The origins and dynamic changes of C3- and S100A10-positive reactive astrocytes after spinal cord injury
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Accaumulating studies focus on the effects of C3-positive A1-like phenotypes and S100A10-positive A2-like phenotypes of reactive astrocytes on spinal cord injury (SCI), however the origins and dynamic changes of C3- and S100A10-positive reactive astrocytes after SCI remain poorly understood. Through transgenic mice and lineage tracing, we aimed to determine the origins of C3- and S100A10-positive reactive astrocytes. Meanwhile, the distribution and dynamic changes in C3- and S100A10-positive reactive astrocytes were also detected in juvenile and adult SCI mice models and cultured astrocytes. Combing with bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq) and bioinformatic analysis, we further explored the dynamic transcripts changes of C3- and S100A10-positive reactive astrocytes after SCI. We confirmed that resident astrocytes produced both C3- and S100A10-positive reactive astrocytes, whereas ependymal cells regenerated only S100A10-positive reactive astrocytes in lesion area. Importantly, C3-positive reactive astrocytes were predominantly activated in adult SCI mice, while S100A10-positive reactive astrocytes were hyperactivated in juvenile mice. Furthermore, we observed that C3- and S100A10-positive reactive astrocytes had a dynamic transformation process at different time in vitro and vivo , and a majority of intermediate states of C3- and S100A10-positive reactive astrocytes were found during transformation. RNA-seq and scRNA-seq results further confirmed that the transcripts of C3-positive reactive astrocytes and their lipid toxicity were gradually increased with time and age. In contrast, S100A10-positive reactive astrocytes transcripts increased at early time and then gradually decreased after SCI. Our results provide insight into the origins and dynamic changes of C3- and S100A10-positive reactive astrocytes after SCI, which would be valuable resources to further target C3- and S100A10-positive reactive astrocytes after SCI.
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DAA pathway phenotypes are associated with AD.
“APOE4 derived iAstrocytes showed increased inflammatory protein expression including those associated with DAA pathway phenotypes in AD [42][43][44][45] .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [43]
The Results (§3.3) discuss C3-positive reactive astrocytes, ApoE-related lipids, and inflammation after spinal cord injury; the Discussion (§4) likewise concerns spinal cord injury in mice. Searches for DAA, Alzheimer’s disease, APOE4, and iAstrocytes found no passage linking DAA pathway phenotypes to AD. (LLM, conf=0.76)
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Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971 · see citing works
Reactive astrocyte nomenclature, definitions, and future directions
Escartin, C., Galea, E., Lakatos, A., O’Callaghan, J. P., Petzold, G. C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00783-4 · Cited by 2,533 · see citing works
Astrocyte scar formation aids central nervous system axon regeneration
Anderson, M. A., Burda, J. E., Ren, Y., Ao, Y., O’Shea, T. M., Kawaguchi, R., Coppola, G., Khakh, B. S., Deming, T. J., & Sofroniew, M. V. (2016) · Nature · doi:10.1038/nature17623 · Cited by 1,851 · see citing works
Self-citationWanner, I. B., Anderson, M. A., Song, B., Levine, J., Fernandez, A., Gray-Thompson, Z., Ao, Y., & Sofroniew, M. V. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2121-13.2013 · Cited by 839 · see citing works
Sofroniew, M. V. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a020420 · Cited by 695 · see citing works
Origin of New Glial Cells in Intact and Injured Adult Spinal Cord
Barnabé-Heider, F., Göritz, C., Sabelström, H., Takebayashi, H., Pfrieger, F. W., Meletis, K., & Frisén, J. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.07.014 · Cited by 628 · see citing works
Flagged first, then by citations
Research works printed but not linked: 35
- Clark D. P. Q. Perreau V. M. Shultz S. R. Brady R. D. Lei E. Dixit S.. (2019). Inflammation in traumatic brain injury: roles for toxic A1 astrocytes and microglial-astrocytic crosstalk. Neurochem. Res. 44, 1410– 1424. 10.1007/s11064-019-02721-8 30661228 · DOI
- Correia S. S. Liu G. Jacobson S. Bernier S. G. Tobin J. V. Schwartzkopf C. D.. (2021). The CNS-penetrant soluble guanylate cyclase stimulator CYR119 attenuates markers of inflammation in the central nervous system. J. Neuroinflamm. 18, 213. 10.1186/s12974-021-02275-z 34537066 PMC8449877 · DOI
- Cui Y. Yang Y. Ni Z. Dong Y. Cai G. Foncelle A.. (2018). Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature 554, 323– 327. 10.1038/nature25752 29446379 · DOI · Paper page
- Cunningham L. A. Su C. (2002). Astrocyte delivery of glial cell line-derived neurotrophic factor in a mouse model of Parkinson's disease. Exp. Neurol. 174, 230– 242. 10.1006/exnr.2002.7877 11922664 · DOI
- Degos V. Charpentier T. L. Chhor V. Brissaud O. Lebon S. Schwendimann L.. (2013). Neuroprotective effects of dexmedetomidine against glutamate agonist-induced neuronal cell death are related to increased astrocyte brain-derived neurotrophic factor expression. Anesthesiology 118, 1123– 1132. 10.1097/ALN.0b013e318286cf36 23353792 · DOI
- Gong L. Gu Y. Han X. Luan C. Liu C. Wang X.. (2022). Spatiotemporal dynamics of the molecular expression pattern and intercellular interactions in the glial scar response to spinal cord injury. Neurosci. Bull. 39, 213– 244. 10.1101/2021.12.20.473346 35788904 PMC9905408 · DOI
- Guttenplan K. A. Weigel M. K. Prakash P. Wijewardhane P. R. Hasel P. Rufen-Blanchette U.. (2021). Neurotoxic reactive astrocytes induce cell death via saturated lipids. Nature 599, 102– 107. 10.1038/s41586-021-03960-y 34616039 PMC12054010 · DOI · Paper page
- Hackett A. R. Lee J. K. (2016). Understanding the NG2 glial scar after spinal cord injury. Front. Neurol. 7, 199. 10.3389/fneur.2016.00199 27895617 PMC5108923 · DOI
- Hansen R. R. Malcangio M. (2013). Astrocytes–multitaskers in chronic pain. Eur. J. Pharmacol. 716, 120– 128. 10.1016/j.ejphar.2013.03.023 23528354 · DOI
- Hou J. Bi H. Ge Q. Teng H. Wan G. Yu B.. (2022). Heterogeneity analysis of astrocytes following spinal cord injury at single-cell resolution. FASEB J. 36, e22442. 10.1096/fj.202200463R 35816276 · DOI
- Huang W. Bai X. Meyer E. Scheller A. (2020). Acute brain injuries trigger microglia as an additional source of the proteoglycan NG2. Acta Neuropathol. Commun. 8, 146. 10.1186/s40478-020-01016-2 32843103 PMC7449013 · DOI
- Khakh B. S. Sofroniew M. V. (2015). Diversity of astrocyte functions and phenotypes in neural circuits. Nat. Neurosci. 18, 942– 952. 10.1038/nn.4043 26108722 PMC5258184 · DOI · Paper page
- Komitova M. Serwanski D. R. Lu Q. R. Nishiyama A. (2011). NG2 cells are not a major source of reactive astrocytes after neocortical stab wound injury. Glia 59, 800– 809. 10.1002/glia.21152 21351161 PMC3560299 · DOI
- Li L. Li Y. He B. Li H. Ji H. Wang Y.. (2021). HSF1 is involved in suppressing A1 phenotype conversion of astrocytes following spinal cord injury in rats. J. Neuroinflamm. 18, 205. 10.1186/s12974-021-02271-3 34530848 PMC8444373 · DOI
- Li T. Liu T. Chen X. Li L. Feng M. Zhang Y.. (2020). Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain. J. Neuroinflamm. 17, 211. 10.1186/s12974-020-01891-5 32665021 PMC7362409 · DOI
- Li X. Yang B. Xiao Z. Zhao Y. Han S. Yin Y.. (2018). Comparison of subacute and chronic scar tissues after complete spinal cord transection. Exp. Neurol. 306, 132– 137. 10.1016/j.expneurol.2018.05.008 29753649 · DOI
- Li Y. He X. Kawaguchi R. Zhang Y. Wang Q. Monavarfeshani A.. (2020). Microglia-organized scar-free spinal cord repair in neonatal mice. Nature 587, 613– 618. 10.1038/s41586-020-2795-6 33029008 PMC7704837 · DOI
- Liu A. Yu L. Li X. Zhang K. Zhang W. So K. F.. (2023). Celsr2-mediated morphological polarization and functional phenotype of reactive astrocytes in neural repair. Glia 71, 1985– 2004. 10.1002/glia.24378 37186402 · DOI
- Liu C. Shen L. Xu L. Zhu A. Huang Y. (2022). Ror2 mediates chronic post-thoracotomy pain by inducing the transformation of A1/A2 reactive astrocytes in rats. Cell. Signal. 89, 110183. 10.1016/j.cellsig.2021.110183 34728368 · DOI
- Liu W. Wang Y. Gong F. Rong Y. Luo Y. Tang P.. (2019). Exosomes derived from bone mesenchymal stem cells repair traumatic spinal cord injury by suppressing the activation of A1 neurotoxic reactive astrocytes. J. Neurotrauma 36, 469– 484. 10.1089/neu.2018.5835 29848167 · DOI
- Meletis K. Barnabe-Heider F. Carlen M. Evergren E. Tomilin N. Shupliakov O.. (2008). Spinal cord injury reveals multilineage differentiation of ependymal cells. PLoS Biol. 6, e182. 10.1371/journal.pbio.0060182 18651793 PMC2475541 · DOI
- Milich L. M. Choi J. S. Ryan C. Cerqueira S. R. Benavides S. Yahn S. L.. (2021). Single-cell analysis of the cellular heterogeneity and interactions in the injured mouse spinal cord. J. Exp. Med. 218, e20210040. 10.1084/jem.20210040 34132743 PMC8212781 · DOI
- Nagai J. Rajbhandari A. K. Gangwani M. R. Hachisuka A. Coppola G. Masmanidis S. C.. (2019). Hyperactivity with disrupted attention by activation of an astrocyte synaptogenic cue. Cell 177, 1280– 1292.e1220. 10.1016/j.cell.2019.03.019 31031006 PMC6526045 · DOI
- Nishiyama A. Yang Z. Butt A. (2005). Astrocytes and NG2-glia: what's in a name? J. Anat. 207, 687– 693. 10.1111/j.1469-7580.2005.00489.x 16367796 PMC1571571 · DOI
- Pekny M. Pekna M. (2014). Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol. Rev. 94, 1077– 1098. 10.1152/physrev.00041.2013 25287860 · DOI · Paper page
- Sabelström H. Stenudd M. Friśen J. (2014). Neural stem cells in the adult spinal cord. Exp. Neurol. 260, 44– 49. 10.1016/j.expneurol.2013.01.026 23376590 · DOI
- Sabelström H. Stenudd M. Réu P. Dias D. O. Elfineh M. Zdunek S.. (2013). Resident neural stem cells restrict tissue damage and neuronal loss after spinal cord injury in mice. Science 342, 637– 640. 10.1126/science.1242576 24179227 · DOI
- Sofroniew M. V. (2009). Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32, 638– 647. 10.1016/j.tins.2009.08.002 19782411 PMC2787735 · DOI · Paper page
- Sofroniew M. V. Vinters H. V. (2010). Astrocytes: biology and pathology. Acta Neuropathol. 119, 7– 35. 10.1007/s00401-009-0619-8 20012068 PMC2799634 · DOI · Paper page
- Vismara I. Papa S. Veneruso V. Mauri E. Mariani A. De Paola M.. (2020). Selective Modulation of A1 astrocytes by drug-loaded nano-structured gel in spinal cord injury. ACS Nano 14, 360– 371. 10.1021/acsnano.9b05579 31887011 · DOI
- Wang J. Cheng C. Liu Z. Lin Y. Yang L. Zhang Z.. (2023). Inhibition of A1 astrocytes and activation of A2 astrocytes for the treatment of spinal cord injury. Neurochem. Res. 48, 767– 780. 10.1007/s11064-022-03820-9 36418652 · DOI
- Wang L. Pei S. Han L. Guo B. Li Y. Duan R.. (2018). mesenchymal stem cell-derived exosomes reduce A1 astrocytes via downregulation of phosphorylated NFkappaB P65 subunit in spinal cord injury. Cell. Physiol. Biochem. 50, 1535– 1559. 10.1159/000494652 30376671 · DOI
- Wang X. Zhang Z. Zhu Z. Liang Z. Zuo X. Ju C.. (2021). Photobiomodulation promotes repair following spinal cord injury by regulating the transformation of A1/A2 reactive astrocytes. Front. Neurosci. 15, 768262. 10.3389/fnins.2021.768262 34795557 PMC8593167 · DOI
- Zamanian J. L. Xu L. Foo L. C. Nouri N. Zhou L. Giffard R. G.. (2012). Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391– 6410. 10.1523/JNEUROSCI.6221-11.2012 22553043 PMC3480225 · DOI · Paper page
- Zhao Q. Zhu Y. Ren Y. Yin S. Yu L. Huang R.. (2022). Neurogenesis potential of oligodendrocyte precursor cells from oligospheres and injured spinal cord. Front. Cell. Neurosci. 16, 1049562. 10.3389/fncel.2022.1049562 36619671 PMC9813964 · DOI
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APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology
Lysaker, C. R., Johnson, C. N., Csikos, V., Franczak, E., Benson, M., Gilmore, C. A., Birky, C. J., Davis, X., McCoin, C. S., Smith, K. P., et al. (2026) · npj Dementia · doi:10.1038/s44400-026-00105-8 · Cited by 1 · see citing works
- Authors
- Zhao, Q., Ren, Y.-L., Zhu, Y.-J., Huang, R.-Q., Zhu, R.-R., Cheng, L.-M., & Xie, N.
- Affiliations
- Tongji University (CN)
- Corresponding author
- Xie, Ning
- ORCID
- Venue
- Frontiers in Cellular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2023-12-22
- Volume
- 17
- Pages
- 1276506-1276506
- ISSN
- 1662-5102 (ISSN-L)
- PMC
- PMC10766709
- OpenAlex
- W4390110986
- Cited by
- 15
- References
- 6
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 5
- FWCI
- 2.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China (81701217, 82271419, 81974190, 82225027, 81810001048, 81901902)
- Shanghai Rising-Star Program (22QA1408200)
- National Health Commission of the People's Republic of China
- Fundamental Research Funds for the Central Universities (22120220555, 22120230138)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- reactive astrocytes, spinal cord injury, complement C3, S100A10, ependymal cells, astrocyte transformation, lipotoxicity, astrocyte transcriptome
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