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Extracellular histones, a new class of inhibitory molecules of CNS axonal regeneration

Mustafa M Siddiq1,2, Sari S Hannila1,3, Yana Zorina2,4

  • 1Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA.

Brain Communications
|January 7, 2022
PubMed

Insights

Extracellular histones, particularly histone H3, inhibit nerve regeneration after CNS injury. Activated protein C treatment reverses this inhibition and promotes axonal regrowth in vivo.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Regenerative Medicine

Background:

  • Axonal regeneration in the mature central nervous system (CNS) is significantly hindered by inhibitory factors present in the extracellular environment.
  • While myelin-associated inhibitors are well-known, their absence in knockout models does not restore spontaneous regeneration, suggesting the existence of other inhibitory molecules.

Purpose of the Study:

  • To identify novel inhibitors of axonal regeneration in the injured CNS.
  • To investigate the role of extracellular histones in limiting nerve repair.

Main Methods:

  • Detection of extracellular histone H3 levels in human cerebrospinal fluid (CSF) and at injury sites in rodent models (spinal cord injury, optic nerve crush).
  • Assessment of histone H3's effect on neurite outgrowth and growth cone collapse in vitro.
  • Investigation of the molecular pathways involved, including Y-box-binding protein 1 (YB-1) and Toll-like receptor 2 (TLR2).
  • Evaluation of activated protein C (APC) in reversing histone-mediated inhibition in vitro and promoting regeneration in vivo.

Main Results:

  • Elevated levels of extracellular histone H3 were found in human CSF post-spinal cord injury and at injury sites in mice and rats.
  • Extracellular histones mimicked myelin-associated inhibitors by inducing growth cone collapse and inhibiting neurite outgrowth.
  • Histone-mediated inhibition was found to be independent of the Nogo receptor but involved YB-1 and TLR2.
  • Activated protein C treatment reversed histone inhibition in vitro and promoted axonal regeneration in vivo.

Conclusions:

  • Extracellular histone H3 represents a newly identified class of molecules that inhibit nerve regeneration in the injured CNS.
  • Targeting extracellular histones or utilizing agents like activated protein C may offer therapeutic strategies for enhancing CNS repair.
Keywords:
CNSaxonal regenerationaxonsextracellular histonesinhibitory molecules

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