FGF/FGFR signaling in health and disease

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: Sept. 2, 2020

Growing evidences suggest that the fibroblast growth factor/FGF receptor (FGF/FGFR) signaling has crucial roles in a multitude of processes during embryonic development and adult homeostasis by regulating cellular lineage commitment, differentiation, proliferation, apoptosis various types cells. In this review, we provide comprehensive overview current understanding FGF its organ development, injury repair, pathophysiology spectrum diseases, which is consequence dysregulation, including cancers chronic kidney disease (CKD). context, agonists antagonists for FGF-FGFRs might have therapeutic benefits multiple systems.

Language: Английский

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Pathophysiology of systemic sclerosis: current understanding and new insights

Expert Review of Clinical Immunology, Journal Year: 2019, Volume and Issue: 15(7), P. 753 - 764

Published: May 3, 2019

Introduction: Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease characterized by chronic and progressive organ fibrosis with broad patient-to-patient variability. Some risk factors are known include combination of persistent Raynaud's phenomenon, steroid hormone imbalance, selected chemicals, thermal, or other injuries. Endogenous and/or exogenous environmental trigger/risk promote epigenetic mechanisms in genetically primed subjects. Disease pathogenesis presents early microvascular changes endothelial cell dysfunction, followed the activation promoting their transition into myofibroblasts. A response, involving innate adaptive immunity specific/functional autoantibody production, characterizes disease. Progressive ischemia involve skin visceral organs resulting irreversible damage/failure. Progenitor circulating cells (monocytes, fibrocytes), together growth cytokines participate diffusion evolution. Epigenetic, vascular immunologic implicated systemic fibrosis, represent major targets for incoming modifying therapeutic approaches. Areas covered: This review discusses current understanding new insights SSc pathogenesis, through an overview most relevant advancements to present aspects involved pathogenesis. Expert opinion: Considering intricacy/heterogeneity, therapy vasodilators, immunosuppressive antifibrotic drugs should successfully downregulate progression, especially if started from beginning.

Language: Английский

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Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Jan. 29, 2021

Abstract Endothelial cells play a critical role in the adaptation of tissues to injury. Tissue ischemia induced by infarction leads profound changes endothelial cell functions and can induce transition mesenchymal state. Here we explore kinetics individual cellular responses after myocardial using single RNA sequencing. This study demonstrates time dependent switch proliferation inflammation associated with transient metabolic gene signatures. Trajectory analysis reveals that majority 3 7 days acquire state, characterized expression, which returns baseline 14 Lineage tracing, Cdh5-CreERT2;mT/mG mice followed sequencing, confirms additional hypoxic inflammatory signatures during early late states These data suggest undergo mes-enchymal activation concomitant within first but do not long-term fate. may facilitate migration clonal expansion regenerate vascular network.

Language: Английский

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EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(12), P. 4271 - 4271

Published: June 16, 2020

Epithelial–mesenchymal transition (EMT) and endothelial–mesenchymal (EndMT) are physiological processes required for normal embryogenesis. However, these can be hijacked in pathological conditions to facilitate tissue fibrosis cancer metastasis. In the eye, EMT EndMT play key roles pathogenesis of subretinal fibrosis, end-stage age-related macular degeneration (AMD) that leads profound permanent vision loss. Predominant fibrotic lesions matrix-producing mesenchymal cells believed originate from retinal pigment epithelium (RPE) and/or choroidal endothelial (CECs) through EndMT, respectively. Recent evidence suggests RPE may also implicated during early stages AMD. Transforming growth factor-beta (TGFβ) is a cytokine orchestrating both EndMT. Investigations molecular mechanisms underpinning AMD have myriad contributing factors including signaling pathways, extracellular matrix remodelling, oxidative stress, inflammation, autophagy, metabolism mitochondrial dysfunction. Questions arise as differences derived two their distinct mechanistic contributions Detailed discussion on microenvironment highlights synergistic interactions between CECs augment vivo. Understanding differential regulatory networks dry wet forms aid development therapeutic strategies targeting potentially reverse aberrant cellular transdifferentiation processes, regenerate retina thus restore vision.

Language: Английский

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Biomarkers of aging

Science China Life Sciences, Journal Year: 2023, Volume and Issue: 66(5), P. 893 - 1066

Published: April 11, 2023

Language: Английский

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TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: April 21, 2020

Endothelial to mesenchymal transition (EndMT) is a complex biological process that gives rise cells with multipotent potential. EndMT essential for the formation of cardiovascular system during embryonic development. Emerging results link postnatal onset and progression fibrotic diseases cancer. Moreover, recent reports have emphasized potential in tissue engineering regenerative applications by regulating differentiation status cells. Transforming growth factor β (TGF-β) engages many important physiological processes potent inducer EndMT. In this review, we first summarize mechanisms TGF-β signaling pathway as it relates Thereafter, discuss pivotal role TGF-β-induced development diseases, fibrosis cancer, well application engineering.

Language: Английский

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Endothelial-to-Mesenchymal Transition in Cancer

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: Aug. 14, 2020

Cancer is one of the most important causes morbidity and mortality worldwide. Tumor cells grow in a complex microenvironment constituted immune, stromal vascular that supports growth, angiogenesis metastasis. Endothelial are major components microenvironment. These have been described for their plasticity potential to transdifferentiate into mesenchymal through process known as endothelial-to transition (EndMT). This controlled by various factors, which endothelial convert phenotype characterized protein expression motile, contractile morphology. Initially normal heart development, EndMT now identified several pathologies, especially cancer. In this review, we highlight context cancer discuss it an adaptive tumor favors growth dissemination but also resistance treatment. Thus, underline targeting therapeutic strategy.

Language: Английский

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SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/osteoblastic redifferentiation

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(8)

Published: Feb. 17, 2021

Significance Cartilage is essential in vertebrate development and adulthood. growth plates ensure skeletal until closing at puberty, articular cartilage ensures lifelong structural functional integrity of joints. Chondrocytes build development, governed by the transcription factor SOX9. Using mouse models transcriptome profiling approaches, we show here that SOX9 also has key roles to maintain open postnatally protect adult from osteoarthritic degradation. In particular, safeguards lineage fate chondrocytes preventing their dedifferentiation into skeletogenic mesenchymal progenitors followed redifferentiation osteoblasts. These findings provide insights cellular plasticity its molecular control developmental, physiological, pathological processes within beyond system.

Language: Английский

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Endothelial Dysfunction and Diabetic Cardiomyopathy

Frontiers in Endocrinology, Journal Year: 2022, Volume and Issue: 13

Published: April 7, 2022

The cardiovascular complications contribute to a majority of diabetes associated morbidity and mortality, accounting for 44% death in those patients with type 1 mellitus (DM) 52% deaths 2 DM. Diabetes elicits dysfunction through major mechanisms: ischemic non-ischemic. Non-ischemic injury is usually under-recognized although common DM patients, also pathogenic factor heart failure diabetic individuals complicated disease. Diabetic cardiomyopathy (DCM) defined as disease which the myocardium structurally functionally abnormal absence coronary artery disease, hypertensive, valvular, or congenital disorders theoretically caused by non-ischemic solely. Current therapeutic strategies targeting DCM mainly address increased blood glucose levels, however, effects on function are disappointed. Accumulating data indicate endothelial plays critical role initiation development DCM. Hyperglycemia, hyperinsulinemia, insulin resistance cause damages function, including barrier dysfunction, impaired nitric oxide (NO) activity, excessive reactive oxygen species (ROS) production, oxidative stress, inflammatory dysregulation. In turn, promotes myocardial metabolism, intracellular Ca 2+ mishandling, endoplasmic reticulum (ER) mitochondrial defect, accumulation advanced glycation end products, extracellular matrix (ECM) deposit, leads cardiac stiffness, fibrosis, remodeling, eventually results diastolic systolic failure. While closely related seen DCM, clinical restoring still missing. This review summarizes timely findings disorder well provides mechanical insights pathogenesis pathophysiology developing, highlights potential targets.

Language: Английский

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Endothelial-Mesenchymal Transition in Cardiovascular Disease

Arteriosclerosis Thrombosis and Vascular Biology, Journal Year: 2021, Volume and Issue: 41(9), P. 2357 - 2369

Published: July 1, 2021

Endothelial-to-mesenchymal transition is a dynamic process in which endothelial cells suppress constituent properties and take on mesenchymal cell behaviors. To begin the process, loosen their cell-cell junctions, degrade basement membrane, migrate out into perivascular surroundings. These initial behaviors reflect transient modulation of cellular phenotype, that is, phenotypic modulation, sometimes referred to as partial endothelial-to-mesenchymal transition. Loosening junctions migration are also seen inflammatory angiogenic settings such initiating have overlapping gene expression with responding signals or sprouting form new blood vessels. Reduced increase permeability, facilitates leukocyte trafficking, whereas precedes neovascularization; both barriers quiescence restored stimuli subside. Complete proceeds beyond characteristics become prominent functions diminish. In proadaptive, regenerative produce extracellular matrix contribute tissue integrity maladaptive, pathologic fibrotic, overproducing cause stiffness, eventually impacts function. Here we will review what known about how TGF (transforming growth factor) β influences this continuum from junctional loosening its relevance cardiovascular diseases.

Language: Английский

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