Col1a1+ perivascular cells in the brain are a source of retinoic acid following stroke.
Open accessAbstract
BACKGROUND: Perivascular stromal cells (PSCs) are a recently identified cell type that comprises a small percentage of the platelet derived growth factor receptor-β+ cells within the CNS perivascular space. PSCs are activated following injury to the brain or spinal cord, expand in number and contribute to fibrotic scar formation within the injury site. Beyond fibrosis, their high density in the lesion core makes them a potential significant source of signals that act on neural cells adjacent to the lesion site. RESULTS: Our developmental analysis of PSCs, defined by expression of Collagen1a1 in the maturing brain, revealed that PSCs first appear postnatally and may originate from the meninges. PSCs express many of the same markers as meningeal fibroblasts, including expression of the retinoic acid (RA) synthesis proteins Raldh1 and Raldh2. Using a focal brain ischemia injury model to induce PSC activation and expansion, we show a substantial increase in Raldh1+/Raldh2+ PSCs and Raldh1+ activated macrophages in the lesion core. We find that RA levels are significantly elevated in the ischemic hemisphere and induce signaling in astrocytes and neurons in the peri-infarct region. CONCLUSIONS: This study highlights a dual role for activated, non-neural cells where PSCs deposit fibrotic ECM proteins and, along with macrophages, act as a potentially important source of RA, a potent signaling molecule that could influence recovery events in a neuroprotective fashion following brain injury.
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Retinoic acid signaling was elevated in neurons and astrocytes in the peri-infarct region.
“Retinoic acid signaling was elevated in neurons and astrocytes in the peri-infarct region”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Kelly et al., 2016
Scar fibroblasts signal to surrounding CNS cells via retinoic acid release.
“suggesting that scar fibroblasts signal to the surrounding CNS cells via retinoic acid release”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Kelly et al., 2016
In both MCAO and SCI models, macrophages are observed in the fibrotic scar and may associate with fibroblasts, and CD11b+ macrophages are partially responsible for recruitment of fibroblasts to the fibrotic scar following SCI.
“In both MCAO and SCI models, macrophages are observed in the fibrotic scar and may associate with fibroblasts”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Kelly et al., 2016
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- [13]Göritz C Dias DO Tomilin N Barbacid M Shupliakov O Frisén J A pericyte origin of spinal cord scar tissue Science 2011 333 238 242 10.1126/science.1203165 21737741 · DOI · Paper page
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Self-citationCNS fibroblasts form a fibrotic scar in response to immune cell infiltration.
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“…changes in meninges located lymphatic vasculature in response to different CNS injuries and disease states. synthesizing enzymes RALDH1 and RALDH2 in uninjured brain, and the number of RALDH-expressing fibroblasts increase in the fibrotic scar following stroke injury in mice (Kelly et al., 2016).”
BackgroundInfluentialSelf-citationPericyte-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
- Kelly, K. K., MacPherson, A. M., Grewal, H., Strnad, F., Jones, J. W., Yu, J., Pierzchalski, K., Kane, M. A., Herson, P. S., & Siegenthaler, J. A.
- Affiliations
- University of Colorado Anschutz (US)
- University of Maryland, Baltimore (US)
- Corresponding author
- Siegenthaler, Julie A.
- ORCID
- Venue
- BMC Neuroscience
- Published
- 2016-07-15
- Volume
- 17
- Issue
- 1
- Pages
- 49-49
- ISSN
- 1471-2202 (ISSN-L)
- PMC
- PMC4947279
- OpenAlex
- W2473785740
- Cited by
- 75
- References
- 53
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 4 · 2023: 8 · 2022: 15 · 2021: 13 · 2020: 8 · 2019: 5 · 2018: 1
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- BMC Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS070920, NS080851)
- American Heart Association (14BGIA18440006)
- National Institute of Child Health and Human Development (HD077260)
- National Institute of Allergy and Infectious Diseases (HHSN272202000046C)
- Children's Hospital of Colorado Research Institute (Start-up funds)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- perivascular stromal cells, retinoic acid, stroke, focal cerebral ischemia, ALDH1A1, Raldh2, meningeal fibroblasts, macrophages, astrocytes, neurons, perivascular spaces, fibrotic scar, neuroinflammation, neuroprotection, developmental origins
- MeSH terms
- Collagen Type I, alpha 1 Chain, Animals, Animals, Newborn, Brain, Disease Models, Animal, Immunohistochemistry, Male, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Transgenic, Tretinoin, Stromal Cells, Infarction, Middle Cerebral Artery, Pericytes, Stroke, Collagen Type I
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