HB-GAM (pleiotrophin) reverses inhibition of neural regeneration by the CNS extracellular matrix

Scientific Reports, 2016 · DOI: 10.1038/srep33916 · Published: September 27, 2016

Neurology Genetics Regenerative Medicine & Stem Cells

Simple Explanation

Chondroitin sulfate (CS) glycosaminoglycans inhibit regeneration in the adult central nervous system (CNS). This study found that HB-GAM, a CS-binding protein, reverses this inhibition, promoting neurite growth of CNS neurons in vitro. HB-GAM promotes neurite growth by binding to glypican-2 on the cell surface and preventing CS ligand binding to the inhibitory receptor PTPσ. In vivo studies support these findings, showing increased dendrite regeneration in the cerebral cortex and axonal regeneration in the spinal cord. These findings suggest that HB-GAM could be used to develop new treatments for CNS injuries by modulating the inhibitory effects of the extracellular matrix.

Study Duration

4 Weeks

Participants

Adult transgenic mice

Evidence Level

Not specified

Key Findings

1
HB-GAM promotes neurite outgrowth on CSPG substrates, overcoming the inhibitory effects of aggrecan, neurocan, and brain-derived CSPGs.
2
HB-GAM-induced neurite outgrowth depends on the CS chains of the substrate and the HS chains of the neuron surface glypican-2.
3
HB-GAM inhibits PTPσ binding to substrate-bound CSPG, competing for CS binding sites.

Research Summary

This study investigates the role of HB-GAM in reversing the inhibitory effects of the CNS extracellular matrix on neural regeneration. It demonstrates that HB-GAM promotes neurite outgrowth by interacting with CS chains and glypican-2, and by inhibiting PTPσ binding to CSPGs. In vivo experiments show that HB-GAM promotes dendritic regeneration in the cerebral cortex and axonal regeneration in the spinal cord following injury. These findings suggest a potential therapeutic role for HB-GAM in treating CNS injuries. The study concludes that HB-GAM modulates the CSPG matrix to promote neural regeneration, offering a new perspective on the role of CSPGs in CNS repair and suggesting potential therapeutic strategies for traumatic brain and spinal cord injuries.

Practical Implications

Therapeutic Development

HB-GAM and similar molecules could be developed into therapeutic strategies for enhancing neural regeneration after traumatic brain and spinal cord injuries.

Understanding CSPG Modulation

The findings revise the accepted concept that CSPG matrices solely inhibit regeneration, demonstrating they can be modulated to promote neural regeneration.

Targeted Drug Delivery

HB-GAM's affinity for the glial scar region offers potential for targeted drug delivery to promote regeneration at injury sites.

Study Limitations

1
The study primarily uses in vitro and animal models, requiring further research to validate the findings in human clinical trials.
2
The exact mechanisms of HB-GAM/glypican-2 interaction and downstream signaling during the regenerative response need further elucidation.
3
The long-term effects and potential side effects of HB-GAM treatment in vivo were not fully explored.

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