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Nature Reviews. Cardiology Dec 2019Vascular smooth muscle cells (VSMCs) are a major cell type present at all stages of an atherosclerotic plaque. According to the 'response to injury' and 'vulnerable... (Review)
Review
Vascular smooth muscle cells (VSMCs) are a major cell type present at all stages of an atherosclerotic plaque. According to the 'response to injury' and 'vulnerable plaque' hypotheses, contractile VSMCs recruited from the media undergo phenotypic conversion to proliferative synthetic cells that generate extracellular matrix to form the fibrous cap and hence stabilize plaques. However, lineage-tracing studies have highlighted flaws in the interpretation of former studies, revealing that these studies had underestimated both the content and functions of VSMCs in plaques and have thus challenged our view on the role of VSMCs in atherosclerosis. VSMCs are more plastic than previously recognized and can adopt alternative phenotypes, including phenotypes resembling foam cells, macrophages, mesenchymal stem cells and osteochondrogenic cells, which could contribute both positively and negatively to disease progression. In this Review, we present the evidence for VSMC plasticity and summarize the roles of VSMCs and VSMC-derived cells in atherosclerotic plaque development and progression. Correct attribution and spatiotemporal resolution of clinically beneficial and detrimental processes will underpin the success of any therapeutic intervention aimed at VSMCs and their derivatives.
Topics: Animals; Atherosclerosis; Cell Plasticity; Cell Proliferation; Cellular Senescence; Disease Progression; Extracellular Matrix; Humans; Myocytes, Smooth Muscle; Phenotype; Plaque, Atherosclerotic
PubMed: 31243391
DOI: 10.1038/s41569-019-0227-9 -
Cell Stem Cell Apr 2020The etiology of aortic aneurysms is poorly understood, but it is associated with atherosclerosis, hypercholesterolemia, and abnormal transforming growth factor β...
The etiology of aortic aneurysms is poorly understood, but it is associated with atherosclerosis, hypercholesterolemia, and abnormal transforming growth factor β (TGF-β) signaling in smooth muscle. Here, we investigated the interactions between these different factors in aortic aneurysm development and identified a key role for smooth muscle cell (SMC) reprogramming into a mesenchymal stem cell (MSC)-like state. SMC-specific ablation of TGF-β signaling in Apoe mice on a hypercholesterolemic diet led to development of aortic aneurysms exhibiting all the features of human disease, which was associated with transdifferentiation of a subset of contractile SMCs into an MSC-like intermediate state that generated osteoblasts, chondrocytes, adipocytes, and macrophages. This combination of medial SMC loss with marked increases in non-SMC aortic cell mass induced exuberant growth and dilation of the aorta, calcification and ossification of the aortic wall, and inflammation, resulting in aneurysm development.
Topics: Animals; Aorta; Aortic Aneurysm; Cellular Reprogramming; Mice; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Transforming Growth Factor beta
PubMed: 32243809
DOI: 10.1016/j.stem.2020.02.013 -
Developmental Cell Oct 2022Smooth muscle cells (SMCs) execute important physiological functions in numerous vital organ systems, including the vascular, gastrointestinal, respiratory, and...
Smooth muscle cells (SMCs) execute important physiological functions in numerous vital organ systems, including the vascular, gastrointestinal, respiratory, and urogenital tracts. SMC differ morphologically and functionally at these different anatomical locations, but the molecular underpinnings of the differences remain poorly understood. Here, using deep single-cell RNA sequencing combined with in situ gene and protein expression analysis in four murine organs-heart, aorta, lung, and colon-we identify a molecular basis for high-level differences among vascular, visceral, and airway SMC, as well as more subtle differences between, for example, SMC in elastic and muscular arteries and zonation of elastic artery SMC along the direction of blood flow. Arterial SMC exhibit extensive organotypic heterogeneity, whereas venous SMC are similar across organs. We further identify a specific SMC subtype within the pulmonary vasculature. This comparative SMC cross-organ resource offers insight into SMC subtypes and their specific functions.
Topics: Mice; Animals; Muscle, Smooth, Vascular; Transcriptome; Myocytes, Smooth Muscle; Aorta; Cells, Cultured
PubMed: 36283392
DOI: 10.1016/j.devcel.2022.09.015 -
European Journal of Clinical... Apr 2022Aortic aneurysms (AA) are pathological dilations of the aorta, associated with an overall mortality rate up to 90% in case of rupture. In addition to dilation, the... (Review)
Review
BACKGROUND
Aortic aneurysms (AA) are pathological dilations of the aorta, associated with an overall mortality rate up to 90% in case of rupture. In addition to dilation, the aortic layers can separate by a tear within the layers, defined as aortic dissections (AD). Vascular smooth muscle cells (vSMC) are the predominant cell type within the aortic wall and dysregulation of vSMC functions contributes to AA and AD development and progression. However, since the exact underlying mechanism is poorly understood, finding potential therapeutic targets for AA and AD is challenging and surgery remains the only treatment option.
METHODS
In this review, we summarize current knowledge about vSMC functions within the aortic wall and give an overview of how vSMC functions are altered in AA and AD pathogenesis, organized per anatomical location (abdominal or thoracic aorta).
RESULTS
Important functions of vSMC in healthy or diseased conditions are apoptosis, phenotypic switch, extracellular matrix regeneration and degradation, proliferation and contractility. Stressors within the aortic wall, including inflammatory cell infiltration and (epi)genetic changes, modulate vSMC functions and cause disturbance of processes within vSMC, such as changes in TGF-β signalling and regulatory RNA expression.
CONCLUSION
This review underscores a central role of vSMC dysfunction in abdominal and thoracic AA and AD development and progression. Further research focused on vSMC dysfunction in the aortic wall is necessary to find potential targets for noninvasive AA and AD treatment options.
Topics: Aortic Dissection; Animals; Aortic Aneurysm; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle
PubMed: 34698377
DOI: 10.1111/eci.13697 -
American Journal of Physiology. Cell... Mar 2020Rat L6, mouse C2C12, and primary human skeletal muscle cells (HSMCs) are commonly used to study biological processes in skeletal muscle, and experimental data on these... (Comparative Study)
Comparative Study
Rat L6, mouse C2C12, and primary human skeletal muscle cells (HSMCs) are commonly used to study biological processes in skeletal muscle, and experimental data on these models are abundant. However, consistently matched experimental data are scarce, and comparisons between the different cell types and adult tissue are problematic. We hypothesized that metabolic differences between these cellular models may be reflected at the mRNA level. Publicly available data sets were used to profile mRNA levels in myotubes and skeletal muscle tissues. L6, C2C12, and HSMC myotubes were assessed for proliferation, glucose uptake, glycogen synthesis, mitochondrial activity, and substrate oxidation, as well as the response to in vitro contraction. Transcriptomic profiling revealed that mRNA of genes coding for actin and myosin was enriched in C2C12, whereas L6 myotubes had the highest levels of genes encoding glucose transporters and the five complexes of the mitochondrial electron transport chain. Consistently, insulin-stimulated glucose uptake and oxidative capacity were greatest in L6 myotubes. Insulin-induced glycogen synthesis was highest in HSMCs, but C2C12 myotubes had higher baseline glucose oxidation. All models responded to electrical pulse stimulation-induced glucose uptake and gene expression but in a slightly different manner. Our analysis reveals a great degree of heterogeneity in the transcriptomic and metabolic profiles of L6, C2C12, or primary human myotubes. Based on these distinct signatures, we provide recommendations for the appropriate use of these models depending on scientific hypotheses and biological relevance.
Topics: Adult; Animals; Cell Line; Cell Proliferation; Cells, Cultured; Energy Metabolism; Gene Expression Profiling; Humans; Male; Mice; Middle Aged; Muscle Cells; Muscle Fibers, Skeletal; Muscle, Skeletal; Rats; Species Specificity; Transcriptome
PubMed: 31825657
DOI: 10.1152/ajpcell.00540.2019 -
Annals of Surgery Sep 2022To determine cell-specific gene expression profiles that contribute to development of abdominal aortic aneurysms (AAAs).
OBJECTIVE
To determine cell-specific gene expression profiles that contribute to development of abdominal aortic aneurysms (AAAs).
BACKGROUND
AAAs represent the most common pathological aortic dilation leading to the fatal consequence of aortic rupture. Both immune and structural cells contribute to aortic degeneration, however, gene specific alterations in these cellular subsets are poorly understood.
METHODS
We performed single-cell RNA sequencing (scRNA-seq) analysis of AAAs and control tissues. AAA-related changes were examined by comparing gene expression profiles as well as detailed receptor-ligand interactions. An integrative analysis of scRNA-seq data with large genome-wide association study data was conducted to identify genes critical for AAA development.
RESULTS
Using scRNA-seq we provide the first comprehensive characterization of the cellular landscape in human AAA tissues. Unbiased clustering analysis of transcriptional profiles identified seventeen clusters representing 8 cell lineages. For immune cells, clustering analysis identified 4 T-cell and 5 monocyte/macrophage subpopulations, with distinct transcriptional profiles in AAAs compared to controls. Gene enrichment analysis on immune subsets identified multiple pathways only expressed in AAA tissue, including those involved in mitochondrial dysfunction, proliferation, and cytokine secretion. Moreover, receptor-ligand analysis defined robust interactions between vascular smooth muscle cells and myeloid populations in AAA tissues. Lastly, integrated analysis of scRNA-seq data with genome-wide association study studies determined that vascular smooth muscle cell expression of SORT1 is critical for maintaining normal aortic wall function.
CONCLUSIONS
Here we provide the first comprehensive evaluation of single-cell composition of the abdominal aortic wall and reveal how the gene expression landscape is altered in human AAAs.
Topics: Aorta, Abdominal; Aortic Aneurysm, Abdominal; Genome-Wide Association Study; Humans; Ligands; Myocytes, Smooth Muscle; Transcriptome
PubMed: 35762613
DOI: 10.1097/SLA.0000000000005551 -
Circulation Jun 2024Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation of various cell types, including immunocytes (eg, macrophages and T...
BACKGROUND
Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation of various cell types, including immunocytes (eg, macrophages and T cells), smooth muscle cells (SMCs), and endothelial cells. Accumulating evidence suggests that transition of SMCs to other cell types, known as phenotypic switching, plays a central role in atherosclerosis development and complications. However, the characteristics of SMC-derived cells and the underlying mechanisms of SMC transition in disease pathogenesis remain poorly understood. Our objective is to characterize tumor cell-like behaviors of SMC-derived cells in atherosclerosis, with the ultimate goal of developing interventions targeting SMC transition for the prevention and treatment of atherosclerosis.
METHODS
We used SMC lineage tracing mice and human tissues and applied a range of methods, including molecular, cellular, histological, computational, human genetics, and pharmacological approaches, to investigate the features of SMC-derived cells in atherosclerosis.
RESULTS
SMC-derived cells in mouse and human atherosclerosis exhibit multiple tumor cell-like characteristics, including genomic instability, evasion of senescence, hyperproliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. Specific expression of the oncogenic mutant in SMCs accelerates phenotypic switching and exacerbates atherosclerosis. Furthermore, we provide proof of concept that niraparib, an anticancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models.
CONCLUSIONS
Our findings demonstrate that atherosclerosis is an SMC-driven tumor-like disease, advancing our understanding of its pathogenesis and opening prospects for innovative precision molecular strategies aimed at preventing and treating atherosclerotic cardiovascular disease.
Topics: Animals; Atherosclerosis; Humans; Myocytes, Smooth Muscle; Mice; Muscle, Smooth, Vascular
PubMed: 38686559
DOI: 10.1161/CIRCULATIONAHA.123.067587 -
International Journal of Molecular... Jun 2020Millions of patients worldwide suffer from gastrointestinal (GI) motility disorders such as gastroparesis. These disorders typically include debilitating symptoms, such... (Review)
Review
Millions of patients worldwide suffer from gastrointestinal (GI) motility disorders such as gastroparesis. These disorders typically include debilitating symptoms, such as chronic nausea and vomiting. As no cures are currently available, clinical care is limited to symptom management, while the underlying causes of impaired GI motility remain unaddressed. The efficient movement of contents through the GI tract is facilitated by peristalsis. These rhythmic slow waves of GI muscle contraction are mediated by several cell types, including smooth muscle cells, enteric neurons, telocytes, and specialised gut pacemaker cells called interstitial cells of Cajal (ICC). As ICC dysfunction or loss has been implicated in several GI motility disorders, ICC represent a potentially valuable therapeutic target. Due to their availability, murine ICC have been extensively studied at the molecular level using both normal and diseased GI tissue. In contrast, relatively little is known about the biology of human ICC or their involvement in GI disease pathogenesis. Here, we demonstrate human gastric tissue as a source of primary human cells with ICC phenotype. Further characterisation of these cells will provide new insights into human GI biology, with the potential for developing novel therapies to address the fundamental causes of GI dysmotility.
Topics: Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal Tract; Humans; Interstitial Cells of Cajal; Intestine, Small; Myocytes, Smooth Muscle; Peristalsis; Stomach
PubMed: 32630607
DOI: 10.3390/ijms21124540 -
The Journal of Heart and Lung... May 2023Pulmonary hypertension (PH), increased blood pressure in the pulmonary arteries, is a morbid and lethal disease. PH is classified into several groups based on etiology,... (Review)
Review
Pulmonary hypertension (PH), increased blood pressure in the pulmonary arteries, is a morbid and lethal disease. PH is classified into several groups based on etiology, but pathological remodeling of the pulmonary vasculature is a common feature. Endothelial cell dysfunction and excess smooth muscle cell proliferation and migration are central to the vascular pathogenesis. In addition, other cell types, including fibroblasts, pericytes, inflammatory cells and platelets contribute as well. Herein, we briefly note most of the main cell types active in PH and for each cell type, highlight select signaling pathway(s) highly implicated in that cell type in this disease. Among others, the role of hypoxia-inducible factors, growth factors (e.g., vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor-β and bone morphogenetic protein), vasoactive molecules, NOTCH3, Kruppel-like factor 4 and forkhead box proteins are discussed. Additionally, deregulated processes of endothelial-to-mesenchymal transition, extracellular matrix remodeling and intercellular crosstalk are noted. This brief review touches upon select critical facets of PH pathobiology and aims to incite further investigation that will result in discoveries with much-needed clinical impact for this devastating disease.
Topics: Humans; Hypertension, Pulmonary; Vascular Endothelial Growth Factor A; Muscle, Smooth, Vascular; Cells, Cultured; Signal Transduction; Pulmonary Artery; Vascular Remodeling; Cell Proliferation; Myocytes, Smooth Muscle
PubMed: 36604291
DOI: 10.1016/j.healun.2022.12.012 -
The FEBS Journal Nov 2022Regeneration of the mammalian adult skeletal muscle is a well-orchestrated process regulated by multiple proteins and signalling pathways. Cytokines constitute a major... (Review)
Review
Regeneration of the mammalian adult skeletal muscle is a well-orchestrated process regulated by multiple proteins and signalling pathways. Cytokines constitute a major class of regulators of skeletal myogenesis. It is well established that infiltrating immune cells at the site of muscle injury secrete cytokines, which play critical roles in the myofibre repair and regeneration process. In the past 10-15 years, skeletal muscle itself has emerged as a prolific producer of cytokines. Much attention in the field has been focused on the endocrine effects of muscle-secreted cytokines (myokines) on metabolic regulation. However, ample evidence suggests that muscle-derived cytokines also regulate myogenic differentiation and muscle regeneration in an autocrine manner. In this review, we survey cytokines that meet two criteria: (a) evidence of expression by muscle cells; (b) evidence demonstrating a myogenic function. Dozens of cytokines representing several major classes make up this group, and together they regulate all steps of the myogenic process. How such a large array of cytokines coordinate their signalling to form a regulatory network is a fascinating, pressing question. Functional studies that can distinguish the source of the cytokines in vivo are also much needed in order to facilitate exploration of their full therapeutic potential.
Topics: Animals; Cell Differentiation; Cytokines; Mammals; Muscle Cells; Muscle Development; Muscle, Skeletal; Regeneration
PubMed: 35073461
DOI: 10.1111/febs.16372