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

Abstract

Fibrotic scar tissue limits central nervous system regeneration in adult mammals. The extent of fibrotic tissue generation and distribution of stromal cells across different lesions in the brain and spinal cord has not been systematically investigated in mice and humans. Furthermore, it is unknown whether scar-forming stromal cells have the same origin throughout the central nervous system and in different types of lesions. In the current study, we compared 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. We show that the extent and distribution of stromal cells are specific to the type of lesion and, in most cases, similar between mice and humans. Employing in vivo lineage tracing, we report 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. Perivascular cells with a type A pericyte marker profile also exist in the human brain and spinal cord. We uncover 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.

Reduced myofibroblast transdifferentiation and fibrotic scarring in ischemic stroke after imatinib treatment

“…More importantly, reduced ischemia-induced expression of PDGFR β in the lesion core has been found to correlate with an enlargement of infarct volume after MCAO 56 and stromal PDGFR β + pericytes have been reported not to contribute to ECM production in the fibrotic lesion after stroke 57 . The latter is however in stark contrast to the lineage tracing studies of type A pericytes 50 , where type A pericytes were shown to give rise to nearly the entire fibrotic scar in the lesion core after cortical MCAO, a region of the fibrotic scar that appeared unaffected by imatinib treatment in our analyses. Nevertheless, this highlights a heterogeneity of the fibrotic scar, where it seems that reducing the PDGFRα + myofibroblast portion is beneficial, whereas tampering with the fibrotic core portion of the scar might be detrimental, although this requires further investigation.…”

“…Contrary to PDGFRα however, PDGFR β is also expressed in vascular mural cells, both in pericytes distributed along the capillaries and vSMC 33 . Also, during ischemic stroke, expression of PDGFR β is highly upregulated throughout the ischemic core region, and not selectively only at the rim of the astroglia scar 50, 55 . More importantly, reduced ischemia-induced expression of PDGFR β in the lesion core has been found to correlate with an enlargement of infarct volume after MCAO 56 and stromal PDGFR β + pericytes have been reported not to contribute to ECM production in the fibrotic lesion after stroke 57 .…”

“…For example, in the liver it has been shown that the primary progenitors for myofibroblasts are perivascular hepatic stellate cells and specific deletion of PDGFRα from these cells in vivo resulted in reduced myofibroblast transdifferentiation and fibrosis in a model of hepatotoxic liver injury 28 . In the CNS, lineage tracing analyses suggest that perivascular cells in the NVU are important for fibrotic scar tissue formation 49, 50 and that reduction of this scarring response promotes recovery after spinal cord injury in mice 51 . These perivascular cells were shown to express PDGFRα and the authors referred to them as type A pericytes 49 , although this has later been challenged by single-cell analyses suggesting the perivascular PDGFRα + cells are not pericytes and should instead be referred to as fibroblast-like cells 33 .…”

“…However, the latter seems likely and is supported e.g. by the fact that type A pericytes are distributed along the capillary bed as well as upstream the arterial/venous vasculature 49, 50 , whereas PDGFRα + perivascular cells are exclusively found around medium/large size vessels and are never distributed along capillaries.…”

Repetitive Trans Spinal Magnetic Stimulation Improves Functional Recovery and Tissue Repair in Contusive and Penetrating Spinal Cord Injury Models in Rats

“…It appears, that further studies will be necessary to understand the mechanisms responsible of this distinct lesion scar evolution overtime. In a broader perspective, it has been recently shown that this brotic scar is present in different central nervous system lesions in mice such as traumatic brain or spinal cord injuries but also after demyelinating or ischemic lesion models 24 . It could be also interesting to demonstrate if this brotic scar is present throughout species after CNS lesions.…”