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

Nat Med. 2017 Jul;23(7):818-828. doi: 10.1038/nm.4354. Epub 2017 Jun 19.

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.

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Cadherins / metabolism*
  • Cell Transplantation
  • Cicatrix / pathology*
  • Collagen Type I / metabolism*
  • Disease Models, Animal
  • Female
  • Flow Cytometry
  • Integrin beta1 / metabolism*
  • Integrins / metabolism
  • Laser Capture Microdissection
  • Mice
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spinal Cord / pathology*
  • Spinal Cord Injuries / metabolism*
  • Spinal Cord Injuries / pathology

Substances

  • Cadherins
  • Cdh2 protein, mouse
  • Col1a2 protein, mouse
  • Collagen Type I
  • Integrin beta1
  • Integrins
  • collagen type I, alpha 1 chain