Pericyte-derived ﬁbrotic scarring is conserved across diverse central nervous system lesions

Nature Communications, 2021 · DOI: https://doi.org/10.1038/s41467-021-25585-5 · Published: September 21, 2021

Regenerative Medicine Neurology Genetics

Simple Explanation

The central nervous system (CNS) in adult mammals has limited regeneration capabilities due to scar tissue formation after lesions. While this scar tissue is important for containing damage, it also prevents axons from regenerating, leading to lasting functional deficits. This study reveals that a specific subset of perivascular cells, termed type A pericytes, are the primary source of scar-forming fibroblasts in various CNS lesions. This finding was consistent across mouse models of spinal cord injury, traumatic brain injury, stroke, and multiple sclerosis. The discovery of type A pericyte-derived fibrosis as a conserved mechanism presents a potential therapeutic target for enhancing recovery after CNS lesions. Understanding and modulating this process could pave the way for treatments aimed at improving axonal regeneration and functional outcomes.

Study Duration

Not specified

Participants

Mice and human tissue samples

Evidence Level

Not specified

Key Findings

1
The study demonstrates that type A pericytes are the primary source of scar-forming fibroblasts across various CNS lesions in mice, including spinal cord injury, traumatic brain injury, ischemic stroke, and multiple sclerosis.
2
The extent and distribution of stromal cells are specific to the type of lesion. Fibrotic scarring is similar in human pathological tissue and corresponding mouse models.
3
Type A pericytes are required for extracellular matrix deposition after CNS lesions. Experiments showed that detachment of type A pericyte-derived cells from the vascular wall is required for fibronectin and collagen I ECM protein deposition.

Research Summary

This study investigates fibrotic scarring in human pathological tissue and corresponding mouse models of penetrating and non-penetrating spinal cord injury, traumatic brain injury, ischemic stroke, multiple sclerosis and glioblastoma. The study reports that in all mouse models that develop fibrotic tissue, the primary source of scar-forming fibroblasts is a discrete subset of perivascular cells, termed type A pericytes. The study uncovers type A pericyte-derived fibrosis as a conserved mechanism that may be explored as a therapeutic target to improve recovery after central nervous system lesions.

Practical Implications

Therapeutic Target Identification

Type A pericytes can be explored as a therapeutic target to improve recovery after central nervous system lesions.

Understanding Scar Formation

Fibrotic scarring by a small subset of perivascular cells, defined as type A pericytes, is an evolutionarily conserved mechanism for scar formation in the CNS.

ECM Deposition

The extent of type A pericyte progeny located outside the vascular wall determines the magnitude of fibrotic ECM deposition after brain lesions.

Study Limitations

1
The study acknowledges that incomplete recombination in lineage tracing experiments may lead to an underestimation of type A pericyte contribution.
2
The GL261 murine glioma model may not fully represent the complexity of human GBM tumors.
3
The study does not fully explore the heterogeneity of type A pericytes at the single-cell level.

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