CNS fibroblasts form a fibrotic scar in response to immune cell infiltration

Nat Neurosci, 2021 · DOI: 10.1038/s41593-020-00770-9 · Published: February 1, 2021

Simple Explanation

Fibrosis, or scarring, is a common response to inflammation that can prevent tissue repair. This study identifies fibrotic scarring in the central nervous system (CNS) following immune cell infiltration in a mouse model of multiple sclerosis. The research indicates that this scar is mainly formed by CNS fibroblasts, not other cell types like pericytes. Reducing these fibrotic cells led to more oligodendrocyte lineage cells and less motor disability. The study also found that interferon gamma signaling is involved in the fibrotic process, suggesting a potential target for treatments to modulate scar formation.

Study Duration

60 days

Participants

Mice (Col1a1-GFP, Rosa-lsl-tdTomato, NG2CreER™, aSMACreERT2, Col1a2CreERT, UBC-GFP, CD45.1, GFAP/tTA;TRE/IFN-γ, Ifngr1fl/fl)

Evidence Level

Not specified

Key Findings

1
A robust Col1+ fibrotic scar forms in response to immune cell infiltration in the CNS, specifically in neuroinflammatory lesions.
2
The fibrotic scar is primarily derived from the proliferation and migration of CNS fibroblasts, not pericytes or bone marrow-derived cells.
3
Ablation of proliferating fibrotic cells leads to decreased fibrotic scarring, reduced motor disability, and an increase in oligodendrocyte lineage cells within the inflammatory lesions.

Research Summary

This study demonstrates the presence of a fibrotic scar in the CNS following immune cell infiltration in a mouse model of multiple sclerosis, suggesting a common response to injury and inflammation across various neurological disorders. Lineage tracing and single-cell sequencing reveal that the fibrotic scar is primarily formed by the proliferation and migration of CNS fibroblasts, challenging previous studies that implicated pericytes as the main source of scar-forming cells. The research identifies interferon gamma signaling as a key regulator of fibrotic scar formation, suggesting potential therapeutic targets for modulating scar formation and enhancing recovery in CNS disorders.

Practical Implications

Therapeutic Target Identification

Interferon gamma signaling is identified as a potential therapeutic target to modulate levels of scar formation in CNS disorders.

Combination Therapies

Combining anti-fibrotic approaches with therapeutics to maintain axon integrity might prove synergistic in the treatment of diseases such as MS.

Understanding Disease Pathophysiology

The findings have wide implications for understanding the pathophysiology and repair of a wide array of neurological diseases and should stimulate future research into the fibrotic response.

Study Limitations

1
Ablation of proliferative fibrotic cells alone does not promote axonal remyelination or full symptomatic recovery in EAE.
2
Ifngr1 deletion from fibrotic cells did not completely ablate the fibrotic scar in neuroinflammatory lesions, other pathways are also likely involved in fibrotic scar formation.
3
The proportion of the scar that comes from the CNS fibroblasts in the meninges vs. those surrounding large blood vessels remains unknown

Your Feedback

Was this summary helpful?

Back to Immunology