Brain-derived neurotrophic factor promotes nerve regeneration by activating the JAK/STAT pathway in Schwann cells

Abstract

BackgroundRadical prostatectomy (RP) carries the risk of erectile dysfunction (ED) due to cavernous nerve (CN) injury. Schwann cells are essential for the maintenance of integrity and function of peripheral nerves such as the CNs. We hypothesize that brain-derived neurotrophic factor (BDNF) activates the Janus kinase (JAK)/(signal transducer and activator of transcription) STAT pathway in Schwann cells, not in neuronal axonal fibers, with the resultant secretion of cytokines from Schwann cells to facilitate nerve recovery.MethodsUsing four different cell lines—human neuroblastoma BE(2)-C and SH-SY5Y, human Schwann cell (HSC), and rat Schwann cell (RSC) RT4-D6P2T—we assessed the effect of BDNF application on the activation of the JAK/STAT pathway. We also assessed the time response of JAK/STAT pathway activation in RSCs and HSCs after BDNF treatment. We then assayed cytokine release from HSCs as a response to BDNF treatment using oncostatin M and IL6 as markers.ResultsWe showed extensive phosphorylation of STAT3/STAT1 by BDNF at high dose (100 pM) in RSCs, with no JAK/STAT pathway activation in human neuroblastoma cell lines. The time response of JAK/STAT pathway activation in RSCs and HSCs after BDNF treatment showed an initial peak at shortly after treatment and then a second higher peak at 24–48 hours. Cytokine release from HSCs increased progressively after BDNF application, reaching statistical significance for IL6.ConclusionsWe demonstrated for the first time the indirect mechanism of BDNF enhancement of nerve regeneration through the activation of JAK/STAT pathway in Schwann cells, rather than directly on neurons. As a result of BDNF application, Schwann cells produce cytokines that promote nerve regeneration.

The advances in nerve tissue engineering: From fabrication of nerve conduit toin vivonerve regeneration assays

“…Some of the growth factors that have been widely used in the peripheral nerve regeneration include NGF (Jafari, Delaviz, Torabi, Mohammadi & Gheitasi, ), GDNF (Marquardt, ), CNTF (Xu, Chen, Lu, & He, ), BDNF (Lin, Zhang, et al (), neurotrophin 3 (Sterne, Coulton, Brown, Green, & Terenghi, ), VEGF (Mohammadi, Ahsan, Masoumi, & Amini, ), insulin‐like growth factor 1 (Sebben, Lichtenfels, & da Silva, ), leukemia inhibitory factor (Razavi et al, ), glial growth factor (Terenghi, ), platelet‐derived growth factor, and fibroblast growth factor 1 (Küçük et al, ). Many studies have shown that various types of vitamins such as vitamin B complex, vitamin B12 (Altun & Kurutas, ), vitamin E (Elsy, Khan, & Maheshwari, ), vitamin D3 (Chabas et al, ), vitamin D2 (Chabas et al, ), and vitamin C (Gess, Rohr, & Young, ) are effective in nerve regeneration.…”

Stem cells purified from human induced pluripotent stem cell-derived neural crest-like cells promote peripheral nerve regeneration

“…10 ). The effect of BDNF and VEGF in peripheral nerve injuries has been shown previously 49 , 50 ; these factors may play important roles in introducing host blood vessels and Schwann cells during peripheral nerve recovery. These indirect contributions to recovery suggested that the LT-NCLCs create an optimal niche for peripheral nerve regeneration.…”

Neurotrophically Induced Mesenchymal Progenitor Cells Derived from Induced Pluripotent Stem Cells Enhance Neuritogenesis via Neurotrophin and Cytokine Production

“…Again, we co‐administered 24 nM of GNF5837 to determine if any factor acting through the Trk receptors played a role in altering length of the extensions. It has been reported that BDNF, acting through TrkB, is capable of activating STAT3, which is essential in axon extension . However, the addition of the pharmacological blocker did not result in a difference in neurite extension lengths (Fig.…”