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Current Rheumatology Reviews Jun 2023Lymphatic muscle cell (LMC) contractility and coverage of collecting lymphatic vessels (CLVs) are integral to effective lymphatic drainage and tissue homeostasis. In... (Review)
Review
Lymphatic muscle cell (LMC) contractility and coverage of collecting lymphatic vessels (CLVs) are integral to effective lymphatic drainage and tissue homeostasis. In fact, defects in lymphatic contractility have been identified in various conditions, including rheumatoid arthritis, inflammatory bowel disease, and obesity. However, the fundamental role of LMCs in these pathologic processes is limited, primarily due to the difficulty in directly investigating the enigmatic nature of this poorly characterized cell type. LMCs are a unique cell type that exhibit dual tonic and phasic contractility with hybrid structural features of both vascular smooth muscle cells (VSMCs) and cardiac myocytes. While advances have been made in recent years to better understand the biochemistry and function of LMCs, central questions regarding their origins, investiture into CLVs, and homeostasis remain unanswered. To summarize these discoveries, unexplained experimental results, and critical future directions, here we provide a focused review of current knowledge and open questions related to LMC progenitor cells, recruitment, maintenance, and regeneration. We also highlight the high-priority research goal of identifying LMC-specific genes towards genetic conditional- inducible in vivo gain and loss of function studies. While our interest in LMCs has been focused on understanding lymphatic dysfunction in an arthritic flare, these concepts are integral to the broader field of lymphatic biology, and have important potential for clinical translation through targeted therapeutics to control lymphatic contractility and drainage.
Topics: Humans; Lymphatic Vessels; Muscle Cells; Arthritis, Rheumatoid; Regeneration
PubMed: 36705238
DOI: 10.2174/1573397119666230127144711 -
American Journal of Physiology. Heart... Jan 2018Alcohol (EtOH) consumption can variously affect cardiovascular disease. Our aim was to compare the effects of EtOH and its primary metabolite acetaldehyde (ACT) on... (Comparative Study)
Comparative Study
Alcohol (EtOH) consumption can variously affect cardiovascular disease. Our aim was to compare the effects of EtOH and its primary metabolite acetaldehyde (ACT) on vascular smooth muscle Notch signaling and cell growth, which are important for atherogenesis. Human coronary artery smooth muscle cells (HCASMCs) were treated with EtOH (25 mM) or ACT (10 or 25 μM). As previously reported, EtOH inhibited Notch signaling and growth of HCASMCs. In contrast, ACT treatment stimulated HCASMC proliferation (cell counts) and increased proliferating cell nuclear antigen expression, concomitant with stimulation of Notch signaling, as determined by increased Notch receptor (N1 and N3) and target gene (Hairy-related transcription factor 1-3) mRNA levels. Interaction of the ligand with the Notch receptor initiates proteolytic cleavage by α- and γ-secretase, resulting in the release of the active Notch intracellular domain. Neither EtOH nor ACT had any significant effect on α-secretase activity. A fluorogenic peptide cleavage assay demonstrated almost complete inhibition by EtOH of Delta-like ligand 4-stimulated γ-secretase activity in solubilized HCASMCs (similar to the effect of the control inhibitor DAPT) but no effect of ACT treatment. EtOH, but not ACT, affected the association and distribution of the γ-secretase catalytic subunit presenilin-1 with lipid rafts, as determined by dual fluorescent labeling and confocal microscopic visualization. In conclusion, ACT stimulates vascular smooth muscle cell Notch signaling and growth, effects opposite to those of EtOH. These differential actions on vascular smooth muscle cells of EtOH and its metabolite ACT may be important in mediating the ultimate effects of drinking on cardiovascular disease. NEW & NOTEWORTHY Acetaldehyde stimulates, in a Notch-dependent manner, the vascular smooth muscle cell growth that contributes to atherogenesis; effects opposite to those of ethanol. These data suggest that in addition to ethanol itself, its metabolite acetaldehyde may also mediate some of the effects of alcohol consumption on vascular cells and, thus, cardiovascular health.
Topics: Acetaldehyde; Amyloid Precursor Protein Secretases; Cell Proliferation; Cells, Cultured; Ethanol; Humans; Membrane Microdomains; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Presenilin-1; Receptor, Notch1; Receptor, Notch3; Signal Transduction
PubMed: 29212792
DOI: 10.1152/ajpheart.00586.2017 -
Cellular and Molecular Life Sciences :... Aug 2012The epidermis and its appendages, such as the hair follicle (HF), continually regenerate throughout postnatal mammalian life due to the activity of resident epithelial... (Review)
Review
The epidermis and its appendages, such as the hair follicle (HF), continually regenerate throughout postnatal mammalian life due to the activity of resident epithelial stem cells (SCs). The follicular SC niche, or the bulge, is composed of a heterogeneous population of self-renewing multipotent cells. Multiple intrinsic molecular mechanisms promote the transition of follicular SCs from quiescence to activation. In addition, numerous extrinsic cell types influence the activity and characteristics of bulge cells. Ultimately, the balance between these intrinsic and extrinsic mechanisms influences the function of bulge cells during homeostasis and tissue regeneration and likely contributes to skin tumorigenesis. Here, we review both the intrinsic and extrinsic factors that contribute to the skin SC niche.
Topics: Adipocytes; Animals; Gene Expression Profiling; Hair Follicle; Humans; Melanocytes; Models, Biological; Multipotent Stem Cells; Muscle Cells; Neurons; Signal Transduction; Skin; Skin Neoplasms; Skin Physiological Phenomena; Stem Cell Niche
PubMed: 22410738
DOI: 10.1007/s00018-012-0943-3 -
ESC Heart Failure Oct 2022Although considerable progress has been made in the diagnosis and treatment of congenital heart disease-associated pulmonary heart hypertension (CHD-PAH), the clinical...
AIMS
Although considerable progress has been made in the diagnosis and treatment of congenital heart disease-associated pulmonary heart hypertension (CHD-PAH), the clinical prognosis and overall survival of patients with CHD-PAH remain poor. Therefore, the molecular pathogenesis of CHD-PAH requires further investigation. The intermediate filament protein synemin (SYN) is reported to modulate phenotypic alterations and varicose vein development, but there is little understanding of its exact functions in CHD-PAH.
METHODS AND RESULTS
SYN expression in the pulmonary arterioles of CHD-PAH patients and shunt-induced PAH rat models was evaluated using immunohistochemistry and western blot. Cell counts and Transwell migration assays were used to assess the effect of SYN on the proliferation and migration capability of human pulmonary smooth muscle cells (hPASMCs). Adeno-associated viruses (AAVs) have been used to suppress SYN expression in the pulmonary arterioles of rats. Such rats were further used to construct a shunt-induced PAH animal model to investigate the function of SYN in PAH and pulmonary vascular remodelling. Compared with the normal control group, SYN expression was found to be clearly up-regulated in the remodelled pulmonary arterioles of CHD-PAH and shunt-induced PAH rat models. In addition, SYN suppression increased the expression of hPASMC contractile-phenotype markers and decreased the expression of synthetic phenotype markers, in contrast to the control group. SYN suppression also dramatically attenuated the proliferation and migration capability of hPASMCs. Conversely, SYN overexpression promoted phenotypic switch, proliferation, and migration of hPASMCs, whereas these effects were notably alleviated by the protein kinase B (AKT) inhibitor MK-2206. Furthermore, we confirmed that SYN suppression mitigated PAH and pulmonary vascular remodelling induced by high blood flow in vivo.
CONCLUSIONS
Our findings indicated that SYN may represent a promising therapeutic target in the treatment of CHD-PAH.
Topics: Animals; Humans; Rats; Heart Defects, Congenital; Hypertension, Pulmonary; Myocytes, Smooth Muscle; Pulmonary Arterial Hypertension; Pulmonary Artery; Vascular Remodeling
PubMed: 35769011
DOI: 10.1002/ehf2.14048 -
Journal of Translational Medicine Mar 2017Endothelial and smooth muscle cells are considered promising resources for regenerative medicine and cell replacement therapy. It has been shown that both types of cells...
BACKGROUND
Endothelial and smooth muscle cells are considered promising resources for regenerative medicine and cell replacement therapy. It has been shown that both types of cells are heterogeneous depending on the type of vessels and organs in which they are located. Therefore, isolation of endothelial and smooth muscle cells from tissues relevant to the area of research is necessary for the adequate study of specific pathologies. However, sources of specialized human endothelial and smooth muscle cells are limited, and the search for new sources is still relevant. The main goal of our study is to demonstrate that functional endothelial and smooth muscle cells can be obtained from an available source-post-surgically discarded cardiac tissue from the right atrial appendage and right ventricular myocardium.
METHODS
Heterogeneous primary cell cultures were enzymatically isolated from cardiac explants and then grown in specific endothelial and smooth muscle growth media on collagen IV-coated surfaces. The population of endothelial cells was further enriched by immunomagnetic sorting for CD31, and the culture thus obtained was characterized by immunocytochemistry, ultrastructural analysis and in vitro functional tests. The angiogenic potency of the cells was examined by injecting them, along with Matrigel, into immunodeficient mice. Cells were also seeded on characterized polycaprolactone/chitosan membranes with subsequent analysis of cell proliferation and function.
RESULTS
Endothelial cells isolated from cardiac explants expressed CD31, VE-cadherin and VEGFR2 and showed typical properties, namely, cytoplasmic Weibel-Palade bodies, metabolism of acetylated low-density lipoproteins, formation of capillary-like structures in Matrigel, and production of extracellular matrix and angiogenic cytokines. Isolated smooth muscle cells expressed extracellular matrix components as well as α-actin and myosin heavy chain. Vascular cells derived from cardiac explants demonstrated the ability to stimulate angiogenesis in vivo. Endothelial cells proliferated most effectively on membranes made of polycaprolactone and chitosan blended in a 25:75 ratio, neutralized by a mixture of alkaline and ethanol. Endothelial and smooth muscle cells retained their functional properties when seeded on the blended membranes.
CONCLUSIONS
We established endothelial and smooth muscle cell cultures from human right atrial appendage and right ventricle post-operative explants. The isolated cells revealed angiogenic potential and may be a promising source of patient-specific cells for regenerative medicine.
Topics: Animals; Blood Vessel Prosthesis; Cell Differentiation; Cell Proliferation; Cell Separation; Cell Survival; Cells, Cultured; Chitosan; Endothelial Cells; Humans; Mice, SCID; Myocardium; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Platelet Endothelial Cell Adhesion Molecule-1; Polyesters; Prosthesis Design; Weibel-Palade Bodies
PubMed: 28257636
DOI: 10.1186/s12967-017-1156-1 -
Cardiovascular Research Jul 2012Differentiated vascular smooth muscle cells (SMCs) retain the capacity to modify their phenotype in response to inflammation or injury. This phenotypic switching is a... (Review)
Review
Differentiated vascular smooth muscle cells (SMCs) retain the capacity to modify their phenotype in response to inflammation or injury. This phenotypic switching is a crucial component of vascular disease, and is partly dependent on epigenetic regulation. An appreciation has been building in the literature for the essential role chromatin remodelling plays both in SMC lineage determination and in influencing changes in SMC behaviour and state. This process includes numerous chromatin regulatory elements and pathways such as histone acetyltransferases, deacetylases, and methyltransferases and other factors that act at SMC-specific marker sites to silence or permit access to the cellular transcriptional machinery and on other key regulatory elements such as myocardin and Kruppel-like factor 4 (KLF4). Various stimuli known to alter the SMC phenotype, such as transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), oxidized phospholipids, and retinoic acid, appear to act in part through effects upon SMC chromatin structure. In recent years, specific covalent histone modifications that appear to establish SMC determinacy have been identified, while others alter the differentiation state. In this article, we review the mechanisms of chromatin remodelling as it applies to the SMC phenotype.
Topics: Animals; Cell Differentiation; Chromatin; Chromatin Assembly and Disassembly; Histones; Humans; Kruppel-Like Factor 4; Myocytes, Smooth Muscle; Phenotype
PubMed: 22362814
DOI: 10.1093/cvr/cvs098 -
PLoS Computational Biology Feb 2011The organization of muscle is the product of functional adaptation over several length scales spanning from the sarcomere to the muscle bundle. One possible strategy for...
The organization of muscle is the product of functional adaptation over several length scales spanning from the sarcomere to the muscle bundle. One possible strategy for solving this multiscale coupling problem is to physically constrain the muscle cells in microenvironments that potentiate the organization of their intracellular space. We hypothesized that boundary conditions in the extracellular space potentiate the organization of cytoskeletal scaffolds for directed sarcomeregenesis. We developed a quantitative model of how the cytoskeleton of neonatal rat ventricular myocytes organizes with respect to geometric cues in the extracellular matrix. Numerical results and in vitro assays to control myocyte shape indicated that distinct cytoskeletal architectures arise from two temporally-ordered, organizational processes: the interaction between actin fibers, premyofibrils and focal adhesions, as well as cooperative alignment and parallel bundling of nascent myofibrils. Our results suggest that a hierarchy of mechanisms regulate the self-organization of the contractile cytoskeleton and that a positive feedback loop is responsible for initiating the break in symmetry, potentiated by extracellular boundary conditions, is required to polarize the contractile cytoskeleton.
Topics: Actins; Animals; Cells, Cultured; Computer Simulation; Cytoskeleton; Focal Adhesions; Immunohistochemistry; Models, Biological; Muscle Contraction; Myocytes, Cardiac; Myofibrils; Rats; Rats, Sprague-Dawley; Sarcomeres
PubMed: 21390276
DOI: 10.1371/journal.pcbi.1001088 -
British Journal of Pharmacology Jan 2013An important objective in asthma therapy is to prevent the accelerated growth of airway smooth muscle cells which leads to hyperplasia and bronchial hyperreactivity. We...
BACKGROUND AND PURPOSE
An important objective in asthma therapy is to prevent the accelerated growth of airway smooth muscle cells which leads to hyperplasia and bronchial hyperreactivity. We investigated the effect of combination of salbutamol and PPARγ agonists on growth factor-stimulated human bronchial smooth muscle cell (BSMC) proliferation.
EXPERIMENTAL APPROACH
Synergism was quantified by the combination index-isobologram method. Assays used here included analyses of growth inhibition, cell viability, DNA fragmentation, gene transcription, cell cycle and protein expression.
KEY RESULTS
The PPARγ gene was highly expressed in BSMC and the protein was identified in cell nuclei. Single-agent salbutamol or PPARγ agonists prevented growth factor-induced human BSMC proliferation within a micromolar range of concentrations through their specific receptor subtypes. Sub-micromolar levels of combined salbutamol-PPARγ agonist inhibited growth by 50% at concentrations from ∼2 to 12-fold lower than those required for each drug alone, without induction of apoptosis or necrosis. Combination treatments also promoted cell cycle arrest at the G1/S transition phase and inhibition of ERK phosphorylation.
CONCLUSIONS AND IMPLICATIONS
The synergistic interaction between PPARγ agonists and β(2) -adrenoceptor agonists on airway smooth muscle cell proliferation highlights the anti-remodelling potential of this combination in chronic lung diseases.
Topics: Airway Remodeling; Albuterol; Bronchi; Cell Cycle; Cell Division; Cell Proliferation; Cells, Cultured; Drug Synergism; Humans; Myocytes, Smooth Muscle; Peroxisome Proliferator-Activated Receptors; Rosiglitazone; Thiazolidinediones
PubMed: 22924744
DOI: 10.1111/j.1476-5381.2012.02180.x -
Acta Physiologica (Oxford, England) Jul 2011The O(2) requirements of contracting skeletal muscle may increase 100-fold above rest. In 1919, August Krogh's brilliant insights recognized the capillary as the... (Review)
Review
The O(2) requirements of contracting skeletal muscle may increase 100-fold above rest. In 1919, August Krogh's brilliant insights recognized the capillary as the principal site for this increased blood-myocyte O(2) flux. Based on the premise that most capillaries did not sustain RBC flux at rest, Krogh proposed that capillary recruitment [i.e. initiation of red blood cell (RBC) flux in previously non-flowing capillaries] increased the capillary surface area available for O(2) flux and reduced mean capillary-to-mitochondrial diffusion distances. More modern experimental approaches reveal that most muscle capillaries may support RBC flux at rest. Thus, rather than contraction-induced capillary recruitment per se, increased RBC flux and haematocrit within already-flowing capillaries probably elevate perfusive and diffusive O(2) conductances and hence blood-myocyte O(2) flux. Additional surface area for O(2) exchange is recruited but, crucially, this may occur along the length of already-flowing capillaries (i.e. longitudinal recruitment). Today, the capillary is still considered the principal site for O(2) and substrate delivery to contracting skeletal muscle. Indeed, the presence of very low intramyocyte O(2) partial pressures (PO(2)s) and the absence of intramyocyte PO(2) gradients, whilst refuting the relevance of diffusion distances, place an even greater importance on capillary hemodynamics. This emergent picture calls for a paradigm-shift in our understanding of the function of capillaries by de-emphasizing de novo'capillary recruitment'. Diseases such as heart failure impair blood-myocyte O(2) flux, in part, by decreasing the proportion of RBC-flowing capillaries. Knowledge of capillary function in healthy muscle is requisite for identification of pathology and efficient design of therapeutic treatments.
Topics: Animals; Capillaries; Erythrocytes; Exercise; Hemodynamics; Humans; Microcirculation; Muscle Cells; Muscle Contraction; Muscle, Skeletal; Oxygen; Partial Pressure
PubMed: 21199399
DOI: 10.1111/j.1748-1716.2010.02246.x -
Scientific Reports Jan 2022In vitro skeletal muscle cell production is emerging in the field of artificial lab-grown meat as alternative future food. Currently, there is an urgent paradigm shift... (Comparative Study)
Comparative Study
In vitro skeletal muscle cell production is emerging in the field of artificial lab-grown meat as alternative future food. Currently, there is an urgent paradigm shift towards a serum replacement culture system. Surprisingly, little is known about the impact of serum-free culture on skeletal muscle cells to date. Therefore, we performed metabolic profiling of the C2C12 myoblasts and myotubes in serum-free mediums (B27, AIM-V) and compared it with conventional serum supplementation culture. Furthermore, cell morphology, viability, and myogenic differentiation were observed for 7 days of cultivation. Intriguingly, the metabolic difference is more dominant between the cell status than medium effects. In addition, proliferative myoblast showed more distinct metabolic differences than differentiated myotubes in different culture conditions. The intracellular levels of GL3P and UDP-GlcNAc were significantly increased in myotubes versus myoblast. Non-essential amino acids and pyruvate reduction and transamination showed significant differences among serum, B27, and AIM-V cultures. Intracellular metabolite profiles indicated that C2C12 myotubes cultured in serum and B27 had predominant glycolytic and oxidative metabolism, respectively, indicating fast and slow types of muscle confirmed by MHC immunostaining. This work might be helpful to understand the altered metabolism of skeletal muscle cells in serum-free culture and contribute to future artificial meat research work.
Topics: Animals; Cell Differentiation; Cells, Cultured; Culture Media, Serum-Free; Food Industry; Meat; Muscle Development; Muscle Fibers, Skeletal; Muscle, Skeletal; Myoblasts; Phenotype; Time Factors
PubMed: 35039582
DOI: 10.1038/s41598-022-04804-z