Col1a1+ perivascular cells in the brain are a source of retinoic acid following stroke

Kelly, Kathleen; MacPherson, Amber M.; Grewal, Himmat; Strnad, Frank; Jones, Jace W.; Yu, Jianshi; Pierzchalski, Keely; Kane, Maureen A.; Herson, Paco S.; Siegenthaler, Julie A.

doi:10.1186/s12868-016-0284-5

Cited by 56 publications

(85 citation statements)

References 52 publications

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“…Do they function as resident stem cells to replace aging/damaged pericytes? Previous work has suggested that tissue injury in the mouse brain and spinal cord often triggers a fibrotic response by blood vessel associated cells (25,34–36). Attenuation of the fibrotic response has been shown to limit scar formation and improve axon regeneration post spinal cord injury in mice, suggesting that perivascular stromal cells might be an important therapeutic target (71).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to mural cells, perivascular fibroblast-like cells adhere loosely to blood vessels and show robust expression of many ECM components, such as collagens. Previous studies have described similar cell populations in the mouse central nervous system that contribute to fibrotic scar formation after injury (34–37). However, where these perivascular fibroblast-like cells originate from during development and how they regulate blood vessel development and stabilization have not been explored.…”

Section: Introductionmentioning

confidence: 90%

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Dual function of perivascular fibroblasts in vascular stabilization in zebrafish

Rajan

Roger

Kocha

et al. 2020

Preprint

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24Blood vessels are vital to sustain life in all vertebrates. While it is known that mural cells (pericytes 25 and smooth muscle cells) regulate vascular integrity, the contribution of other cell types to vascular 26 stabilization has been largely unexplored. Using zebrafish, we identified sclerotome-derived 27 perivascular fibroblasts as a novel population of blood vessel associated cells. In contrast to pericytes, 28 perivascular fibroblasts emerge early during development, express the extracellular matrix (ECM) 29 genes col1a2 and col5a1, and display distinct morphology and distribution. Time-lapse imaging 30 reveals that perivascular fibroblasts serve as pericyte precursors. Genetic ablation of perivascular 31 fibroblasts results in dysmorphic blood vessels with variable diameters. Strikingly, col5a1 mutants 32show spontaneous hemorrhage, and the penetrance of the phenotype is strongly enhanced by the 33 additional loss of col1a2. Together, our work reveals dual roles of perivascular fibroblasts in vascular 34 stabilization where they establish the ECM around nascent vessels and function as pericyte 35 progenitors. 36 3 AUTHOR SUMMARY 37 38 Blood vessels are essential to sustain life in humans. Defects in blood vessels can lead to serious 39 diseases, such as hemorrhage, tissue ischemia, and stroke. However, how blood vessel stability is 40 maintained by surrounding support cells is still poorly understood. Using the zebrafish model, we 41 identify a new population of blood vessel associated cells termed perivascular fibroblasts, which 42 originate from the sclerotome, an embryonic structure that is previously known to generate the 43 skeleton of the animal. Perivascular fibroblasts are distinct from pericytes, a known population of 44 blood vessel support cells. They become associated with blood vessels much earlier than pericytes 45 and express several collagen genes, encoding main components of the extracellular matrix. Loss of 46 perivascular fibroblasts or mutations in collagen genes result in fragile blood vessels prone to 47 53 54The vascular system is crucial to the survival of vertebrates. Blood vessels must rapidly expand 55 and contract in response to systemic cues, but also maintain the stability to withstand the stress of 56 blood flow. To maintain their integrity, blood vessels are supported by a highly specialized 57 perivascular architecture comprised of blood vessel associated cells and the surrounding extracellular 58 matrix (ECM) (1,2). Compromised vascular integrity can result in devastating human diseases, such 59 as aneurysms, vascular malformations, and hemorrhagic strokes (3-6). However, how blood vessels 60 are stabilized by different perivascular components is still poorly understood. 61The prevailing model is that vascular stability is maintained at three different levels: endothelial 62 cells, mural cells and the surrounding ECM (2). First, blood vessels are lined by endothelial cells. 63Adherens and tight junctions between endothelial cells provide the primary barrier to passage o...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Dual function of perivascular fibroblasts in vascular stabilization in zebrafish

Rajan

Roger

Kocha

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…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, ).…”

Section: Discussionmentioning

confidence: 99%

“…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, 2016;Komuta et al, 2009;Riew, Choi, Kim, Jin, & Lee, 2018;Soderblom et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

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

Roth

Enström

Aghabeick

et al. 2019

J of Neuroscience Research

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Scar formation after injury of the brain or spinal cord is a common event. While glial scar formation by astrocytes has been extensively studied, much less is known about the fibrotic scar, in particular after stroke. Platelet‐derived growth factor receptor ß‐expressing (PDGFRß+) pericytes have been suggested as a source of the fibrotic scar depositing fibrous extracellular matrix (ECM) proteins after detaching from the vessel wall. However, to what extent these parenchymal PDGFRß+ cells contribute to the fibrotic scar and whether targeting these cells affects fibrotic scar formation in stroke is still unclear. Here, we utilize male transgenic mice that after a permanent middle cerebral artery occlusion stroke model have a shift from a parenchymal to a perivascular location of PDGFRß+ cells due to the loss of regulator of G‐protein signaling 5 in pericytes. We find that only a small fraction of parenchymal PDGFRß+ cells co‐label with type I collagen and fibronectin. Consequently, a reduction in parenchymal PDGFRß+ cells by ca. 50% did not affect the overall type I collagen or fibronectin deposition after stroke. The redistribution of PDGFRß+ cells to a perivascular location, however, resulted in a reduced thickening of the vascular basement membrane and changed the temporal dynamics of glial scar maturation after stroke. We demonstrate that parenchymal PDGFRß+ cells are not the main contributor to the fibrotic ECM, and therefore targeting these cells might not impact on fibrotic scar formation after stroke.

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“…Although different cell types were proposed to contribute [8][9][10][11] , the cellular origin of scar-forming fibroblasts following CNS lesions in the brain remains elusive, due to the lack of in vivo genetic fate mapping studies required to unequivocally trace cells and establish lineage relationships. It is also unclear to what extent fibrotic scar tissue enriched in stromal fibroblasts is formed in humans after CNS lesions, such as spinal cord injury, stroke, multiples sclerosis (MS) and glioblastoma multiforme (GBM).…”

Section: Introductionmentioning

confidence: 99%

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

Dias

Kalkitsas

Kelahmetoglu

et al. 2020

Preprint

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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 developing fibrotic tissue, the primary source of scar-forming fibroblasts is a discrete subset of perivascular cells, termed type A pericytes.We uncover pericyte-derived fibrosis as a conserved mechanism that may be explored as a therapeutic target to improve recovery after central nervous system lesions.

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Col1a1+ perivascular cells in the brain are a source of retinoic acid following stroke

Cited by 56 publications

References 52 publications

Dual function of perivascular fibroblasts in vascular stabilization in zebrafish

Dual function of perivascular fibroblasts in vascular stabilization in zebrafish

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

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

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