Silmara De Lima1,2,3,4*
Bruno Siqueira Mietto5
Vinicius Toledo Ribas6
Victor Tulio Ribeiro-Resende7
Alexandre Leite Rodrigues Oliveira8
Kevin K. Park9- 1Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
- 2F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
- 3Department of Molecular and Cellular Biology, Faculty of Arts and Sciences, Harvard University, Cambridge, MA, United States
- 4Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
- 5Department of Biology, Institute of Biomedical Science, Juiz de Fora Federal University, Juiz de Fora, Minas Gerais, Brazil
- 6Morphology Department, Institute of Biomedical Science, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- 7Biophysics Department, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- 8Biology Institute, State University of Campinas, Campinas, São Paulo, Brazil
- 9Department of Ophthalmology and Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, United States
Editorial on the Research Topic
Promoting nervous system regeneration by treatments targeting neuron-glia interactions
Puzzled by the differences on how the central and peripheral nervous system behave when challenged, researchers are pursuing the intriguing long standing unanswered question: “can we heal the injured nervous system back to its original function?” As it seems to happen, the nervous system presents major obstacles and tissue-related characteristics, with regards to its regenerative capacity. While some repair can spontaneously occur after peripheral nervous system (PNS) injury, the regenerative capacity of the central nervous system (CNS) is limited. Interestingly, studies on PNS regeneration suggest that Schwann cells coordinate the healing process and adopt a cellular phenotype that favors removal of debris, neuronal survival, axon regeneration, remyelination, transfer of cargos, among many other aspects (Mietto et al., 2015, 2021; Jessen and Mirsky, 2019; Babetto et al., 2020; Bombeiro et al., 2020a,b; Sardella-Silva et al., 2021). Conversely, perturbed Schwann cells metabolism is linked to axonal pathology (Viader et al., 2013; Girardi et al., 2023). Therefore, regeneration of PNS has taught us many lessons, some of them reviewed in Neuron-Schwann interaction in peripheral nervous system homeostasis, disease, and preclinical treatment (Oliveira et al.). PNS regeneration has also inspired investigators to study the similarities and differences between the CNS and PNS after a lesion or in the course of neurodegenerative diseases. For more insights, see: Glia from central and peripheral nervous system are differentially affected by paclitaxel chemotherapy and neurodegenerative properties (Klein et al.). Others focus on understanding how glial cells within the CNS respond to the stimulation arising from signaling pathways known to stimulate neurogenesis, reported in: Activation of cannabinoid type 1 receptor modulates oligodendroglial process branching complexity in rat hippocampal cultures stimulated by olfactory ensheathing glial-conditioned medium (Paes-Colli et al.). On the other hand, very little is known about neuron-glia interaction which affects CNS regeneration. Therefore, investigations into the regenerative process in the CNS needs a broader approach, to show how specific therapies tested in preclinical studies interfere with the regenerative microenvironment (neuronal and glial cells)—as it is shown in Neuroprotection by upregulation of the major compatibility complex class I in SODG93A mice (Tomiyama et al.), where the authors describe that the upregulation of the major histocompatibility complex of class I (MHC I) after interferon beta treatment, at different concentrations, affects spinal motoneuron survival, astrocytic response, microglial activation, synapse modulation, and motor function, in an ALS disease model. In the past decade, great efforts were made to prove that the intrinsic growth capacity of mature CNS neurons could be stimulated and that they could regenerate and reconnect with specific targets after an injury. These efforts led many labs to contribute with evidences that, this is achievable, to some extent, with treatments that start either in the acute or chronic phase after the injury (Kurimoto et al., 2010; Sun et al., 2011; de Lima et al., 2012; Lim et al., 2016; Yungher et al., 2017; Xie et al., 2022). Unfortunately, however, there is a lack of data on the role that glial cells play in this process and, also, whether their interaction can be beneficial or detrimental to the process. Following those studies, it has been shown that regenerating axons can become myelinated (de Lima et al., 2012; Lu et al., 2012; Marin et al., 2016). However, depending on the treatment there is no spontaneous myelination of regenerating axons, but myelination can be stimulated after using a pro-myelination treatment (Wang et al., 2020). There is also evidence that astrocytic scar formation at the injury site supports axon regeneration (Anderson et al., 2016) and stimulation of the growth intrinsic capacity of adult neurons in the retina induces formation of newly formed astrocytes in the regenerating optic nerve (Ribeiro et al., 2022), and that complement cascade at the injury site is required for axon regeneration (Peterson et al., 2021). These are some important evidences that glial cells are active in the process of CNS recovery. These cells play a major role in neuronal integrity and homeostasis, and undoubtedly can cause and/or contribute to axonal pathology during disease conditions. The comprehension of this intricate neuron-glia interaction may provide the basis for promising therapies to repair the nervous system and boost its regenrative capacity after an injury, or prevent neurodegenerative conditions associated with dysfunction of glial cells.
Author contributions
SD: Conceptualization, Project administration, Supervision, Writing – original draft, Writing – review & editing. BM: Writing – original draft, Writing – review & editing. VR: Writing – review & editing. VR-R: Writing – review & editing. AO: Writing – review & editing. KP: Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Anderson, M. A., Burda, J. E., Ren, Y., Ao, Y., O'Shea, T. M., Kawaguchi, R., et al. (2016). Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200. doi: 10.1038/nature17623
Babetto, E., Wong, K. M., and Beirowski, B. (2020). A glycolytic shift in Schwann cells supports injured axons. Nat. Neurosci. 23, 1215–1228. doi: 10.1038/s41593-020-0689-4
Bombeiro, A. L., Lima, B. H. M., Bonfanti, A. P., and Oliveira, A. L. R. (2020a). Improved mouse sciatic nerve regeneration following lymphocyte cell therapy. Mol. Immunol. 121, 81–91. doi: 10.1016/j.molimm.2020.03.003
Bombeiro, A. L., Pereira, B. T. N., Bonfanti, A. P., and Oliveira, A. L. R. (2020b). Immunomodulation by dimethyl fumarate treatment improves mouse sciatic nerve regeneration. Brain Res. Bull. 160, 24–32. doi: 10.1016/j.brainresbull.2020.04.005
de Lima, S., Koriyama, Y., Kurimoto, T., Oliveira, J. T., Yin, Y., Li, Y., et al. (2012). Full-length axon regeneration in the adult mouse optic nerve and partial recovery of simple visual behaviors. Proc. Natl. Acad. Sci. USA. 109, 9149–9154. doi: 10.1073/pnas.1119449109
Girardi, K. C. V., Mietto, B. S., Lima, K. D., Atella, G. C., da Silva, D. S., Pereira, A. M. R., et al. (2023). Phenolic glycolipid-1 of mycobacterium leprae is involved in human Schwann cell line ST8814 neurotoxic phenotype. J. Neurochem. 164, 158–171. doi: 10.1111/jnc.15722
Jessen, K. R., and Mirsky, R. (2019). The success and failure of the schwann cell response to nerve injury. Front. Cell. Neurosci. 11, 13. doi: 10.3389/fncel.2019.00033
Kurimoto, T., Yin, Y., Omura, K., Gilbert, H.-y., Kim, D., Cen, L.-P., et al. (2010). Long-distance axon regeneration in the mature optic nerve: contributions of oncomodulin, cAMP, and pten gene deletion. J. Neurosci. 30, 15654–15663. doi: 10.1523/JNEUROSCI.4340-10.2010
Lim, J. H., Stafford, B. K., Nguyen, P. L., Lien, B. V., Wang, C., Zukor, K., et al. (2016). Neural activity promotes long-distance, target-specific regeneration of adult retinal axons. Nat. Neurosci. 19, 1073–84. doi: 10.1038/nn.4340
Lu, P., Wang, Y., Graham, L., McHale, K., Gao, M., Wu, D., et al. (2012). Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150, 1264–1273. doi: 10.1016/j.cell.2012.08.020
Marin, M. A., Stafford, B. K., Nguyen, P. L., Lien, B. V., Wang, C., and Zukor, K. (2016). Reassembly of excitable domains after CNS axon regeneration. J. Neurosci. 36, 9148–9160. doi: 10.1523/JNEUROSCI.1747-16.2016
Mietto, B. S., Jhelum, P., Schulz, K., and David, S. (2021). Schwann cells provide iron to axonal mitochondria and its role in nerve regeneration. J. Neurosci. 41, 7300–7313. doi: 10.1523/JNEUROSCI.0900-21.2021
Mietto, B. S., Mostacada, K., and Martinez, A. M. B. (2015). Neurotrauma and inflammation: CNS and PNS responses. Mediators Inflamm. 2015, 251204. doi: 10.1155/2015/251204
Peterson, S. L., Li, Y., Sun, C. J., Wong, K. A., Leung, K. S., de Lima, S., et al. (2021). Retinal ganglion cell axon regeneration requires complement and myeloid cell activity within the optic nerve. J. Neurosci. 41, 8508–8531. doi: 10.1523/JNEUROSCI.0555-21.2021
Ribeiro, M., Ayupe, A. C., Beckedorff, F. C., Levay, K., Rodriguez, S., Tsoulfas, P., et al. (2022). Retinal ganglion cell expression of cytokine enhances occupancy of NG2 cell-derived astrocytes at the nerve injury site: Implication for axon regeneration. Exp. Neurol. 355, 114147. doi: 10.1016/j.expneurol.2022.114147
Sardella-Silva, G., Mietto, B. S., and Ribeiro-Resende, V. T. (2021). Four seasons for schwann cell biology, revisiting key periods: development, homeostasis, repair, and aging. Biomolecules 11, 1887. doi: 10.3390/biom11121887
Sun, F., Park, K.. K., Belin, S., Wang, D., Lu, T., Chen, G., et al. (2011). Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature 480, 372–375. doi: 10.1038/nature10594
Viader, A., Sasaki, Y., Kim, S., Strickland, A., Workman, C. S., Yang, K., et al. (2013). Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axonal degeneration and neuropathy. Neuron 77, 886–898. doi: 10.1016/j.neuron.2013.01.012
Wang, J., He, X., Meng, H., Li, Y., Dmitriev, P., Tian, F., et al. (2020). Robust myelination of regenerated axons induced by combined manipulations of GPR17 and microglia. Neuron 108, 876–886. e4. doi: 10.1016/j.neuron.2020.09.016
Xie, L., Cen, L. P., Li, Y., Gilbert, H. Y., Strelko, O., Berlinicke, C., et al. (2022). Monocyte-derived SDF1 supports optic nerve regeneration and alters retinal ganglion cells' response to Pten deletion. Natl. Acad. Sci. USA. 119, e2113751119. doi: 10.1073/pnas.2113751119
Keywords: PNS, CNS, axon regeneration, glial cells, neuronal survival, neuron-glia crosstalk
Citation: De Lima S, Mietto BS, Ribas VT, Ribeiro-Resende VT, Oliveira ALR and Park KK (2024) Editorial: Promoting nervous system regeneration by treatments targeting neuron-glia interactions. Front. Cell. Neurosci. 17:1355469. doi: 10.3389/fncel.2023.1355469
Received: 14 December 2023; Accepted: 19 December 2023;
Published: 11 January 2024.
Edited and reviewed by: Dirk M. Hermann, University of Duisburg-Essen, Germany
Copyright © 2024 De Lima, Mietto, Ribas, Ribeiro-Resende, Oliveira and Park. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Silmara De Lima, silmara.soutodelima@childrens.harvard.edu