Spinal Glia Division Contributes to Conditioning Lesion-Induced Axon Regeneration Into the Injured Spinal Cord: Potential Role of Cyclic AMP-Induced Tissue Inhibitor of Metalloproteinase-1.

Abstract

Regeneration of sensory neurons after spinal cord injury depends on the function of dividing neuronal-glial antigen 2 (NG2)-expressing cells. We have shown that increases in the number of dividing NG2-positive cells through short-term pharmacologic inhibition of matrix metalloproteinases contributes to recovery after spinal cord injury. A conditioning sciatic nerve crush (SNC) preceding spinal cord injury stimulates central sensory axon regeneration via the intraganglionic action of cyclic adenosine monophosphate. Here, using bromodeoxyuridine, mitomycin (mitosis inhibitor), and cholera toxin B tracer, we demonstrate that SNC-induced division of spinal glia is related to the spinal induction of tissue inhibitor of metalloproteinase-1 and contributes to central sensory axon growth into the damaged spinal cord. Dividing cells were mainly NG2-positive and Iba1-positive and included myeloid NG2-positive populations. The cells dividing in response to SNC mainly matured into oligodendrocytes and microglia within the injured spinal cord. Some postmitotic cells remained NG2-reactive and were associated with regenerating fibers. Moreover, intraganglionic tissue inhibitor of metalloproteinase-1 expression was induced after administration of SNC or cyclic adenosine monophosphate analog (dbcAMP) to dorsal root ganglia in vivo and in primary adult dorsal root ganglia cultures. Collectively, these findings support a novel model whereby a cyclic adenosine monophosphate-activated regeneration program induced in sensory neurons by a conditioning peripheral nerve lesion uses tissue inhibitor of metalloproteinase-1 to protect against short-term proteolysis, enabling glial cell division and promoting axon growth into the damaged CNS.

• Authors: Huaqing Liu, Mila Angert, Tasuku Nishihara, Igor Shubayev, Jennifer Dolkas, Veronica I Shubayev
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 74 Issue 6 Pg. 500-11 (Jun 2015) ISSN: 1554-6578 [Electronic] England
• PMID: 25933384 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antigens
• Nucleic Acid Synthesis Inhibitors
• Proteoglycans
• Tissue Inhibitor of Metalloproteinase-1
• chondroitin sulfate proteoglycan 4
• Cyclic AMP
• Bromodeoxyuridine

Topics

• Animals
• Antigens (metabolism)
• Bromodeoxyuridine (metabolism)
• Cell Division (physiology)
• Cells, Cultured
• Cyclic AMP (metabolism)
• Disease Models, Animal
• Female
• Ganglia, Spinal (cytology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Mitosis (drug effects, physiology)
• Nerve Regeneration (drug effects, physiology)
• Neuroglia (physiology)
• Nucleic Acid Synthesis Inhibitors (pharmacology)
• Proteoglycans (metabolism)
• Rats
• Rats, Sprague-Dawley
• Sciatic Nerve (cytology)
• Sensory Receptor Cells (pathology)
• Spinal Cord Injuries (etiology, pathology)
• Time Factors
• Tissue Inhibitor of Metalloproteinase-1 (metabolism)