EphB Signaling Directs Peripheral Nerve Regeneration through Sox2-Dependent Schwann Cell Sorting

Abstract

The peripheral nervous system has astonishing regenerative capabilities in that cut nerves are able to reconnect and re-establish their function. Schwann cells are important players in this process, during which they dedifferentiate to a progenitor/stem cell and promote axonal regrowth. Here, we report that fibroblasts also play a key role. Upon nerve cut, ephrin-B/EphB2 signaling between fibroblasts and Schwann cells results in cell sorting, followed by directional collective cell migration of Schwann cells out of the nerve stumps to guide regrowing axons across the wound. Mechanistically, we find that cell-sorting downstream of EphB2 is mediated by the stemness factor Sox2 through N-cadherin relocalization to Schwann cell-cell contacts. In vivo, loss of EphB2 signaling impaired organized migration of Schwann cells, resulting in misdirected axonal regrowth. Our results identify a link between Ephs and Sox proteins, providing a mechanism by which progenitor cells can translate environmental cues to orchestrate the formation of new tissue.

The Intermediate Filament Vimentin Mediates MicroRNA miR-378 Function in Cellular Self-renewal by Regulating the Expression of the Sox2 Transcription Factor

“…Sox2 is a major regulator of stem cell activities (47)(48)(49)(50)(51). It is highly expressed in the brain and plays a critical role in the development of the neural system (32,52). Because U87 cells were originally developed from astrocytes, we investigated how miR-378 modulated stem cell transformation by regulating Sox2 expression.…”

miR-9 inhibits Schwann cell migration by targeting CTHRC1 following sciatic nerve injury

“…Following peripheral nerve injury, mature differentiated Schwann cells undergo significant phenotypic modulation, in particular shedding their myelin sheaths and dedifferentiating to a progenitor/stem-cell-like state (Freidin et al, 2009). The dedifferentiated Schwann cells can replenish lost or damaged tissue through proliferation and migration, and can produce a favorable environment for axonal outgrowth through clearing myelin debris and forming cellular conduits or corridors (called bands of Buengner) to guide the directional growth of axons (Parrinello et al, 2010;Yao et al, 2013). Furthermore, many previous studies have described that the phenotypic modulation of Schwann cells is governed by activation of a regulatory network, including the transcription factors Sox2, Sox10, Krox20/Egr2, Oct6/SCIP, Brn2, NFATc4 (Ghislain and Charnay 2006;Kao et al, 2009;Parrinello et al, 2010).…”

“…The dedifferentiated Schwann cells can replenish lost or damaged tissue through proliferation and migration, and can produce a favorable environment for axonal outgrowth through clearing myelin debris and forming cellular conduits or corridors (called bands of Buengner) to guide the directional growth of axons (Parrinello et al, 2010;Yao et al, 2013). Furthermore, many previous studies have described that the phenotypic modulation of Schwann cells is governed by activation of a regulatory network, including the transcription factors Sox2, Sox10, Krox20/Egr2, Oct6/SCIP, Brn2, NFATc4 (Ghislain and Charnay 2006;Kao et al, 2009;Parrinello et al, 2010). The detailed mechanisms that account for dedifferentiation, proliferation, migration and redifferentiation of Schwann cells during axonal regeneration, however, remain largely unclear.…”

Nitric Oxide Synthase (NOS) Isoform Expression after Peripheral Nerve Transection in Mice

“…These cells then form aggregates, i.e., nerve bridges, and axons extend into these cell aggregates 18) . Cell growth factors, such as nerve growth factor 35) , brain-derived neurotrophic factor 22) , ciliary neurotrophic factor 31) , fibroblast growth factor 17) , transforming growth factor-β 33) , transcription factors 21) , and signaling pathways 29) are involved in this process of nerve regeneration. In addition, several cell adhesion molecules are expressed on the cell membrane of Schwann cells, and these molecules have been reported to play a role in the promotion of nerve regeneration 14) .…”