Fibrotic scar after experimental autoimmune encephalomyelitis inhibits oligodendrocyte differentiation.
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Abstract
Remyelination failure is a crucial component of disease progression in the autoimmune demyelinating disease Multiple Sclerosis (MS). The regenerative capacity of oligodendrocyte progenitor cells (OPCs) to replace myelinating oligodendrocytes is likely influenced by many aspects of the lesion environment including inflammatory signaling and extracellular matrix (ECM) deposition. These features of MS lesions are typically attributed to infiltrating leukocytes and reactive astrocytes. Here we demonstrate that fibroblasts also contribute to the inhibitory environment in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Using Col1α1GFP transgenic mice, we show that perivascular fibroblasts are activated in the spinal cord at EAE onset, and infiltrate the parenchyma by the peak of behavioral deficits where they are closely associated with areas of demyelination, myeloid cell accumulation, and ECM deposition. We further show that both fibroblast conditioned media and fibroblast ECM inhibit the differentiation of OPCs into mature oligodendrocytes. Taken together, our results indicate that the fibrotic scar is a major component of EAE pathology that leads to an inhibitory environment for remyelination, thus raising the possibility that anti-fibrotic mechanisms may serve as novel therapeutic targets for MS.
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Using a Col1a1-GFP mouse line in conjunction with an EAE model, two independent groups identified substantial increases in fibroblasts within spinal cord lesion sites, and fibroblast expansion was deleterious for oligodendrocyte precursor cell (OPC) differentiation into mature oligodendrocytes and OPC migration into the lesion.
“Using a Col1a1-GFP mouse line in conjunction with an EAE model, two independent groups identified substantial increases in fibroblasts within spinal cord lesion sites”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Yahn et al., 2020
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Cites
A molecular atlas of cell types and zonation in the brain vasculature
Vanlandewijck, M., He, L., Mäe, M. A., Andrae, J., Ando, K., Del Gaudio, F., Nahar, K., Lebouvier, T., Laviña, B., Gouveia, L., et al. (2018) · Nature · doi:10.1038/nature25739 · Cited by 2,074 · see citing works
Cell death and control of cell survival in the oligodendrocyte lineage
Barres, B. A., Hart, I. K., Coles, H. S. R., Burne, J. F., Voyvodic, J. T., Richardson, W. D., & Raff, M. C. (1992) · Cell · doi:10.1016/0092-8674(92)90531-g · Cited by 1,345 · see citing works
The anatomical and cellular basis of immune surveillance in the central nervous system
Ransohoff, R. M., & Engelhardt, B. (2012) · Nature reviews. Immunology · doi:10.1038/nri3265 · Cited by 975 · see citing works
RAFF, M. C., Lillien, L. E., Richardson, W. D., Burne, J. F., & Noble, M. (1988) · Nature · doi:10.1038/333562a0 · Cited by 761 · see citing works
Multiple extracellular signals are required for long-term oligodendrocyte survival
Barres, B. A., Schmid, R., Sendnter, M., & Raff, M. C. (1993) · Development · doi:10.1242/dev.118.1.283 · Cited by 712 · see citing works
NG2-Positive Oligodendrocyte Progenitor Cells in Adult Human Brain and Multiple Sclerosis Lesions
Chang, A., Nishiyama, A., Peterson, J. W., Prineas, J. W., & Trapp, B. D. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-17-06404.2000 · Cited by 711 · see citing works
Crosstalk between fibroblasts and inflammatory cells
Linthout, S. V., Miteva, K., & Tschöpe, C. (2014) · Cardiovascular Research · doi:10.1093/cvr/cvu062 · Cited by 572 · see citing works
Pathophysiology of the brain extracellular matrix: a new target for remyelination
Lau, L. W., Cua, R., Keough, M. B., Haylock-Jacobs, S., & Yong, V. W. (2013) · Nature reviews. Neuroscience · doi:10.1038/nrn3550 · Cited by 549 · see citing works
Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation
Mayo, L., Trauger, S. A., Blain, M., Nadeau, M., Patel, B., Alvarez, J. I., Mascanfroni, I. D., Yeste, A., Kivisäkk, P., Kallas, K., et al. (2014) · Nature Medicine · doi:10.1038/nm.3681 · Cited by 472 · see citing works
Perivascular Fibroblasts Form the Fibrotic Scar after Contusive Spinal Cord Injury
Soderblom, C., Luo, X., Blumenthal, E., Bray, E. R., Lyapichev, K. A., Ramos, J., Krishnan, V., Lai-Hsu, C., Park, K. K., Tsoulfas, P., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2524-13.2013 · Cited by 419 · see citing works
Self-citationTripathi, R. B., Rivers, L. E., Young, K. M., Jamen, F., & Richardson, W. D. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.3411-10.2010 · Cited by 277 · see citing works
Fibronectin aggregation in multiple sclerosis lesions impairs remyelination
Stoffels, J. M. J., de Jonge, J. C., Stancic, M., Nomden, A., van Strien, M. E., Ma, D., Šišková, Z., Maier, O., ffrench‐Constant, C., Franklin, R. J. M., et al. (2013) · Brain · doi:10.1093/brain/aws313 · Cited by 206 · see citing works
Zhu, Y., Soderblom, C., Krishnan, V., Ashbaugh, J., Bethea, J. R., & Lee, J. K. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.10.024 · Cited by 199 · see citing works
Self-citationDNase I-hypersensitive sites enhance α1(I) collagen gene expression in hepatic stellate cells
Yata, Y., Scanga, A. E., Gillan, A., Yang, L., Reif, S. S., Breindl, M., Brenner, D. A., & Rippe, R. A. (2003) · Hepatology · doi:10.1053/jhep.2003.50067 · Cited by 192 · see citing works
Sobel, R. A., & Ahmed, A. S. (2001) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/60.12.1198 · Cited by 167 · see citing works
Mohan, H., Krumbholz, M., Sharma, R. D., Eisele, S. C., Junker, A., Sixt, M., Newcombe, J., Wekerle, H., Hohlfeld, R., Lassmann, H., et al. (2010) · Brain Pathology · doi:10.1111/j.1750-3639.2010.00399.x · Cited by 160 · see citing works
Fibrotic scarring following lesions to the central nervous system
Dias, D. O., & Göritz, C. (2018) · Matrix Biology · doi:10.1016/j.matbio.2018.02.009 · Cited by 151 · see citing works
The oligodendrocyte precursor mitogen PDGF stimulates proliferation by activation of αvβ3 integrins
Baron, W., Shattil, S. J., & ffrench‐Constant, C. (2002) · The EMBO Journal · doi:10.1093/emboj/21.8.1957 · Cited by 147 · see citing works
Long-Term Culture of Purified Postnatal Oligodendrocyte Precursor Cells
Tang, D. G., Tokumoto, Y. M., & RAFF, M. C. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.148.5.971 · Cited by 144 · see citing works
Cheng, X., Wang, Y., He, Q., Qiu, M. S., Whittemore, S. R., & Cao, Q. (2007) · Stem Cells · doi:10.1634/stemcells.2007-0284 · Cited by 132 · see citing works
van Horssen, J., Bø, L., Vos, C. M. P., Virtanen, I., & de Vries, H. E. (2005) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/01.jnen.0000173894.09553.13 · Cited by 129 · see citing works
Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination
de la Fuente, A. G., Lange, S., Silva, M. E., González, G. A., Tempfer, H., van Wijngaarden, P., Zhao, C., Canio, L. D., Trost, A., Bieler, L., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.007 · Cited by 129 · see citing works
Astrogliosis during acute and chronic cuprizone demyelination and implications for remyelination
Hibbits, N., Yoshino, J., Le, T. Q., & Armstrong, R. C. (2012) · ASN Neuro · doi:10.1042/an20120062 · Cited by 125 · see citing works
Gard, A. L., Burrell, M., Pfeiffer, S. E., Rudge, J. S., & Williams, W. C. (1995) · Development · doi:10.1242/dev.121.7.2187 · Cited by 120 · see citing works
Extensive extracellular matrix depositions in active multiple sclerosis lesions.
van Horssen, J., Bö, L., Dijkstra, C. D., & de Vries, H. E. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.08.005 · Cited by 119 · see citing works
The Fibrotic Scar in Neurological Disorders
Fernández‐Klett, F., & Priller, J. (2014) · Brain Pathology · doi:10.1111/bpa.12162 · Cited by 108 · see citing works
Pang, Y., Fan, L., Tien, L., Dai, X., Zheng, B., Cai, Z., Lin, R. C. S., & Bhatt, A. (2013) · Brain and Behavior · doi:10.1002/brb3.152 · Cited by 98 · see citing works
The Extracellular Matrix in Multiple Sclerosis Lesions
Sobel, R. A. (1998) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199803000-00001 · Cited by 84 · see citing works
Teesalu, T., Hinkkanen, A., & Vaheri, A. I. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63073-8 · Cited by 83 · see citing works
Maier, O., van der Heide, T., van Dam, A., Baron, W., de Vries, H., & Hoekstra, D. (2004) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2004.09.012 · Cited by 69 · see citing works
Zhao, C., Fancy, S. P. J., Franklin, R. J. M., & ffrench‐Constant, C. (2009) · Journal of Neuroscience Research · doi:10.1002/jnr.22231 · Cited by 65 · see citing works
Stoffels, J., Hoekstra, D., Franklin, R., Baron, W., & Zhao, C. (2014) · Glia · doi:10.1002/glia.22748 · Cited by 51 · see citing works
An autoimmunity odyssey: how autoreactive T cells infiltrate into the CNS
Kawakami, N., Bartholomäus, I., Pesic, M., & Mues, M. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01133.x · Cited by 49 · see citing works
Haist, V., Ulrich, R., Kalkuhl, A., Deschl, U., & Baumgärtner, W. (2011) · Brain Pathology · doi:10.1111/j.1750-3639.2011.00518.x · Cited by 44 · see citing works
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CNS fibroblasts form a fibrotic scar in response to immune cell infiltration.
Dorrier, C. E., Aran, D., Haenelt, E. A., Sheehy, R. N., Hoi, K. K., Pintarić, L., Chen, Y., Lizama, C. O., Cautivo, K. M., Weiner, G. A., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00770-9 · Cited by 199 · see citing works
Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease
Derk, J., Jones, H. E., Como, C., Pawlikowski, B., & Siegenthaler, J. A. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.703944 · Cited by 120 · see citing works
“Using a Col1a1-GFP mouse line in conjunction with an EAE model, two independent groups identified substantial increases in fibroblasts within spinal cord lesion sites (Yahn et al., 2020; Dorrier et al., 2021).”
BackgroundMethodPericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions.
Dias, D. O., Kalkitsas, J., Kelahmetoglu, Y., Estrada, C. P., Tatarishvili, J., Ernst, A., Huttner, H. B., Kokaia, Z., Lindvall, O., Brundin, L., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.30.068965
- Authors
- Yahn, S. L., Li, J., Goo, I., Gao, H., Brambilla, R., & Lee, J. K.
- Affiliations
- University of Miami (US)
- Corresponding author
- Lee, Jae K.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 134
- Pages
- 104674
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC7547849
- OpenAlex
- W2985047112
- Cited by
- 45
- References
- 34
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 12 · 2020: 3
- FWCI
- 3.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Neurological Disorders and Stroke
- National Multiple Sclerosis Society
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- experimental autoimmune encephalomyelitis, multiple sclerosis, fibrotic scar, perivascular fibroblasts, fibroblast activation, oligodendrocyte precursor cells, oligodendrocyte differentiation, remyelination failure, extracellular matrix deposition, fibroblast-conditioned medium, spinal cord demyelination, antifibrotic therapy
- MeSH terms
- Animals, Cell Differentiation, Encephalomyelitis, Autoimmune, Experimental, Fibroblasts, Fibrosis, Male, Mice, Inbred C57BL, Mice, Transgenic, Oligodendroglia, Spinal Cord, Myeloid Cells, White Matter
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