Proteomics and transcriptomics of peripheral nerve tissue and cells unravel new aspects of the human Schwann cell repair phenotype

Abstract

The remarkable feature of Schwann cells (SCs) to transform into a repair phenotype turned the spotlight on this powerful cell type. SCs provide the regenerative environment for axonal re-growth after peripheral nerve injury (PNI) and play a vital role in differentiation of neuroblastic tumors into a benign subtype of neuroblastoma, a tumor originating from neural crestderived neuroblasts. Hence, understanding their mode-of-action is of utmost interest for new approaches in regenerative medicine, but also for neuroblastoma therapy. However, literature on human SCs is scarce and it is unknown to which extent human SC cultures reflect the SC repair phenotype developing after PNI in patients. We performed high-resolution proteome profiling and RNA-sequencing on highly enriched human SC and fibroblast cultures, control and ex vivo degenerated nerve explants to identify novel molecules and functional processes active in repair SCs. In fact, we found cultured SCs and degenerated nerves to share a similar repair SC-associated expression signature, including the upregulation of JUN, as well as two prominent functions, i.e., myelin debris clearance and antigen presentation via MHCII. In addition to myelin degradation, cultured SCs were capable of actively taking up cell-extrinsic components in functional phagocytosis and co-cultivation assays. Moreover, in cultured SCs and degenerated nerve tissue MHCII was upregulated at the cellular level along with high expression of chemoattractants and co-inhibitory rather than -stimulatory molecules. These results demonstrate human SC cultures to execute an inherent program of nerve repair and support two novel repair SC functions, debris clearance via phagocytosisrelated mechanisms and type II immune-regulation.

Myelination key factor krox‐20 is downregulated in Schwann cells and murine sciatic nerves infected by Mycobacterium leprae

“…22 Weiss et al 20 elegantly demonstrated that among the key factors associated with the repair programme, c-Jun was strongly expressed in human SC cultures and explants from peripheral nerve fascicles. 20 In the present study, we sought to determine the expression of this same transcription factor in the murine model.…”

“…Büngner cells actively participate in the immune response, in addition to degrading myelin debris that could potentially inhibit axonal regeneration . The proto‐oncogene c‐Jun controls the conversion of Büngner cells after neural injury by mechanisms not yet fully clarified . C‐Jun is present at high levels in SCs prior to the establishment of the myelinating profile, and its expression is suppressed by Krox‐20 during cell maturation .…”

“…19 The proto-oncogene c-Jun controls the conversion of Büngner cells after neural injury by mechanisms not yet fully clarified. 20 C-Jun is present at high levels in SCs prior to the establishment of the myelinating profile, and its expression is suppressed by Krox-20 during cell maturation. 17,21 Additionally, the restriction of c-Jun interferes in the expression of important neurotrophic factors and cell surface proteins, limiting the potential of peripheral nerve to repair.…”

Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8

“…Human peripheral nerves were collected during reconstructive surgery, amputations or organ donations of male and female patients between 16 and 70 years of age. The ex vivo nerve injury model as well as the isolation procedure and culture conditions of primary human SCs have been performed as previously described Weiss et al, 2016 For IF analysis, SCs from 3 independent donors were co-cultured with STA-NB-6 or CLB-Ma NB cell lines in coated wells of an 8-well chamber slide (Ibidi), respectively, alongside with controls for 11 days.…”

“…This phenotypical switch involves dedifferentiation into a proliferative state with immature/precursor SC properties and redifferentiation along an alternative pathway (Jessen & Mirsky, 2016). The resulting repair SC phenotype represents a transient cell state equipped with a certain skill set specialized to the needs during wound healing such as degradation of myelin debris, attraction of phagocytes, and the expression of cell surface proteins and trophic (neuroprotective and neuritogentic) factors promoting axon re-growth and pathfinding (Gomez-Sanchez et al, 2015;Jang et al, 2016;Jessen & Mirsky, 2016;Tofaris et al, 2002;Weiss et al, 2016). Furthermore, we have previously shown that human repair SCs express molecules involved in antigen processing and presentation via MHC-II as well as co-inhibitory receptors that support an immunomodulatory role of SCs during nerve regeneration .…”