ray scattering and scanning electron microscopy. The unique structure of SIPN hydrogel enhanced the spreading, migration, proliferation, and differentiation of encapsulated neural stem cells in vitro. Compared to the pristine chitosan-based self-healing hydrogel, the SIPN hydrogel showed better biocompatibility, CNS injury repair, and functional recovery evaluated by the traumatic brain injury zebrafish model and intracerebral hemorrhage rat model. We proposed that the SIPN of HA and chitosan self-healing hydrogel allowed an adaptable environment for cell spreading and migration and had the potential as an injectable defect support for CNS repair.

Cytokines Induce Monkey Neural Stem Cell Differentiation through Notch Signaling.

The mammalian central nervous system (CNS) has a limited ability to renew the damaged cells after a brain or spinal cord injury whether it is nonhuman primates like monkeys or humans. Transplantation of neural stem cells (NSCs) is a potential therapy for CNS injuries due to their pluripotency and differentiation abilities. Cytokines play an important role in CNS development and repair of CNS injuries. However, the detailed cytokine signaling response in monkey neural stem cells is rarely studied. In our previous research, we isolated NSCs from the adult monkey brain and found the effects of cytokines on monkey NSCs. Now, we further analyzed the regulation mechanisms of cytokines to the proliferation of monkey NSCs such as bone morphogenic protein 4 (BMP4), BMP4/leukaemia inhibitory factor (LIF), or retinoic acid (RA)/Forskolin. The data showed that BMP4 inhibited cell proliferation to arrest, but it did not affect the stemness of NSCs. BMP4/LIF promoted the astrocyte-like differentiation of monkey NSCs, and RA/forskolin induced the neuronal differentiation of monkey NSCs. BMP4/LIF and RA/forskolin induced monkey NSC differentiation by regulating Notch signaling. These results provide some theoretical evidence for NSC therapy to brain or spinal cord injury in regenerative medicine.

The Impact of Tissue Storage Conditions on Rat Olfactory Ensheathing Cell Yield and the Future Clinical Implications

Trauma causes spinal cord injury, and the devastating consequences of the injury are due to the failure of the damaged central nervous system (CNS) axons to regenerate. Previous studies have shown that olfactory ensheathing cells (OECs) are a unique type of glial cell and they can promote regeneration of CNS axons to aid recovery after spinal cord injury. Transplantation of OECs, in particular from the olfactory bulb (OB), is considered one of the most promising therapeutic strategies for the repair of CNS injuries, including spinal cord injury. Transplantation of OECs can be autologous or allogenic. Here we focused on the less invasive and more error-proof allograft approach which needs a collection of donor OB tissue for OEC production. In this study, we investigated the effects on the yield and proportions of OECs and olfactory nerve fibroblasts (ONFs) from storing OB tissue in various media for periods of 24 and 48 hours. The OEC yield contributes to the viability of a successful cell transplant. We concluded that storing OB tissue for a period longer than 24 hours negatively impacted the total cell number and subsequently the OEC population. This study provides useful information for future clinical applications.

Unbiased transcriptomic analyses reveal distinct effects of immune deficiency in CNS function with and without injury

The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.

Integrated Stress Response as a Therapeutic Target for CNS Injuries.

Central nervous system (CNS) injuries, caused by cerebrovascular pathologies or mechanical contusions (e.g., traumatic brain injury, TBI) comprise a diverse group of disorders that share the activation of the integrated stress response (ISR). This pathway is an innate protective mechanism, with encouraging potential as therapeutic target for CNS injury repair. In this review, we will focus on the progress in understanding the role of the ISR and we will discuss the effects of various small molecules that target the ISR on different animal models of CNS injury.