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Mouse Study Describes Novel Therapeutic Targets for Spinal Cord Injury Treatment

Review of  “Epidermal growth factor receptor‐extracellular‐regulated kinase blockade upregulates TRIM32 signaling cascade and promotes neurogenesis after spinal cord injury” from STEM CELLS by Stuart P. Atkinson

The complex myelin‐associated inhibitory microenvironment in the lesion site following spinal cord injury (SCI) inhibits axon regeneration and has complicated the development of effective therapeutic approaches. Studies aiming to understand the pathways involved have suggested that myelin inhibits axonal regeneration through epidermal growth factor receptor (EGFR) [1], with EGFR activation known to inhibit neuronal differentiation and promote glial differentiation over neurogenesis [2].

Previous studies from the laboratory of Jianwu Dai (Chinese Academy of Sciences, Beijing, China) found similar results, establishing that myelin inhibits the neuronal differentiation of neural stem cells (NSCs) [3, 4]. Writing in STEM CELLS, Xue et al. now describe their more recent research which focused on Tripartite motif (TRIM)‐NHL proteins, conserved stem cell regulators [5], in the hope of explaining the underlying mechanisms behind inhibited nerve regeneration after spinal cord injury (SCI) [6]. The authors hope that their new findings, which highlight a significant role for an EGFR‐ERK-TRIM32 axis, will provide new targets for SCI repair.

Initial in vitro immunoprecipitation- and lentivirus‐induced overexpression-based analyses suggested that myelin inhibited the neuronal differentiation of NSCs by activating the EGFR‐extracellular‐regulated kinase (ERK) signaling cascade, through EGFR phosphorylation induced by protein kinase C (PKC) and Src‐Pyk2 transactivation pathways. The myelin-mediated activation of this pathway then led to reduced protein levels of the ubiquitously expressed E3 ubiquitin ligase TRIM32, suggesting that the presence of this neuronal fate‐determining factor may permit axonal regeneration and SCI repair. 

Confirming these findings, the authors next established that EGFR‐ERK inhibition led to an increase in TRIM32 expression, which, in turn, allowed for the neural differentiation of NSCs in the presence of myelin. Furthermore, the authors also employed immunofluorescence colocalization analyses to provide evidence that ERK interacts with TRIM32 to regulate neuronal differentiation in the presence of myelin. Subsequent animal experiments and lineage tracing methods used to identify nascent neurogenesis after SCI also confirmed the role of the EGFR‐ERK-TRIM32 axis, by revealing that treatment with EGFR‐ERK inhibitors increased TRIM32 expression, promoted neurogenesis by injury‐activated nestin-positive ependymal NSC-like cells in the affected area, and permitted functional recovery after SCI.

The authors of this encouraging new study hope that their findings will prompt screening efforts aimed at discovering novel specific small molecule drugs that can effectively promote SCI repair within the myelin‐associated inhibitory microenvironment.

For more on new strategies aiming to promote effective spinal cord repair, stay tuned to the Stem Cells Portal!

References

  1. Koprivica V, Cho K-S, Park JB, et al., EGFR Activation Mediates Inhibition of Axon Regeneration by Myelin and Chondroitin Sulfate Proteoglycans. Science 2005;310:106.
  2. Ayuso-Sacido A, Moliterno JA, Kratovac S, et al., Activated EGFR signaling increases proliferation, survival, and migration and blocks neuronal differentiation in post-natal neural stem cells. Journal of Neuro-Oncology 2010;97:323-337.
  3. Li X, Xiao Z, Han J, et al., Promotion of neuronal differentiation of neural progenitor cells by using EGFR antibody functionalized collagen scaffolds for spinal cord injury repair. Biomaterials 2013;34:5107-5116.
  4. Wang B, Xiao Z, Chen B, et al., Nogo-66 Promotes the Differentiation of Neural Progenitors into Astroglial Lineage Cells through mTOR-STAT3 Pathway. PLoS ONE 2008;3:e1856.
  5. Tocchini C and Ciosk R, TRIM-NHL proteins in development and disease. Seminars in Cell & Developmental Biology 2015;47-48:52-59.
  6. Xue W, Zhao Y, Xiao Z, et al., Epidermal growth factor receptor-extracellular-regulated kinase blockade upregulates TRIM32 signaling cascade and promotes neurogenesis after spinal cord injury. STEM CELLS 2020;38:118-133.