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

View Article: PubMed Central - PubMed

ABSTRACT

Chondroitin sulfate (CS) glycosaminoglycans inhibit regeneration in the adult central nervous system (CNS). We report here that HB-GAM (heparin-binding growth-associated molecule; also known as pleiotrophin), a CS-binding protein expressed at high levels in the developing CNS, reverses the role of the CS chains in neurite growth of CNS neurons in vitro from inhibition to activation. The CS-bound HB-GAM promotes neurite growth through binding to the cell surface proteoglycan glypican-2; furthermore, HB-GAM abrogates the CS ligand binding to the inhibitory receptor PTPσ (protein tyrosine phosphatase sigma). Our in vivo studies using two-photon imaging of CNS injuries support the in vitro studies and show that HB-GAM increases dendrite regeneration in the adult cerebral cortex and axonal regeneration in the adult spinal cord. Our findings may enable the development of novel therapies for CNS injuries.

No MeSH data available.


Related in: MedlinePlus

Summary of the current study.HB-GAM forms a complex with substrate-bound CSPGs and induces neurite outgrowth by binding to glypican-2 at the neuron surface. In addition, HB-GAM abrogates binding of PTPσ to CSPGs. At tissue level, CSPG-dependent inhibition of neurite outgrowth is seen as regeneration failure at the CSPG-rich astrocytic scar. As in vitro, inhibition of regeneration by the CSPG-rich matrix is reversed by HB-GAM as demonstrated by in vivo two-photon microscopy for dendritic regeneration in the cortex and axonal regeneration in the spinal cord.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5037378&req=5

f8: Summary of the current study.HB-GAM forms a complex with substrate-bound CSPGs and induces neurite outgrowth by binding to glypican-2 at the neuron surface. In addition, HB-GAM abrogates binding of PTPσ to CSPGs. At tissue level, CSPG-dependent inhibition of neurite outgrowth is seen as regeneration failure at the CSPG-rich astrocytic scar. As in vitro, inhibition of regeneration by the CSPG-rich matrix is reversed by HB-GAM as demonstrated by in vivo two-photon microscopy for dendritic regeneration in the cortex and axonal regeneration in the spinal cord.

Mentions: In agreement with the generally held view, our findings show that chondroitinase ABC reduces CSPG inhibition of neurite outgrowth. However, chondroitinase ABC also abolishes the capability of soluble HB-GAM to induce neurite outgrowth on CSPG substrate. Therefore, HB-GAM reverses the effects of the CS chains from potent inhibitors to potent activators of neurite outgrowth (see the summary of the current study in Fig. 8). This finding agrees with our previous studies showing that HB-GAM in solution does not enhance neurite outgrowth but may even be growth inhibitory24. Collectively, these data suggest that CS chains may provide ideal structures to trap HB-GAM from solution to make a polyvalent interaction surface that enhances neurite growth (Fig. 8).


HB-GAM (pleiotrophin) reverses inhibition of neural regeneration by the CNS extracellular matrix
Summary of the current study.HB-GAM forms a complex with substrate-bound CSPGs and induces neurite outgrowth by binding to glypican-2 at the neuron surface. In addition, HB-GAM abrogates binding of PTPσ to CSPGs. At tissue level, CSPG-dependent inhibition of neurite outgrowth is seen as regeneration failure at the CSPG-rich astrocytic scar. As in vitro, inhibition of regeneration by the CSPG-rich matrix is reversed by HB-GAM as demonstrated by in vivo two-photon microscopy for dendritic regeneration in the cortex and axonal regeneration in the spinal cord.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037378&req=5

f8: Summary of the current study.HB-GAM forms a complex with substrate-bound CSPGs and induces neurite outgrowth by binding to glypican-2 at the neuron surface. In addition, HB-GAM abrogates binding of PTPσ to CSPGs. At tissue level, CSPG-dependent inhibition of neurite outgrowth is seen as regeneration failure at the CSPG-rich astrocytic scar. As in vitro, inhibition of regeneration by the CSPG-rich matrix is reversed by HB-GAM as demonstrated by in vivo two-photon microscopy for dendritic regeneration in the cortex and axonal regeneration in the spinal cord.
Mentions: In agreement with the generally held view, our findings show that chondroitinase ABC reduces CSPG inhibition of neurite outgrowth. However, chondroitinase ABC also abolishes the capability of soluble HB-GAM to induce neurite outgrowth on CSPG substrate. Therefore, HB-GAM reverses the effects of the CS chains from potent inhibitors to potent activators of neurite outgrowth (see the summary of the current study in Fig. 8). This finding agrees with our previous studies showing that HB-GAM in solution does not enhance neurite outgrowth but may even be growth inhibitory24. Collectively, these data suggest that CS chains may provide ideal structures to trap HB-GAM from solution to make a polyvalent interaction surface that enhances neurite growth (Fig. 8).

View Article: PubMed Central - PubMed

ABSTRACT

Chondroitin sulfate (CS) glycosaminoglycans inhibit regeneration in the adult central nervous system (CNS). We report here that HB-GAM (heparin-binding growth-associated molecule; also known as pleiotrophin), a CS-binding protein expressed at high levels in the developing CNS, reverses the role of the CS chains in neurite growth of CNS neurons in vitro from inhibition to activation. The CS-bound HB-GAM promotes neurite growth through binding to the cell surface proteoglycan glypican-2; furthermore, HB-GAM abrogates the CS ligand binding to the inhibitory receptor PTPσ (protein tyrosine phosphatase sigma). Our in vivo studies using two-photon imaging of CNS injuries support the in vitro studies and show that HB-GAM increases dendrite regeneration in the adult cerebral cortex and axonal regeneration in the adult spinal cord. Our findings may enable the development of novel therapies for CNS injuries.

No MeSH data available.


Related in: MedlinePlus