PDGFRA in vascular adventitial MSCs promotes neointima formation in arteriovenous fistula in chronic kidney disease

Song, Ke; Qing, Ying; Guo, Qunying; Peden, Eric K.; Chen, Changyi; Truong, Luan D.; Cheng, Jizhong

doi:10.1172/jci.insight.137298

Cited by 24 publications

(21 citation statements)

References 41 publications

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“…10a). These findings support the ability of circulating hedgehog ligands to induce remote fibrosis, consistent with recent reports of raised systemic Hh signalling in human patients with renal failure 36 .…”

Section: Renal Injury Induces Transcriptional Changes In Remote Organssupporting

confidence: 92%

Indian Hedgehog release from renal epithelia drives local and remote organ fibrosis

Ferenbach

O’Sullivan

Mylonas

et al. 2021

Preprint

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Chronic kidney disease (CKD) and ageing inhibit tissue regeneration and increase risks of organ fibrosis and cardiovascular disease. Increased numbers of leukocytes are present in the circulation and within the kidney of ageing individuals and patients with CKD where they correlate with progressive fibrosis. The involvement of activated leukocytes in progressive renal and systemic fibrosis remains incompletely understood. Here we show that renal leukocyte derived tumour necrosis factor alpha (TNFα) promotes renal and cardiac fibrosis via downstream induction of Indian Hedgehog (IHH). We identify the Ubiquitin D expressing ‘inflammatory’ proximal tubular epithelia (iPT) population responsible for TNFα/NFκB induced IHH production. iPT cells are upregulated in the kidney in experimental murine and human renal disease and ageing. iPT derived IHH activates canonical Hedgehog signalling in Gli1+ stromal cells, inducing their activation, proliferation and fibrosis in the surrounding kidney and in remote organs including the heart. This can be inhibited by selective genetic Ihh deletion from Pax8 expressing renal epithelia, or pharmacological blockade of TNFα, NFκB or Hedgehog signalling. This data connects inflammation to progressive renal and cardiac fibrosis and identifies new targets for anti-fibrotic therapies.

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Section: Renal Injury Induces Transcriptional Changes In Remote Organssupporting

confidence: 92%

Indian Hedgehog release from renal epithelia drives local and remote organ fibrosis

Ferenbach

O’Sullivan

Mylonas

et al. 2021

Preprint

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“…We and others have shown that VSMCs, bone marrow–derived FSP-1 cells, monocyte chemoattractant protein-1 positive cells, and vascular adventitial mesenchymal stem cells involve in the growth of neointima of AVFs ( 40 , 41 , 42 ). Multiple factors, such as oxidative stress, Notch, platelet-derived growth factor, vascular endothelial growth factor, hypoxia-inducible factor, and others, promote the migration, proliferation, and activation of VSMCs in the venous anastomosis of AVFs ( 43 , 44 , 45 ). ECs form a monolayer covering the inner surface of the vascular tree.…”

Section: Discussionmentioning

confidence: 99%

“…We and others have shown that VSMCs, bone marrow-derived FSP-1 cells, MCP-1 positive cells, and vascular adventitial mesenchymal stem cells involve in J o u r n a l P r e -p r o o f the growth of neointima of AVFs(40)(41)(42). Multiple factors such as oxidative stress, Notch, PDGF, VEGF, HIF etc., promote the migration, proliferation, and activation of VSMCs in the venous anastomosis of AVFs(43)(44)(45). ECs form a monolayer covering the inner surface of the vascular tree.…”

mentioning

confidence: 99%

Downregulation of the endothelial histone demethylase JMJD3 is associated with neointimal hyperplasia of arteriovenous fistulas in kidney failure

Feng

Peden

Guo

et al. 2022

Journal of Biological Chemistry

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“…Adventitia is composed of fibroblasts, macrophages, inflammatory cells, and vasa vasorum in the case of humans, and is also suggested to contain vascular progenitor cells marked with Sca1 13 , 14 . Some studies have provided clues regarding the dynamism of blood vessels, arguing that stem/progenitor cells residing in vessel walls are responsible for the proliferative state of adult vessels and potentially serve essential roles in vascular diseases 15 , 16 . Progenitor cells that reside in the adventitia have been characterized by their ability to proliferate and differentiate into different cell lineages, which are usually positive for markers such as Sca1, Gli, CD34, and CD45.…”

Section: Introductionmentioning

confidence: 99%

“…While several Pdgfra-CreER mouse lines have been established, relatively few studies on the lineage tracing of adventitial cells have focused on the vascular wall 16 , 19 . In the present study, we characterized a Pdgfra-CreER knock-in line and examined PDGFRa-derived cells during homeostasis and injury response in large vessels to investigate the complex nature of vascular remodeling and the contribution of PDGFRa+ cells in vivo.…”

Section: Introductionmentioning

confidence: 99%

Contribution of PDGFRα-positive cells in maintenance and injury responses in mouse large vessels

Kimura

Ramírez

Nguyen

et al. 2021

Sci Rep

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The maladaptive remodeling of vessel walls with neointima formation is a common feature of proliferative vascular diseases. It has been proposed that neointima formation is caused by the dedifferentiation of mature smooth muscle cells (SMCs). Recent evidence suggests that adventitial cells also participate in neointima formation; however, their cellular dynamics are not fully understood. In this study, we utilized a lineage tracing model of platelet-derived growth factor receptor alpha (PDGFRa) cells and examined cellular behavior during homeostasis and injury response. PDGFRa marked adventitial cells that were largely positive for Sca1 and a portion of medial SMCs, and both cell types were maintained for 2 years. Upon carotid artery ligation, PDGFRa-positive (+) cells were slowly recruited to the neointima and exhibited an immature SMC phenotype. In contrast, in a more severe wire denudation injury, PDGFRa+ cells were recruited to the neointima within 14 days and fully differentiated into SMCs. Under pressure overload induced by transverse aortic constriction, PDGFRa+ cells developed marked adventitial fibrosis. Taken together, our observations suggest that PDGFRa+ cells serve as a reservoir of adventitial cells and a subset of medial SMCs and underscore their context-dependent response to vascular injuries.

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PDGFRA in vascular adventitial MSCs promotes neointima formation in arteriovenous fistula in chronic kidney disease

Cited by 24 publications

References 41 publications

Indian Hedgehog release from renal epithelia drives local and remote organ fibrosis

Indian Hedgehog release from renal epithelia drives local and remote organ fibrosis

Downregulation of the endothelial histone demethylase JMJD3 is associated with neointimal hyperplasia of arteriovenous fistulas in kidney failure

Contribution of PDGFRα-positive cells in maintenance and injury responses in mouse large vessels

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