Thrombin regulates the ability of Schwann cells to support neuritogenesis and to maintain the integrity of the nodes of Ranvier

Abstract

Schwann cells (SC) are characterized by a remarkable plasticity that enables them to promptly respond to nerve injury promoting axonal regeneration. In peripheral nerves after damage SC convert to a repair-promoting phenotype activating a sequence of supportive functions that drive myelin clearance, prevent neuronal death, and help axon growth and guidance. Regeneration of peripheral nerves after damage correlates inversely with thrombin levels. Thrombin is not only the key regulator of the coagulation cascade but also a protease with hormone-like activities that affects various cells of the central and peripheral nervous system mainly through the protease-activated receptor 1 (PAR1). Aim of the present study was to investigate if and how thrombin could affect the axon supportive functions of SC. In particular, our results show that the activation of PAR1 in rat SC cultures with low levels of thrombin or PAR1 agonist peptides induces the release of molecules, which favor neuronal survival and neurite elongation. Conversely, the stimulation of SC with high levels of thrombin or PAR1 agonist peptides drives an opposite effect inducing SC to release factors that inhibit the extension of neurites. Moreover, high levels of thrombin administered to sciatic nerve ex vivo explants induce a dramatic change in SC morphology causing disappearance of the Cajal bands, enlargement of the Schmidt-Lanterman incisures and calcium-mediated demyelination of the paranodes. Our results indicate thrombin as a novel modulator of SC plasticity potentially able to favor or inhibit SC pro-regenerative properties according to its level at the site of lesion.

Treatment of Diabetic Neuropathy with A Novel PAR1-Targeting Molecule

“…These effects are prevented by using thrombin and PAR1 inhibitors. High thrombin levels and PAR1 activation with an agonist peptide cause Schwann cell changes, including demyelination of the paranode region [ 14 ], and induce motor neuron cell death in ALS models [ 15 ]. However, low thrombin levels induce PAR1 Schwann cell modification to support neuronal survival [ 14 ].…”

“…High thrombin levels and PAR1 activation with an agonist peptide cause Schwann cell changes, including demyelination of the paranode region [ 14 ], and induce motor neuron cell death in ALS models [ 15 ]. However, low thrombin levels induce PAR1 Schwann cell modification to support neuronal survival [ 14 ]. Interestingly, PAR1 activation by a different coagulation factor, activated protein C (aPC), induces neuronal differentiation [ 16 ], enhances LTP in the CNS [ 17 ] and promotes a neuroprotective phenotype in Schwann cells in the PNS [ 18 ].…”

“…The STZ injection rodent DM model, which has the benefits of being both easily established and reliably monitored by blood glucose measurements, presents with hyperalgesia reminiscent of that of patients [ 27 ]. Furthermore, this model previously showed elevated levels of thrombin in the sciatic nerve, disruption of the node of Ranvier and decreased conduction velocity, which were prevented by thrombin inhibition [ 9 , 14 ]. Indeed, our results in the untreated DM mice indicate slower nerve conduction velocities, decreased motor function and the expected hyperalgesia which is a common characteristic for diabetic patients.…”

BDNF‐Gene Transfected Schwann Cell‐Assisted Axonal Extension and Sprouting on New PLA–PPy Microfiber Substrates

“…[5][6][7][8] Axonal extension is accompanied and influenced by interactions with auxiliary cells that behave as factories for the biological factors and that play a decisive role in axonal growth. [9,10] Schwann cells (SCs) are essential in both the development and the regeneration in the PNS, while oligodendrocytes are essential in the CNS. [11][12][13][14] SCs are naturally present in the PNS, forming the myelin sheath around the axons and playing a key role in neuronal survival and axonal regeneration.…”

“…[11][12][13][14] SCs are naturally present in the PNS, forming the myelin sheath around the axons and playing a key role in neuronal survival and axonal regeneration. [10,[15][16][17] In case of injury, SCs are necessary to achieve the axonal regeneration since they form regeneration columns (called Büngner's bands) that guide the regenerating axons. [11,12] SCs also release cytokines such as LIF and IL-6 that promote the survival of neurons.…”