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

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. Chondroitinase ABC (ChABC) treatment has been extensively used to demonstrate that the CS side chains of CSPGs are potent inhibitors of regeneration and plasticity in the extracellular matrix (ECM) of brain and spinal cord 1–7. We have sought for less invasive ways to enhance CNS regeneration and plasticity, which might be useful for the development of therapies for CNS traumas. To this end, we considered endogenously occurring molecules that might modulate functions of the CNS matrix in the juvenile brain which displays high plasticity in comparison to the adult brain. HB-GAM/pleiotrophin was initially isolated as a heparin-binding neurite outgrowth-promoting factor for central neurons 8,9. Its expression peaks during the first 3–4 weeks of postnatal development in rat brain 10 corresponding to heightened plasticity of the juvenile brain 11. The expression level at this stage is very high, up to 10–15 μ g/g of wet tissue weight 8 , which might be sufficient to modulate matrix structures 12 that typically inhibit neural plasticity and regeneration. HB-GAM is secreted from neurons and glial cells upon cleav-age of a classic-type secretion signal 10 , binds CS side chains of CSPGs with nanomolar K d values 12–14 , and lines nearly all fiber tracts of the early postnatal rat brain 15. Furthermore, the growth factor Midkine, which displays homology with HB-GAM, was recently reported to partially overcome CSPG inhibition of neurite extension 16. Taken together, these studies suggest HB-GAM as a candidate molecule to modify interactions of CNS neu-rons with inhibitory ECM structures such as CSPGs. However, the possibility that HB-GAM could overcome or even reverse the inhibitory effects of the ECM on growth and regeneration of neurites has not previously been explored. Results HB-GAM promotes neurite outgrowth on CSPG substrates. We first studied the effect of HB-GAM on neurite growth from primary CNS neurons plated on aggrecan, a major CSPG in the CNS 17. As expected, the aggrecan matrix effectively prevented neurite outgrowth from the CNS neurons (Fig. 1a–c). Coating of HB-GAM together with aggrecan overcame the inhibitory effect (Fig. 1c,d). Moreover, delayed addition of HB-GAM to culture media promoted neurite extension from the primary CNS neurons already inhibited by aggrecan (Supplementary Fig. S1).
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Submitted on : Wednesday, February 15, 2017 - 4:46:43 PM
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Mikhail Paveliev, Keith Fenrich, Mikhail Kislin, Juha Kuja-Panula, Evgeny Kulesskiy, et al.. HB-GAM (pleiotrophin) reverses inhibition of neural regeneration by the CNS extracellular matrix . Scientific Reports, Nature Publishing Group, 2016, ⟨10.1038/srep33916⟩. ⟨hal-01468727⟩



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