Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches

Cell, Journal Year: 2022, Volume and Issue: 185(2), P. 379 - 396.e38

Published: Jan. 1, 2022

The liver is the largest solid organ in body, yet it remains incompletely characterized. Here we present a spatial proteogenomic atlas of healthy and obese human murine combining single-cell CITE-seq, single-nuclei sequencing, transcriptomics, proteomics. By integrating these multi-omic datasets, provide validated strategies to reliably discriminate localize all hepatic cells, including population lipid-associated macrophages (LAMs) at bile ducts. We then align this across seven species, revealing conserved program bona fide Kupffer cells LAMs. also uncover respective spatially resolved cellular niches microenvironmental circuits driving their unique transcriptomic identities. demonstrate that LAMs are induced by local lipid exposure, leading induction steatotic regions liver, while cell development crucially depends on cross-talk with stellate via evolutionarily ALK1-BMP9/10 axis.

Language: Английский

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Hereditary hemorrhagic telangiectasia: from signaling insights to therapeutic advances

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(4)

Published: Feb. 14, 2024

Hereditary hemorrhagic telangiectsia (HHT) is an inherited vascular disorder with highly variable expressivity, affecting up to 1 in 5,000 individuals. This disease characterized by small arteriovenous malformations (AVMs) mucocutaneous areas (telangiectases) and larger visceral AVMs the lungs, liver, brain. HHT caused loss-of-function mutations BMP9-10/ENG/ALK1/SMAD4 signaling pathway. Review presents up-to-date insights on this mutated pathway its crosstalk proangiogenic pathways, particular VEGF pathway, that has allowed repurposing of new drugs for treatment. However, despite substantial benefits these treatments terms alleviating symptom severity, not-so-uncommon bleeding still currently lacks any FDA- or European Medicines Agency-approved (EMA-approved) therapies.

Language: Английский

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Therapeutic Approaches for Treating Pulmonary Arterial Hypertension by Correcting Imbalanced TGF-β Superfamily Signaling

Frontiers in Medicine, Journal Year: 2022, Volume and Issue: 8

Published: Jan. 24, 2022

Pulmonary arterial hypertension (PAH) is a rare disease characterized by high blood pressure in the pulmonary circulation driven pathological remodeling of distal arteries, leading typically to death right ventricular failure. Available treatments improve physical activity and slow progression, but they act primarily as vasodilators have limited effects on biological cause disease—the uncontrolled proliferation vascular endothelial smooth muscle cells. Imbalanced signaling transforming growth factor-β (TGF-β) superfamily contributes extensively dysregulated cell PAH, with overactive pro-proliferative SMAD2/3 occurring alongside deficient anti-proliferative SMAD1/5/8 signaling. We review TGF-β mechanisms underlying PAH pathogenesis, interactions inflammation mechanobiological forces, therapeutic strategies under development that aim restore SMAD balance diseased vessels. These could potentially reverse targeting causative therefore hold significant promise for patient population.

Language: Английский

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TGF-β Signaling Pathways in the Development of Diabetic Retinopathy

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 3052 - 3052

Published: March 6, 2024

Diabetic retinopathy (DR), a prevalent complication of diabetes mellitus affecting significant portion the global population, has long been viewed primarily as microvascular disorder. However, emerging evidence suggests that it should be redefined neurovascular disease with multifaceted pathogenesis rooted in oxidative stress and advanced glycation end products. The transforming growth factor-β (TGF-β) signaling family emerged major contributor to DR due its pivotal role retinal vascular homeostasis, endothelial cell barrier function, pericyte differentiation. precise roles TGF-β remain incompletely understood, conflicting reports on impact different stages disease. Additionally, BMP subfamily within superfamily introduces further complexity, BMPs exhibiting both pro- anti-angiogenic properties. Furthermore, extends beyond realm, encompassing immune regulation, neuronal survival, maintenance. intricate interactions between reactive oxygen species (ROS), non-coding RNAs, inflammatory mediators have implicated DR. This review delves into complex web pathways orchestrated by their involvement A comprehensive understanding these may hold key developing targeted therapies halt or mitigate progression devastating consequences.

Language: Английский

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Disrupted BMP-9 Signaling Impairs Pulmonary Vascular Integrity in Hepatopulmonary Syndrome

American Journal of Respiratory and Critical Care Medicine, Journal Year: 2024, Volume and Issue: 210(5), P. 648 - 661

Published: Sept. 1, 2024

Hepatopulmonary syndrome (HPS) is a severe complication of liver diseases characterized by abnormal dilation pulmonary vessels, resulting in impaired oxygenation. Recent research highlights the pivotal role liver-produced BMP-9 (bone morphogenetic protein-9) maintaining vascular integrity.

Language: Английский

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Pulmonary vascular phenotype identified in patients withGDF2(BMP9) orBMP10variants: an international multicentre study

European Respiratory Journal, Journal Year: 2024, Volume and Issue: 63(4), P. 2301634 - 2301634

Published: March 21, 2024

Background Bone morphogenetic proteins 9 and 10 (BMP9 BMP10), encoded by GDF2 BMP10 , respectively, play a pivotal role in pulmonary vascular regulation. variants have been reported arterial hypertension (PAH) hereditary haemorrhagic telangiectasia (HHT). However, the phenotype of carriers remains largely unexplored. Methods We report characteristics outcomes PAH patients from French Dutch registries. A literature review explored phenotypic spectrum these patients. Results 26 were identified: 20 harbouring heterozygous variants, one homozygous variant, four with both variants. The prevalence was 1.3% 0.4%, respectively. Median age at diagnosis 30 years, female/male ratio 1.9. Congenital heart disease (CHD) present 15.4% At diagnosis, most (61.5%) New York Heart Association Functional Class III or IV severe haemodynamic compromise (median (range) resistance 9.0 (3.3–40.6) WU). Haemoptysis patients; none met HHT criteria. Two carrying underwent lung transplantation, revealing typical histopathology. analysis showed that 7.6% developed isolated HHT, identified cardiomyopathy developmental disorders carriers. Conclusions pathogenic are rare among patients, occasionally associated CHD. cases limited according to literature. full ramifications warrant further investigation.

Language: Английский

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Impact of heterozygous ALK1 mutations on the transcriptomic response to BMP9 and BMP10 in endothelial cells from hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension donors

Angiogenesis, Journal Year: 2024, Volume and Issue: 27(2), P. 211 - 227

Published: Jan. 31, 2024

Abstract Heterozygous activin receptor-like kinase 1 ( ALK1 ) mutations are associated with two vascular diseases: hereditary hemorrhagic telangiectasia (HHT) and more rarely pulmonary arterial hypertension (PAH). Here, we aimed to understand the impact of on BMP9 BMP10 transcriptomic responses in endothelial cells. Endothelial colony-forming cells (ECFCs) microvascular (HMVECs) carrying loss function were isolated from newborn HHT adult PAH donors, respectively. RNA-sequencing was performed each type compared controls following an 18 h stimulation or BMP10. In control ECFCs, stimulations induced similar around 800 differentially expressed genes (DEGs). -mutated ECFCs unexpectedly revealed highly profiles controls, both at baseline upon stimulation, normal activation Smad1/5 that could not be explained by a compensation cell-surface level. Conversely, HMVECs strong transcriptional dysregulations > 1200 DEGs baseline. Consequently, because our study involved variables, genotype BMP two-factor differential expression analysis identified 44 BMP9-dysregulated mutated HMVECs, but none ECFCs. Yet, impaired regulation least one hit, namely lunatic fringe LFNG ), validated RT-qPCR three different models. conclusion, heterozygosity only modified BMP9/BMP10 few genes, including NOTCH signaling. Future studies will uncover whether such hits enough promote HHT/PAH pathogenesis, making them potential therapeutic targets, if second necessary.

Language: Английский

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Bone morphogenetic protein signalling in pulmonary arterial hypertension: revisiting the BMPRII connection

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: 52(3), P. 1515 - 1528

Published: May 8, 2024

Pulmonary arterial hypertension (PAH) is a rare and life-threatening vascular disorder, characterised by abnormal remodelling of the pulmonary vessels elevated artery pressure, leading to right ventricular hypertrophy right-sided heart failure. The importance bone morphogenetic protein (BMP) signalling in pathogenesis PAH demonstrated human genetic studies. Many risk genes are involved BMP pathway highly expressed or preferentially act on endothelial cells. Endothelial dysfunction recognised as an initial trigger for PAH, plays crucial role maintenance integrity. BMPR2 most prevalent gene, found over 80% heritable cases. As BMPRII major type II receptor large family ligands ubiquitously many tissues, dysregulated other cells may also contribute pathobiology. Sotatercept, which contains extracellular domain another transforming growth factor-β ActRIIA fused immunoglobin Fc domain, was recently approved FDA treatment PAH. Neither its target nor mechanism action fully understood. This review will revisit function regulation, summarise how smooth muscle pathogenesis, discuss novel therapeutics targeting regulation signalling, such BMP9 can be related restoring function.

Language: Английский

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Life at the crossroads: the nuclear LINC complex and vascular mechanotransduction

Frontiers in Physiology, Journal Year: 2024, Volume and Issue: 15

Published: May 20, 2024

Vascular endothelial cells line the inner surface of all blood vessels, where they are exposed to polarized mechanical forces throughout their lifespan. Both basal substrate interactions and apical flow-induced shear stress regulate vessel development, remodeling, maintenance vascular homeostasis. Disruption these leads dysfunction pathologies, although how sensed integrated affect cell behaviors is incompletely understood. Recently nucleus has emerged as a prominent force-transducing organelle that participates in mechanotransduction, via communication from cell-cell cell-matrix junctions. The LINC complex, composed SUN nesprin proteins, spans nuclear membranes connects lamina, envelope, cytoskeleton. Here we review complex involvement describe unique overlapping functions each component, consider emerging evidence two major SUN1 SUN2, orchestrate interplay extends outward junctions inward within chromatin. We discuss findings relation pathologies such Hutchinson-Gilford progeria syndrome, premature aging disorder with cardiovascular impairment. More knowledge regulation function will help understand force sensing disease.

Language: Английский

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Antifibrotic Therapies for Metabolic Dysfunction-associated Steatotic Liver Disease

JHEP Reports, Journal Year: 2025, Volume and Issue: unknown, P. 101421 - 101421

Published: April 1, 2025

Language: Английский

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