Interaction of reactive astrocytes with type I collagen induces astrocytic scar formation through the integrin–N-cadherin pathway after spinal cord injury

Abstract

Central nervous system (CNS) injury transforms naive astrocytes into reactive astrocytes, which eventually become scar-forming astrocytes that can impair axonal regeneration and functional recovery. This sequential phenotypic change, known as reactive astrogliosis, has long been considered unidirectional and irreversible. However, we report here that reactive astrocytes isolated from injured spinal cord reverted in retrograde to naive astrocytes when transplanted into a naive spinal cord, whereas they formed astrocytic scars when transplanted into injured spinal cord, indicating the environment-dependent plasticity of reactive astrogliosis. We also found that type I collagen was highly expressed in the spinal cord during the scar-forming phase and induced astrocytic scar formation via the integrin-N-cadherin pathway. In a mouse model of spinal cord injury, pharmacological blockade of reactive astrocyte-type I collagen interaction prevented astrocytic scar formation, thereby leading to improved axonal regrowth and better functional outcomes. Our findings reveal environmental cues regulating astrocytic fate decisions, thereby providing a potential therapeutic target for CNS injury.

The diversity and disparity of the glial scar

“…In support of this theory, a recent study by Hara et al pharmacologically blocked integrin signaling 2 weeks after SCI, thereby attenuating astrocyte scar formation and improving locomotor performance 32 . However, Anderson et al ablated reactive astrocytes in chronic glial scars 5 weeks after SCI and found that it did not promote axonal growth 49 .…”

“…While NG2-derived Schwann cells likely contribute to remyelination, albeit at low levels, the role of NG2-derived reactive astrocytes remains unclear. Because NG2-derived reactive astrocytes are a transient population that do not upregulate proteins expressed highly by scar-forming astrocytes (nestin and vimentin), it is possible that they resemble more ‘helpful’ reactive astrocytes 32 . Overall, NG2 glia participate in the formation and resolution of glial scars beyond serving simply as a reservoir for generating oligodendrocytes.…”

“…Within the same injury, subtypes of reactive astrocytes may also express differing levels of inhibitory proteins. Following contusion SCI, scar-forming astrocytes upregulate several genes that distinguish them from milder reactive astrocytes, including CSPGs and the repulsive axon guidance protein Slit2 32 .…”

“…So what explains these differing outcomes? Anderson et al ablated scar-forming astrocytes using genetically targeted diphtheria toxin receptor and low doses of diphtheria toxin 49 , whereas Hara et al administered an anti-β1-integrin antibody to the lesion epicenter, blocking the interaction of reactive astrocytes with collagen I 32 . It is possible that the latter approach preserved beneficial reactive astrocytes in the glial scar—perhaps akin to those in the ischemic glial scar.…”

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

“…Astrocytes were isolated according to previous methods [25,26]. At 3d post SCI, rats from the Sham and SCI groups (n = 6) were sacrificed, and the T9-T11 segment of the ventral spinal cord was dissected from Sham rats while a 2-cm long ventral segment that included the rostral and caudal areas to the injury epicenter was removed from SCI rats.…”