Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses

Abstract

Deficits in neuronal function are a hallmark of spinal cord injury (SCI) and therapeutic efforts are often focused on central nervous system (CNS) axon regeneration. However, secondary injury responses by astrocytes, microglia, pericytes, endothelial cells, Schwann cells, fibroblasts, meningeal cells, and other glia not only potentiate SCI damage but also facilitate endogenous repair. Due to their profound impact on the progression of SCI, glial cells and modification of the glial scar are focuses of SCI therapeutic research. Within and around the glial scar, cells deposit extracellular matrix (ECM) proteins that affect axon growth such as chondroitin sulfate proteoglycans (CSPGs), laminin, collagen, and fibronectin. This dense deposition of material, i.e., the fibrotic scar, is another barrier to endogenous repair and is a target of SCI therapies. Infiltrating neutrophils and monocytes are recruited to the injury site through glial chemokine and cytokine release and subsequent upregulation of chemotactic cellular adhesion molecules and selectins on endothelial cells. These peripheral immune cells, along with endogenous microglia, drive a robust inflammatory response to injury with heterogeneous reparative and pathological properties and are targeted for therapeutic modification. Here, we review the role of glial and inflammatory cells after SCI and the therapeutic strategies that aim to replace, dampen, or alter their activity to modulate SCI scarring and inflammation and improve injury outcomes.

Observations on the recovering lumbar spinal cord of lizards show multiple origins of the cells forming the bridge region including immune cells

“…From the injured meninges a number of fibrocytes tends to surround and mix with the nervous tissue remnants after 22–34 days. Differently from mammals (Orr & Gensel, ), the intense glial proliferation and scar does not completely blocks the passage of axons through the bridge region.…”

“…From the injured meninges a number of fibrocytes tends to surround and mix with the nervous tissue remnants after 22-34 days. Differently from mammals (Orr & Gensel, 2018), the intense glial proliferation and scar does Like in lizards with SC transection, also in the turtle Trachemys dorbignyi, stepping-swimming movements were partially recovered 3-4 weeks after SC transection when some regenerating nerves reconnected the proximal with the distal stumps of the interrupted thoracic SC (Reherman et al, 2009(Reherman et al, , 2011. Therefore, in both lizards and turtle the partial recovery of the SC follows similar histological and temporal sequences, and the glial scar does not completely blocks axonal regeneration.…”

“…After damaging the spinal arteries and veins present in the meninges surrounding the SC, a broad influx of blood cells into the damaged nervous tissues occurs (Borgens, ; Gadani, Walsh, Lukens, & Kipnis, ; Orr & Gensel, ; Schwab & Bartholdi, ). Most of these cells are granulocytes during the first 3–4 days postinjury, mainly fighting invading microorganisms.…”

“…After damaging the spinal arteries and veins present in the meninges surrounding the SC, a broad influx of blood cells into the damaged nervous tissues occurs (Borgens, 2003 Orr & Gensel, 2018;Schwab & Bartholdi, 1996) The immigration of granulocytes and macrophages in the SC 1 week after transection was also noted in the lizard Calotus calotus while lymphocytes were found even after 1 month postinjury, suggesting persistence of inflammation while few nerve fibers crossed the gap between proximal and distal stumps (Srivastava et al, 1994).…”

“…Regeneration of brain and spinal cord (SC) after injury such as crush or transection is limited in amniotes, sauropsids and mammals, where complex nervous circuits sustaining sophisticated behaviors are present (Borgens, ; Orr & Gensel, ; Schwab & Bartholdi, ). In contrast, a variable but complete anatomical and functional regeneration of the SC is possible in anamniotes, for example, teleost fish and amphibians, where nervous circuits are less complex and sustain stereotypical and less complex behaviors (Chernoff, ; Ferretti, Zhang, & O'Neil, ; Joven & Simon, ; Tanaka & Ferretti, ).…”