Neutrophil contribution to spinal cord injury and repair.
Neirinckx Virginie,Coste Cécile,Franzen Rachelle,Gothot André,Rogister Bernard,Wislet Sabine
Journal of neuroinflammation
Spinal cord injuries remain a critical issue in experimental and clinical research nowadays, and it is now well accepted that the immune response and subsequent inflammatory reactions are of significant importance in regulating the damage/repair balance after injury. The role of macrophages in such nervous system lesions now becomes clearer and their contribution in the wound healing process has been largely described in the last few years. Conversely, the contribution of neutrophils has traditionally been considered as detrimental and unfavorable to proper tissue regeneration, even if there are very few studies available on their precise impact in spinal cord lesions. Indeed, recent data show that neutrophils are required for promoting functional recovery after spinal cord trauma. In this review, we gathered recent evidence concerning the role of neutrophils in spinal cord injuries but also in some other neurological diseases, highlighting the need for further understanding the different mechanisms involved in spinal cord injury and repair.
10.1186/s12974-014-0150-2
Microglia and macrophages promote corralling, wound compaction and recovery after spinal cord injury via Plexin-B2.
Nature neuroscience
Tissue repair after spinal cord injury requires the mobilization of immune and glial cells to form a protective barrier that seals the wound and facilitates debris clearing, inflammatory containment and matrix compaction. This process involves corralling, wherein phagocytic immune cells become confined to the necrotic core, which is surrounded by an astrocytic border. Here we elucidate a temporally distinct gene signature in injury-activated microglia and macrophages (IAMs) that engages axon guidance pathways. Plexin-B2 is upregulated in IAMs and is required for motor sensory recovery after spinal cord injury. Plexin-B2 deletion in myeloid cells impairs corralling, leading to diffuse tissue damage, inflammatory spillover and hampered axon regeneration. Corralling begins early and requires Plexin-B2 in both microglia and macrophages. Mechanistically, Plexin-B2 promotes microglia motility, steers IAMs away from colliding cells and facilitates matrix compaction. Our data therefore establish Plexin-B2 as an important link that integrates biochemical cues and physical interactions of IAMs with the injury microenvironment during wound healing.
10.1038/s41593-020-0597-7
Derivation and transcriptional reprogramming of border-forming wound repair astrocytes after spinal cord injury or stroke in mice.
Nature neuroscience
Central nervous system (CNS) lesions become surrounded by neuroprotective borders of newly proliferated reactive astrocytes; however, fundamental features of these cells are poorly understood. Here we show that following spinal cord injury or stroke, 90% and 10% of border-forming astrocytes derive, respectively, from proliferating local astrocytes and oligodendrocyte progenitor cells in adult mice of both sexes. Temporal transcriptome analysis, single-nucleus RNA sequencing and immunohistochemistry show that after focal CNS injury, local mature astrocytes dedifferentiate, proliferate and become transcriptionally reprogrammed to permanently altered new states, with persisting downregulation of molecules associated with astrocyte-neuron interactions and upregulation of molecules associated with wound healing, microbial defense and interactions with stromal and immune cells. These wound repair astrocytes share morphologic and transcriptional features with perimeningeal limitans astrocytes and are the predominant source of neuroprotective borders that re-establish CNS integrity around lesions by separating neural parenchyma from stromal and immune cells as occurs throughout the healthy CNS.
10.1038/s41593-024-01684-6
Rat models of spinal cord injury: from pathology to potential therapies.
Kjell Jacob,Olson Lars
Disease models & mechanisms
A long-standing goal of spinal cord injury research is to develop effective spinal cord repair strategies for the clinic. Rat models of spinal cord injury provide an important mammalian model in which to evaluate treatment strategies and to understand the pathological basis of spinal cord injuries. These models have facilitated the development of robust tests for assessing the recovery of locomotor and sensory functions. Rat models have also allowed us to understand how neuronal circuitry changes following spinal cord injury and how recovery could be promoted by enhancing spontaneous regenerative mechanisms and by counteracting intrinsic inhibitory factors. Rat studies have also revealed possible routes to rescuing circuitry and cells in the acute stage of injury. Spatiotemporal and functional studies in these models highlight the therapeutic potential of manipulating inflammation, scarring and myelination. In addition, potential replacement therapies for spinal cord injury, including grafts and bridges, stem primarily from rat studies. Here, we discuss advantages and disadvantages of rat experimental spinal cord injury models and summarize knowledge gained from these models. We also discuss how an emerging understanding of different forms of injury, their pathology and degree of recovery has inspired numerous treatment strategies, some of which have led to clinical trials.
10.1242/dmm.025833
The origin, fate, and contribution of macrophages to spinal cord injury pathology.
Acta neuropathologica
Virtually all phases of spinal cord injury pathogenesis, including inflammation, cell proliferation and differentiation, as well as tissue remodeling, are mediated in part by infiltrating monocyte-derived macrophages. It is now clear that these infiltrating macrophages have distinct functions from resident microglia and are capable of mediating both harmful and beneficial effects after injury. These divergent effects have been largely attributed to environmental cues, such as specific cytokines, that influence the macrophage polarization state. In this review, we also consider the possibility that different macrophage origins, including the spleen, bone marrow, and local self-renewal, may also affect macrophage fate, and ultimately their function that contribute to the complex pathobiology of spinal cord injury.
10.1007/s00401-019-01992-3
Microglia-organized scar-free spinal cord repair in neonatal mice.
Li Yi,He Xuelian,Kawaguchi Riki,Zhang Yu,Wang Qing,Monavarfeshani Aboozar,Yang Zhiyun,Chen Bo,Shi Zhongju,Meng Huyan,Zhou Songlin,Zhu Junjie,Jacobi Anne,Swarup Vivek,Popovich Phillip G,Geschwind Daniel H,He Zhigang
Nature
Spinal cord injury in mammals is thought to trigger scar formation with little regeneration of axons. Here we show that a crush injury to the spinal cord in neonatal mice leads to scar-free healing that permits the growth of long projecting axons through the lesion. Depletion of microglia in neonatal mice disrupts this healing process and stalls the regrowth of axons, suggesting that microglia are critical for orchestrating the injury response. Using single-cell RNA sequencing and functional analyses, we find that neonatal microglia are transiently activated and have at least two key roles in scar-free healing. First, they transiently secrete fibronectin and its binding proteins to form bridges of extracellular matrix that ligate the severed ends of the spinal cord. Second, neonatal-but not adult-microglia express several extracellular and intracellular peptidase inhibitors, as well as other molecules that are involved in resolving inflammation. We transplanted either neonatal microglia or adult microglia treated with peptidase inhibitors into spinal cord lesions of adult mice, and found that both types of microglia significantly improved healing and axon regrowth. Together, our results reveal the cellular and molecular basis of the nearly complete recovery of neonatal mice after spinal cord injury, and suggest strategies that could be used to facilitate scar-free healing in the adult mammalian nervous system.
10.1038/s41586-020-2795-6
Current Advancements in Spinal Cord Injury Research-Glial Scar Formation and Neural Regeneration.
Cells
Spinal cord injury (SCI) is a complex tissue injury resulting in permanent and degenerating damage to the central nervous system (CNS). Detrimental cellular processes occur after SCI, including axonal degeneration, neuronal loss, neuroinflammation, reactive gliosis, and scar formation. The glial scar border forms to segregate the neural lesion and isolate spreading inflammation, reactive oxygen species, and excitotoxicity at the injury epicenter to preserve surrounding healthy tissue. The scar border is a physicochemical barrier composed of elongated astrocytes, fibroblasts, and microglia secreting chondroitin sulfate proteoglycans, collogen, and the dense extra-cellular matrix. While this physiological response preserves viable neural tissue, it is also detrimental to regeneration. To overcome negative outcomes associated with scar formation, therapeutic strategies have been developed: the prevention of scar formation, the resolution of the developed scar, cell transplantation into the lesion, and endogenous cell reprogramming. This review focuses on cellular/molecular aspects of glial scar formation, and discusses advantages and disadvantages of strategies to promote regeneration after SCI.
10.3390/cells12060853
Spinal-cord injury.
McDonald John W,Sadowsky Cristina
Lancet (London, England)
More than a decade ago, spinal-cord injury meant confinement to a wheelchair and a lifetime of medical comorbidity. The physician's armamentarium of treatments was very limited, and provision of care for individuals with spinal-cord injury was usually met with frustration. Advances in the neurosciences have drawn attention to research into spinal-cord injury. Nowadays, advanced interventions provide high hope for regeneration and functional restoration. As scientific advances become more frequent, scepticism is giving way to the ideas that spinal-cord injury will eventually be repairable and that strategies to restore function are within our grasp. We address the present understanding of spinal-cord injury, its cause, pathophysiology, diagnosis, and treatment, and look at promising research avenues. We also discuss new treatment options, including functional electric stimulation and part-weight-supported walking.
10.1016/S0140-6736(02)07603-1
Role of endogenous neural stem cells in spinal cord injury and repair.
Stenudd Moa,Sabelström Hanna,Frisén Jonas
JAMA neurology
Spinal cord injury is followed by glial scar formation, which has positive and negative effects on recovery from the lesion. More than half of the astrocytes in the glial scar are generated by ependymal cells, the neural stem cells in the spinal cord. We recently demonstrated that the neural stem cell-derived scar component has several beneficial functions, including restricting tissue damage and neural loss after spinal cord injury. This finding identifies endogenous neural stem cells as a potential therapeutic target for treatment of spinal cord injury.
10.1001/jamaneurol.2014.2927