PDGFR-β-Positive Perivascular Adventitial Cells Expressing Nestin Contribute to Fibrotic Scar Formation in the Striatum of 3-NP Intoxicated Rats

Abstract

Perivascular cells expressing platelet-derived growth factor receptor beta (PDGFR-β) have recently been implicated in fibrotic scar formation after acute brain injury, but their precise identity and detailed morphological characteristics remain elusive. This study sought to characterize and define the cellular phenotype of vascular-associated cells expressing PDGFR-β in the striatum of rats treated with the mitochondrial toxin 3-nitropropionic acid (3-NP). In the control striatum, PDGFR-β-positive cells were invariably localized on the abluminal side of smooth muscle cells of larger caliber vessels, and demonstrated morphological features typical of perivascular fibroblasts. PDGFR-β expression increased and expanded to almost all vessels, including microvessels in the lesion core, at 7 days after 3-NP injection. The cells expressing PDGFR-β had ultrastructural features of fibroblasts undergoing active collagen synthesis: large euchromatic nuclei with a prominent nucleolus, well-developed rough endoplasmic reticulum (rER) with dilated cisterns and extracellular collagen fibrils. By 14 days, PDGFR-β-positive cells had somata located at a distance from the vasculature, and their highly ramified, slender processes overlapped with those from other cells, thus forming a plexus of processes in the extravascular space of the lesion core. In addition, their ultrastructural morphology and spatial correlation with activated microglia/macrophages were elaborated by three-dimensional reconstruction. Using a correlative light- and electron-microscopy technique, we found that the intermediate filament proteins nestin and vimentin were induced in PDGFRβ-positive fibroblasts in the lesion core. Collectively, our data suggest that perivascular PDGFR-β-positive fibroblasts are distinct from other vascular cell types, including pericytes and contribute to fibrotic scar formation in the lesion core after acute brain injury. Nestin and vimentin play critical roles in the structural dynamics of these reactive fibroblasts.

A pericyte‐glia scarring develops at the leaky capillaries in the hippocampus during seizure activity

“…In these experimental conditions we did not observe significant colocalization between IBA1 and PDGFRβ (example of Imaris rendering in Figure E1). The results reported here converge with the existing knowledge of a PDGFRβ fibrotic scar forming in the lesional core, for example, post‐brain injury or ischemic insults …”

“…We next examined the expression levels of PDGFRβ, a biomarker of fibrotic modifications and stromal cell occupancy within a scar . Figure A shows a representation of the spatiotemporal PDGFRβ changes.…”

“…PDGFRβ is a tyrosine kinase receptor originally used to identify pericytes and it was shown to control cellular proliferation and differentiation . PDGFRβ was recently reported as a biomarker of stromal cell activation, indicating fibrotic changes in peripheral and brain pathologies . Accumulating evidence indicates that perivascular PDGFRβ cells contribute to the buildup of fibrotic scar in lesions .…”

“…Accumulating evidence indicates that perivascular PDGFRβ cells contribute to the buildup of fibrotic scar in lesions . The origin of PDGFRβ cells at the outer vascular wall is somehow controversial, either differentiating from a pericyte subtype or deriving from a specific resident population . Inhibition of PDGFRβ signaling is proposed as a strategy to limit chronic inflammation and fibrosis .…”

Parenchymal pericytes are not the major contributor of extracellular matrix in the fibrotic scar after stroke in male mice

“…The origin of scar‐forming cells is still debated. In particular, fibroblasts have been shown to co‐label with type I collagen after stroke and other CNS injuries (Kelly et al, ; Komuta et al, ; Riew, Choi, Kim, Jin, & Lee, ; Soderblom et al, ). To date, the only linage‐tracing study that suggests a pericyte origin of scar‐forming cells was performed in spinal cord injury (Göritz et al, ).…”