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.
Highlights
Insults to the central nervous system (CNS), such as traumatic brain injury, spinal cord injury and ischemic strokes, trigger tissue scarring
In the striata of saline-treated controls, where we observed no specific staining for Fluoro-Jade B (FJB), but found evident DARPP-32-positive striatal neurons, weak platelet-derived growth factor receptor beta (PDGFR-β) expression was observed in two cell types that differed according to their morphology and topographical distribution
Three days after the last 3-nitropropionic acid (3-NP) injection, intense PDGFR-β immunoreactivity was noted on the vascular profiles of varying sizes in the lesion core, which had been defined by strong FJB staining and concomitant loss of DARPP-32positive neurons
Summary
Insults to the central nervous system (CNS), such as traumatic brain injury, spinal cord injury and ischemic strokes, trigger tissue scarring (for review, see Fernández-Klett and Priller, 2014). Other studies have presented evidence that other types of vascular cells, perivascular stromal cells or perivascular fibroblasts, which are distinct from pericytes in their classical definition, contribute to fibrotic scar formation after CNS insults (Fernández-Klett et al, 2013; Soderblom et al, 2013). Despite the controversy, such cells, called by different names, share some characteristics, such as their perivascular localization and expression of a common marker, platelet-derived growth factor receptor beta (PDGFR-β). Since several cell types, including pericytes, perivascular macrophages and adventitial cells, reside within the perivascular space and there are no perfect markers for discriminating among them, their exact origin cannot be confirmed by light microscopic observation alone and requires immunoelectron microscopy studies
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