STAT3 Controls the Long-Term Survival and Phenotype of Repair Schwann Cells during Nerve Regeneration

Abstract

After nerve injury, Schwann cells convert to a phenotype specialized to promote repair. But during the slow process of axonal regrowth, these repair Schwann cells gradually lose their regeneration-supportive features and eventually die. Although this is a key reason for the frequent regeneration failures in humans, the transcriptional mechanisms that control long-term survival and phenotype of repair cells have not been studied, and the molecular signaling underlying their decline is obscure. We show, in mice, that Schwann cell STAT3 has a dual role. It supports the long-term survival of repair Schwann cells and is required for the maintenance of repair Schwann cell properties. In contrast, STAT3 is less important for the initial generation of repair Schwann cells after injury. In repair Schwann cells, we find that Schwann cell STAT3 activation by Tyr705 phosphorylation is sustained during long-term denervation. STAT3 is required for maintaining autocrine Schwann cell survival signaling, and inactivation of Schwann cell STAT3 results in a striking loss of repair cells from chronically denervated distal stumps. STAT3 inactivation also results in abnormal morphology of repair cells and regeneration tracks, and failure to sustain expression of repair cell markers, including Shh, GDNF, and BDNF. Because Schwann cell development proceeds normally without STAT3, the function of this factor appears restricted to Schwann cells after injury. This identification of transcriptional mechanisms that support long-term survival and differentiation of repair cells will help identify, and eventually correct, the failures that lead to the deterioration of this important cell population.SIGNIFICANCE STATEMENT Although injured peripheral nerves contain repair Schwann cells that provide signals and spatial clues for promoting regeneration, the clinical outcome after nerve damage is frequently poor. A key reason for this is that, during the slow growth of axons through the proximal parts of injured nerves repair, Schwann cells gradually lose regeneration-supporting features and eventually die. Identification of signals that sustain repair cells is therefore an important goal. We have found that in mice the transcription factor STAT3 protects these cells from death and contributes to maintaining the molecular and morphological repair phenotype that promotes axonal regeneration. Defining the molecular mechanisms that maintain repair Schwann cells is an essential step toward developing therapeutic strategies that improve nerve regeneration and functional recovery.

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

“…We speculate the normal demethylation of H3K27, at least in young mice, may be sufficient to drive expression of adequate amounts of critical nerve repair genes. However, the ultrastructural analysis revealed that the function of Schwann cell EED is critical for timely axon regeneration, a function likely to be critical for efficient nerve regeneration since the survival and capacity of Schwann cells decrease at more distal sites that are chronically denervated (Benito et al 2017; Eggers et al 2010; Höke et al 2002; Jessen and Mirsky 1999; Jonsson et al 2013; Li et al 1997; Michalski et al 2008; Ronchi et al 2017; Sulaiman and Gordon 2009). …”

Repair Schwann cell update: Adaptive reprogramming, EMT, and stemness in regenerating nerves

“…The first known transcription factor with this function is STAT3. This protein is not required for the initial generation of repair Schwann cells, but during chronic denervation, STAT3 is important both for the long‐term survival of these cells and for promoting the expression of c‐Jun and other repair program genes (Benito et al, ).…”

“…Similarly, developmental myelination is not controlled by the chromatin cross talk that in repair cells promotes silencing of myelin genes and activation of injury genes, and involves H3K27 demethylation coupled with H3K27 acetylation and H3K4 methylation (Hung et al, ; reviewed Ma & Svaren, ). STAT3 likewise is not involved in Schwann cell development although this factor is important for long‐term repair cell maintenance (Benito et al, ). Furthermore, the proliferation of adult Schwann cells that is triggered by injury and associated with the generation of repair cells requires cyclin D1, although this protein is not involved in the proliferation of developing Schwan cells (Kim et al, ).…”

“…Two transcriptional controls, c‐Jun and chromatin modifications involving H3K27 demethylation, H3K27 deacetylation and H3K4 methylation, were found to be important for the normal execution of the Schwann cell injury response, although these mechanisms did not regulate neonatal Schwann cells or myelination (Arthur‐Farraj et al, ; Hung, Sun, Keles, & Svaren, ; reviewed in Ma & Svaren, ). Additional control mechanisms that are selectively important in denervated cells have now been identified, including Merlin and STAT3 (Benito et al, ; Mindos et al, ). Denervated adult Schwann cells have also been shown to express de novo molecular markers that are low/absent during development, including Sonic Hedgehog (Shh), and Olig1 (Lu et al, ; Bosse et al, ; Arthur‐Farraj et al, ; Fontana et al, ; Lin, Oksuz, Edward Hurley, Wrabetz, & Awatramani, ; reviewed in Jessen & Mirsky, ).…”

Motor and sensory Schwann cell phenotype commitment is diminished by extracorporeal shockwave treatment in vitro

“…Additionally, we show that supernatant of ESWT‐treated Schwann cell cultures is significantly more potent in inducing neurites in vitro. This could be explained by an increased and prolonged induction of c‐jun and subsequent secretion of neurotrophic factor production, as other groups have shown that c‐jun activation results in a strong induction of pro‐regenerative genes …”