Macrophage Transitions in Heart Valve Development and Myxomatous Valve Disease

Hulin, Alexia; Anstine, Lindsey J.; Kim, Andrew J.; Potter, Sarah; DeFalco, Tony; Lincoln, Joy; Yutzey, Katherine E.

doi:10.1161/atvbaha.117.310667

Cited by 63 publications

(75 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This aligns with previous data that murine aging and human disease correlate with M1 polarization, 5,8,45 and that M1 polarization itself promotes cellular calcification. 5,46 This suggests that perhaps differences in macrophage phenotype at baseline in Notch1 +/mice are driving AV phenotypes.…”

Section: Discussionsupporting

confidence: 92%

“…9,44 Here, we have focused on macrophages, which make up the majority of hematopoietic cells in the AV in both health and disease. 8 We have shown that Notch1 +/-AVICs promote macrophage maturation and infiltration, and that macrophages promote AVIC calcification through STAT3-dependent mechanisms (Fig 6).…”

Section: Discussionmentioning

confidence: 84%

“…Non-myeloid cell types include CD11b -/MHCII + antigen-presenting cells, similar to previous reports (Fig 1H, I). 8 Simultaneously, BMMs were generated from the same wild-type and Notch1 +/mice and no differences were found (Supp Fig IV). In summary, macrophages make up the majority of hematopoietic cells in the AV and are different in the valves of Notch1 +/vs wild-type mice.…”

Section: Notch1 +/-Aortic Valves Have An Altered Myeloid Profilementioning

confidence: 99%

“…Immune cells, and specifically macrophages, are linked to CAVD, 7 and up to 10-15% of cells in the healthy valve are CD45 + , a hematopoietic lineage marker. 8,9 These cells are primarily major histocompatibility complex II + (MHCII + ) macrophages. 8,10 M1-like macrophages, of which MHCII positivity is a marker, are more metabolically active, direct a proinflammatory immune response, and are further increased in CAVD.…”

Section: Introductionmentioning

confidence: 99%

“…8,9 These cells are primarily major histocompatibility complex II + (MHCII + ) macrophages. 8,10 M1-like macrophages, of which MHCII positivity is a marker, are more metabolically active, direct a proinflammatory immune response, and are further increased in CAVD. 5,11,12 As part of this proinflammatory response, these macrophages secrete interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), both of which promote calcification of AVICs.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Macrophages Promote Aortic Valve Cell Calcification Through STAT3 Splicing

et al. 2020

Preprint

View full text Add to dashboard Cite

ObjectiveMacrophages have been described in calcific aortic valve disease, but it is unclear if they promote or counteract calcification. We aimed to determine how macrophages are involved in calcification using the Notch1 +/model of calcific aortic valve disease. Approach and ResultsMacrophages in wild-type and Notch1 +/murine aortic valves were characterized by flow cytometry. Macrophages in Notch1 +/aortic valves had increased expression of MHCII. We then used bone marrow transplants to test if differences in Notch1 +/macrophages drive disease.Notch1 +/mice had increased valve thickness, macrophage infiltration, and M1-like macrophage polarization regardless of transplanted bone marrow genotype. In vitro approaches confirm that Notch1 +/aortic valve cells promote macrophage invasion as quantified by migration index and M1-like polarization quantified by Ly6C and CCR2 positivity regardless of macrophage genotype. Finally, we found that macrophage interaction with aortic valve cells promotes osteogenic, but not dystrophic, calcification by decreasing abundance of the STAT3β isoform. ConclusionsThis study reveals that Notch1 +/aortic valve disease involves increased macrophage recruitment and polarization driven by altered aortic valve cell secretion, and that increased macrophage recruitment promotes osteogenic calcification through STAT3 splicing changes.Further investigation of STAT3 and macrophage-driven inflammation as therapeutic targets in calcific aortic valve disease is warranted.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 84%

Section: Notch1 +/-Aortic Valves Have An Altered Myeloid Profilementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Macrophages Promote Aortic Valve Cell Calcification Through STAT3 Splicing

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

Endothelial Cell Lineage Analysis Does Not Provide Evidence for EMT in Adult Valve Homeostasis and Disease

Kim

Alfieri

Yutzey³

2018

The Anatomical Record

Self Cite

View full text Add to dashboard Cite

Epithelial-to-mesenchymal transition (EMT) enables stationary epithelial cells to exhibit migratory behavior and is the key step that initiates heart valve development. Recent studies suggest that EMT is reactivated in the pathogenesis of myxomatous valve disease (MVD), a condition that involves the progressive degeneration and thickening of valve leaflets. These studies have been limited to in vitro experimentation and reliance on histologic co-staining of epithelial and mesenchymal markers as evidence of EMT in mouse and sheep models of valve disease. However, longitudinal analysis of cell lineage origins and potential pathogenic or reparative contributions of newly generated mesenchymal cells have not been reported previously. In this study, a genetic lineage tracing strategy was pursued by irreversibly labeling valve endothelial cells in the Osteogenesis imperfecta and Marfan syndrome mouse models to determine whether they undergo EMT during valve disease. Tie2-CreERT2 and Cdh5(PAC)-CreERT2 mouse lines were used in combination with colorimetric and fluorescent reporters for longitudinal assessment of endothelial cells. These lineage tracing experiments showed no evidence of EMT during adult valve homeostasis or valve pathogenesis. Additionally, CD31 and smooth muscle α-actin (αSMA) double-positive cells, used as an indicator of EMT, were not detected, and levels of EMT transcription factors were not altered. Interestingly, contrary to the endothelial cell-specific Cdh5(PAC)-CreERT2 driver line, Tie2-CreERT2 lineage-derived cells in diseased heart valves also included CD45+ leukocytes. Altogether, our data indicate that EMT is not a feature of valve homeostasis and disease but that increased immune cells may contribute to MVD.

show abstract

Resident macrophages as potential therapeutic targets for cardiac ageing and injury

et al. 2020

View full text Add to dashboard Cite

Cardiac‐resident macrophages (CRMs) play critical roles in maintaining cardiac homoeostasis and removing senescent and dying cells. Recent preclinical data have re‐energised the area of cardioimmunology and provided improved understanding of the modulation of compositional and functional phenotypes of CRMs. These data can aid in achieving improved cardiac regeneration, repair and functional remodelling following cardiac injury. In this review, we discuss the composition and renewal of various subsets of CRMs. Specific attention has been given to delineate the roles of various CRM subsets with respect to (1) facilitation of cardiac development and maintenance of physiological function such as electrical conduction and rhythm; (2) promotion of cardiac regeneration, inflammation resolution and functional remodelling following a cardiac injury; and (3) therapeutic potential. We have also highlighted the relationship between CRM replenishment and cardiomyocyte senescence as well as cardiovascular diseases development. Finally, we have addressed future perspectives and directions in basic research and potentially clinical applications of CRMs.

show abstract

Macrophage Transitions in Heart Valve Development and Myxomatous Valve Disease

Abstract: Our study demonstrates the heterogeneity of myeloid cells in heart valves and highlights an alteration of macrophage subpopulations, notably an increased presence of infiltrating CCR2+ monocytes and CD206+ macrophages, in myxomatous valve disease.

Cited by 63 publications

References 27 publications

Macrophages Promote Aortic Valve Cell Calcification Through STAT3 Splicing

Macrophages Promote Aortic Valve Cell Calcification Through STAT3 Splicing

Endothelial Cell Lineage Analysis Does Not Provide Evidence for EMT in Adult Valve Homeostasis and Disease

Resident macrophages as potential therapeutic targets for cardiac ageing and injury

Contact Info

Product

Resources

About