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Cells Mar 2021Muscle tissue is often removed during hamstring tendon graft preparation for anterior cruciate ligament (ACL) reconstruction. The purpose of the study was to test...
Muscle tissue is often removed during hamstring tendon graft preparation for anterior cruciate ligament (ACL) reconstruction. The purpose of the study was to test whether preservation of muscle remnants on a tendon graft is beneficial to the graft healing process following ACL reconstruction. Co-culturing of tendon-derived cells (TDCs) and muscle-derived cells (MDCs) was performed at various ratios, and their potential for cell viability and multilineage differentiation was compared to a single TDC cell group. Ligamentous and chondrogenic differentiation was most enhanced when a small population of MDCs was co-cultured with TDCs (6:2 co-culture group). Cell viability and osteogenic differentiation were proportionally enhanced with increasing MDC population size. MDCs co-cultured with TDCs possess both the ability to enhance cell viability and differentiate into other cell lineages.
Topics: Adolescent; Adult; Becaplermin; Calcification, Physiologic; Cell Differentiation; Cell Survival; Chondrocytes; Chondrogenesis; Coculture Techniques; Collagen; Extracellular Matrix; Female; Gene Expression Regulation; Hamstring Tendons; Humans; Ligaments; Male; Muscle Cells; Osteogenesis; Preservation, Biological; Young Adult
PubMed: 33801626
DOI: 10.3390/cells10040740 -
Communications Biology Sep 2022Dystrophin is the central protein of the dystrophin-glycoprotein complex (DGC) in skeletal and heart muscle cells. Dystrophin connects the actin cytoskeleton to the... (Review)
Review
Dystrophin is the central protein of the dystrophin-glycoprotein complex (DGC) in skeletal and heart muscle cells. Dystrophin connects the actin cytoskeleton to the extracellular matrix (ECM). Severing the link between the ECM and the intracellular cytoskeleton has a devastating impact on the homeostasis of skeletal muscle cells, leading to a range of muscular dystrophies. In addition, the loss of a functional DGC leads to progressive dilated cardiomyopathy and premature death. Dystrophin functions as a molecular spring and the DGC plays a critical role in maintaining the integrity of the sarcolemma. Additionally, evidence is accumulating, linking the DGC to mechanosignalling, albeit this role is still less understood. This review article aims at providing an up-to-date perspective on the DGC and its role in mechanotransduction. We first discuss the intricate relationship between muscle cell mechanics and function, before examining the recent research for a role of the dystrophin glycoprotein complex in mechanotransduction and maintaining the biomechanical integrity of muscle cells. Finally, we review the current literature to map out how DGC signalling intersects with mechanical signalling pathways to highlight potential future points of intervention, especially with a focus on cardiomyopathies.
Topics: Dystrophin; Glycoproteins; Mechanotransduction, Cellular; Muscle Fibers, Skeletal; Sarcolemma
PubMed: 36168044
DOI: 10.1038/s42003-022-03980-y -
Aging Cell Feb 2024Aging of the vasculature is associated with detrimental changes in vascular smooth muscle cell (VSMC) mechanosensitivity to extrinsic forces in their surrounding...
Aging of the vasculature is associated with detrimental changes in vascular smooth muscle cell (VSMC) mechanosensitivity to extrinsic forces in their surrounding microenvironment. However, how chronological aging alters VSMCs' ability to sense and adapt to mechanical perturbations remains unexplored. Here, we show defective VSMC mechanosensation in aging measured with ultrasound tweezers-based micromechanical system, force instantaneous frequency spectrum, and transcriptome analyses. The study reveals that aged VSMCs adapt to a relatively inert mechanobiological state with altered actin cytoskeletal integrity, resulting in an impairment in their mechanosensitivity and dynamic mechanoresponse to mechanical perturbations. The aging-associated decline in mechanosensation behaviors is mediated by hyperactivity of Piezo1-dependent calcium signaling. Inhibition of Piezo1 alleviates vascular aging and partially restores the loss in dynamic contractile properties in aged cells. Altogether, our study reveals the signaling pathway underlying aging-associated aberrant mechanosensation in VSMC and identifies Piezo1 as a potential therapeutic mechanobiological target to alleviate vascular aging.
Topics: Muscle, Smooth, Vascular; Actins; Cytoskeleton; Signal Transduction; Myocytes, Smooth Muscle; Cells, Cultured
PubMed: 37941511
DOI: 10.1111/acel.14036 -
FASEB Journal : Official Publication of... Nov 2021Kabuki syndrome (KS) is a rare genetic disorder caused primarily by mutations in the histone modifier genes KMT2D and KDM6A. The genes have broad temporal and spatial...
Kabuki syndrome (KS) is a rare genetic disorder caused primarily by mutations in the histone modifier genes KMT2D and KDM6A. The genes have broad temporal and spatial expression in many organs, resulting in complex phenotypes observed in KS patients. Hypotonia is one of the clinical presentations associated with KS, yet detailed examination of skeletal muscle samples from KS patients has not been reported. We studied the consequences of loss of KMT2D function in both mouse and human muscles. In mice, heterozygous loss of Kmt2d resulted in reduced neuromuscular junction (NMJ) perimeter, decreased muscle cell differentiation in vitro and impaired myofiber regeneration in vivo. Muscle samples from KS patients of different ages showed presence of increased fibrotic tissue interspersed between myofiber fascicles, which was not seen in mouse muscles. Importantly, when Kmt2d-deficient muscle stem cells were transplanted in vivo in a physiologic non-Kabuki environment, their differentiation potential is restored to levels undistinguishable from control cells. Thus, the epigenetic changes due to loss of function of KMT2D appear reversible through a change in milieu, opening a potential therapeutic avenue.
Topics: Abnormalities, Multiple; Adolescent; Animals; Cell Differentiation; Child; Child, Preschool; DNA-Binding Proteins; Disease Models, Animal; Face; Female; Hematologic Diseases; Histone-Lysine N-Methyltransferase; Humans; Infant; Male; Mice; Mice, Transgenic; Muscle Cells; Muscle Fibers, Skeletal; Mutation; Myeloid-Lymphoid Leukemia Protein; Neoplasm Proteins; Neuromuscular Junction; Signal Transduction; Vestibular Diseases
PubMed: 34613626
DOI: 10.1096/fj.202100823R -
Cells Feb 2022Smooth muscle cells (SMCs), present in the media layer of blood vessels, are crucial in maintaining vascular homeostasis. Upon vascular injury, SMCs show a high degree... (Review)
Review
Smooth muscle cells (SMCs), present in the media layer of blood vessels, are crucial in maintaining vascular homeostasis. Upon vascular injury, SMCs show a high degree of plasticity, undergo a change from a "contractile" to a "synthetic" phenotype, and play an essential role in the pathophysiology of diseases including atherosclerosis and restenosis. Integrins are cell surface receptors, which are involved in cell-to-cell binding and cell-to-extracellular-matrix interactions. By binding to extracellular matrix components, integrins trigger intracellular signaling and regulate several of the SMC function, including proliferation, migration, and phenotypic switching. Although pharmacological approaches, including antibodies and synthetic peptides, have been effectively utilized to target integrins to limit atherosclerosis and restenosis, none has been commercialized yet. A clear understanding of how integrins modulate SMC biology is essential to facilitate the development of integrin-based interventions to combat atherosclerosis and restenosis. Herein, we highlight the importance of integrins in modulating functional properties of SMCs and their implications for vascular pathology.
Topics: Atherosclerosis; Extracellular Matrix; Humans; Integrins; Myocytes, Smooth Muscle; Vascular Remodeling
PubMed: 35203297
DOI: 10.3390/cells11040646 -
Cells Jul 2021Among reactive oxygen species, superoxide mediates the critical vascular redox signaling, resulting in the regulation of the human cardiovascular system. The reduced... (Review)
Review
Among reactive oxygen species, superoxide mediates the critical vascular redox signaling, resulting in the regulation of the human cardiovascular system. The reduced form of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, NOX) is the source of superoxide and relates to the crucial intracellular pathology and physiology of vascular smooth muscle cells, including contraction, proliferation, apoptosis, and inflammatory response. Human vascular smooth muscle cells express NOX1, 2, 4, and 5 in physiological and pathological conditions, and those enzymes play roles in most cardiovascular disorders caused by hypertension, diabetes, inflammation, and arteriosclerosis. Various physiologically active substances, including angiotensin II, stimulate NOX via the cytosolic subunits' translocation toward the vascular smooth muscle cell membrane. As we have shown, some pathological stimuli such as high glucose augment the enzymatic activity mediated by the phosphatidylinositol 3-kinase-Akt pathway, resulting in the membrane translocation of cytosolic subunits of NOXs. This review highlights and details the roles of human vascular smooth muscle NOXs in the pathophysiology and clinical aspects. The regulation of the enzyme expressed in the vascular smooth muscle cells may lead to the prevention and treatment of human cardiovascular diseases.
Topics: Cardiovascular Diseases; Hemodynamics; Humans; Isoenzymes; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NADPH Oxidases; Oxidative Stress; Superoxides
PubMed: 34440716
DOI: 10.3390/cells10081947 -
Scientific Reports Jan 2017The process of stem cell myogenesis (transformation into skeletal muscle cells) includes several stages characterized by the expression of certain combinations of...
The process of stem cell myogenesis (transformation into skeletal muscle cells) includes several stages characterized by the expression of certain combinations of myogenic factors. The first part of this process is accompanied by cell division, while the second part is mainly associated with direct differentiation. The mechanical cues are known to enhance stem cell myogenesis, and the paper focuses on the stem cell differentiation under the condition of externally applied strain. The process of stem cell myogenic differentiation is interpreted as the interplay among transcription factors, targeted proteins and strain-generated signaling molecule, and it is described by a kinetic multi-stage model. The model parameters are optimally adjusted by using the available data from the experiment with adipose-derived stem cells subjected to the application of cyclic uniaxial strains of the magnitude of 10%. The modeling results predict the kinetics of the process of myogenic differentiation, including the number of cells in each stage of differentiation and the rates of differentiation from one stage to another for different strains from 4% to 16%. The developed model can help better understand the process of myogenic differentiation and the effects of mechanical cues on stem cell use in muscle therapies.
Topics: Algorithms; Cell Differentiation; Kinetics; Models, Biological; Muscle Development; Muscle Fibers, Skeletal; Stem Cells
PubMed: 28106095
DOI: 10.1038/srep40639 -
International Journal of Biological... 2020Normally, smooth muscle cells (SMCs) are localized in the tunica media of the vasculature, where they take responsibility for vascular contraction and extracellular... (Review)
Review
Normally, smooth muscle cells (SMCs) are localized in the tunica media of the vasculature, where they take responsibility for vascular contraction and extracellular matrix (ECM) generation. SMCs also play a significant role in obedience and elastic rebound of the artery in response to the haemodynamic condition. However, under pathological or stressed conditions, phenotype switching from contractile to synthetic state or other cell types will occur in SMCs to positively or negatively contribute to disease progression. Various studies demonstrated that functional changes of SMCs are implicated in several cardiovascular diseases. In this review, we present the function of vascular SMCs (VSMCs) and the involved molecular mechanisms about phenotype switching, and summarize the roles of SMCs in atherosclerosis, hypertension, arterial aneurysms and myocardial infarction, hoping to obtain potential therapeutic targets against cardiovascular disease in the clinical practices.
Topics: Animals; Cardiovascular Diseases; Cell Plasticity; Epigenesis, Genetic; Female; Humans; Muscle, Smooth; Myocytes, Smooth Muscle
PubMed: 33110393
DOI: 10.7150/ijbs.49871 -
Current Opinion in Pharmacology Apr 2020Asthma is an obstructive inflammatory airway disease. Airway obstruction is mediated by hyperresponsive airway smooth muscle cell contraction, which is induced and... (Review)
Review
Asthma is an obstructive inflammatory airway disease. Airway obstruction is mediated by hyperresponsive airway smooth muscle cell contraction, which is induced and compounded by inflammation caused by T lymphocytes. One important signal transduction pathway that is involved in the activation of these cell types involves the generation of a lipid second messenger known as diacylglycerol (DAG). DAG levels are controlled in cells by a negative regulator known as DAG kinase (DGK). In this review, we discuss how the DAG signaling pathway attenuates the pathological function of immune cells and airway smooth muscle cells in allergic airway disease and asthma. Furthermore, we discuss how the enhancement of the DAG signaling pathway through the inhibition of DGK may represent a novel therapeutic strategy for these diseases.
Topics: Animals; Anti-Asthmatic Agents; Diacylglycerol Kinase; Humans; Hypersensitivity; Lung Diseases; Myocytes, Smooth Muscle; T-Lymphocytes
PubMed: 32836013
DOI: 10.1016/j.coph.2020.07.008 -
JCI Insight May 2021Excessive proliferation of vascular smooth muscle cells (SMCs) remains a significant cause of in-stent restenosis. Integrins, which are heterodimeric transmembrane...
Excessive proliferation of vascular smooth muscle cells (SMCs) remains a significant cause of in-stent restenosis. Integrins, which are heterodimeric transmembrane receptors, play a crucial role in SMC biology by binding to the extracellular matrix protein with the actin cytoskeleton within the SMC. Integrin α9 plays an important role in cell motility and autoimmune diseases; however, its role in SMC biology and remodeling remains unclear. Herein, we demonstrate that stimulated human coronary SMCs upregulate α9 expression. Targeting α9 in stimulated human coronary SMCs, using anti-integrin α9 antibody, suppresses synthetic phenotype and inhibits SMC proliferation and migration. To provide definitive evidence, we generated an SMC-specific α9-deficient mouse strain. Genetic ablation of α9 in SMCs suppressed synthetic phenotype and reduced proliferation and migration in vitro. Mechanistically, suppressed synthetic phenotype and reduced proliferation were associated with decreased focal adhesion kinase/steroid receptor coactivator signaling and downstream targets, including phosphorylated ERK, p38 MAPK, glycogen synthase kinase 3β, and nuclear β-catenin, with reduced transcriptional activation of β-catenin target genes. Following vascular injury, SMC-specific α9-deficient mice or wild-type mice treated with murine anti-integrin α9 antibody exhibited reduced injury-induced neointimal hyperplasia at day 28 by limiting SMC migration and proliferation. Our findings suggest that integrin α9 regulates SMC biology, suggesting its potential therapeutic application in vascular remodeling.
Topics: Animals; Female; Integrin alpha Chains; Male; Mice; Mice, Transgenic; Myocytes, Smooth Muscle; Phenotype; Vascular Remodeling
PubMed: 34027892
DOI: 10.1172/jci.insight.147134