-
Annual Review of Physiology Feb 2020Cardiac fibrosis is a pathological condition that occurs after injury and during aging. Currently, there are limited means to effectively reduce or reverse fibrosis. Key... (Review)
Review
Cardiac fibrosis is a pathological condition that occurs after injury and during aging. Currently, there are limited means to effectively reduce or reverse fibrosis. Key to identifying methods for curbing excess deposition of extracellular matrix is a better understanding of the cardiac fibroblast, the cell responsible for collagen production. In recent years, the diversity and functions of these enigmatic cells have been gradually revealed. In this review, I outline current approaches for identifying and classifying cardiac fibroblasts. An emphasis is placed on new insights into the heterogeneity of these cells as determined by lineage tracing and single-cell sequencing in development, adult, and disease states. These recent advances in our understanding of the fibroblast provide a platform for future development of novel therapeutics to combat cardiac fibrosis.
Topics: Animals; Cell Lineage; Fibroblasts; Fibrosis; Heart; Humans; Myocardium
PubMed: 32040933
DOI: 10.1146/annurev-physiol-021119-034527 -
Nature May 2022Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes. As plaques lack innervation, the effects of neuronal...
Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes. As plaques lack innervation, the effects of neuronal control on atherosclerosis remain unclear. However, the immune system responds to plaques by forming leukocyte infiltrates in the outer connective tissue coat of arteries (the adventitia). Here, because the peripheral nervous system uses the adventitia as its principal conduit to reach distant targets, we postulated that the peripheral nervous system may directly interact with diseased arteries. Unexpectedly, widespread neuroimmune cardiovascular interfaces (NICIs) arose in mouse and human atherosclerosis-diseased adventitia segments showed expanded axon networks, including growth cones at axon endings near immune cells and media smooth muscle cells. Mouse NICIs established a structural artery-brain circuit (ABC): abdominal adventitia nociceptive afferents entered the central nervous system through spinal cord T-T dorsal root ganglia and were traced to higher brain regions, including the parabrachial and central amygdala neurons; and sympathetic efferent neurons projected from medullary and hypothalamic neurons to the adventitia through spinal intermediolateral neurons and both coeliac and sympathetic chain ganglia. Moreover, ABC peripheral nervous system components were activated: splenic sympathetic and coeliac vagus nerve activities increased in parallel to disease progression, whereas coeliac ganglionectomy led to the disintegration of adventitial NICIs, reduced disease progression and enhanced plaque stability. Thus, the peripheral nervous system uses NICIs to assemble a structural ABC, and therapeutic intervention in the ABC attenuates atherosclerosis.
Topics: Animals; Atherosclerosis; Disease Progression; Ganglia, Spinal; Ganglia, Sympathetic; Mice; Neurons; Plaque, Atherosclerotic
PubMed: 35477759
DOI: 10.1038/s41586-022-04673-6 -
British Journal of Hospital Medicine... Dec 2022True aneurysms are dilatations of blood vessels, bounded by the tunica intima, tunica media and tunica adventitia. False aneurysms are dilatations bounded by the tunica... (Review)
Review
True aneurysms are dilatations of blood vessels, bounded by the tunica intima, tunica media and tunica adventitia. False aneurysms are dilatations bounded by the tunica adventitia only, and are more common than true aneurysms. The femoral artery is the second most common location for true peripheral artery aneurysms, and the most common site of false aneurysms. If left untreated, devastating complications can occur, such as infection, rupture, ischaemia and limb loss. Femoral artery aneurysms should be identified early and managed by a vascular specialist. This article outlines the evidence for the epidemiology, investigation and management of femoral artery aneurysms.
Topics: Humans; Aneurysm, False; Femoral Artery; Aneurysm; Lower Extremity
PubMed: 36594777
DOI: 10.12968/hmed.2022.0258 -
Bosnian Journal of Basic Medical... Feb 2020Atherosclerosis is a chronic inflammatory disease of arteries and it affects the structure and function of all three layers of the coronary artery wall. Current theories... (Review)
Review
Atherosclerosis is a chronic inflammatory disease of arteries and it affects the structure and function of all three layers of the coronary artery wall. Current theories suggest that the dysfunction of endothelial cells is one of the initial steps in the development of atherosclerosis. The view that the tunica intima normally consists of a single layer of endothelial cells attached to the subendothelial layer and internal elastic membrane has been questioned in recent years. The structure of intima changes with age and it becomes multilayered due to migration of smooth muscle cells from the media to intima. At this stage, the migration and proliferation of smooth muscle cells do not cause pathological changes in the intima. The multilayering of intima is classically considered to be an important stage in the development of atherosclerosis, but in fact atherosclerotic plaques develop only focally due to the interplay of various processes that involve the resident and invading inflammatory cells. The tunica media consists of multiple layers of smooth muscle cells that produce the extracellular matrix, and this layer normally does not contain microvessels. During the development of atherosclerosis, the microvessels from the tunica adventitia or from the lumen may penetrate thickened media to provide nutrition and oxygenation. According to some theories, the endothelial dysfunction of these nutritive vessels may significantly contribute to the atherosclerosis of coronary arteries. The adventitia contains fibroblasts, progenitor cells, immune cells, microvessels, and adrenergic nerves. The degree of inflammatory cell infiltration into the adventitia, which can lead to the formation of tertiary lymphoid organs, correlates with the severity of atherosclerotic plaques. Coronary arteries are surrounded by perivascular adipose tissue that also participates in the atherosclerotic process.
Topics: Adventitia; Coronary Artery Disease; Humans; Plaque, Atherosclerotic; Tunica Intima; Tunica Media
PubMed: 31465719
DOI: 10.17305/bjbms.2019.4320 -
Nature Nov 2021Tissue maintenance and repair depend on the integrated activity of multiple cell types. Whereas the contributions of epithelial, immune and stromal cells in intestinal...
Tissue maintenance and repair depend on the integrated activity of multiple cell types. Whereas the contributions of epithelial, immune and stromal cells in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here we uncover important roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus leads to enteric gliosis and the upregulation of an interferon gamma (IFNγ) gene signature. IFNγ-dependent gene modules were also induced in EGCs from patients with inflammatory bowel disease. Single-cell transcriptomics analysis of the tunica muscularis showed that glia-specific abrogation of IFNγ signalling leads to tissue-wide activation of pro-inflammatory transcriptional programs. Furthermore, disruption of the IFNγ-EGC signalling axis enhanced the inflammatory and granulomatous response of the tunica muscularis to helminths. Mechanistically, we show that the upregulation of Cxcl10 is an early immediate response of EGCs to IFNγ signalling and provide evidence that this chemokine and the downstream amplification of IFNγ signalling in the tunica muscularis are required for a measured inflammatory response to helminths and resolution of the granulomatous pathology. Our study demonstrates that IFNγ signalling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFNγ-EGC-CXCL10 axis in immune response and tissue repair after infectious challenge.
Topics: Adventitia; Animals; Chemokine CXCL10; Duodenum; Female; Gliosis; Homeostasis; Humans; Inflammation; Interferon-gamma; Intestines; Male; Mice; Nematospiroides dubius; Neuroglia; Regeneration; Signal Transduction; Strongylida Infections
PubMed: 34671159
DOI: 10.1038/s41586-021-04006-z -
Immunity Mar 2023Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease...
Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease characterized by infectious exacerbations and loss of alveolar epithelium. Single-cell analysis of human emphysema lungs revealed the expansion of tissue-resident lymphocytes (TRLs). Murine studies identified a stromal niche for TRLs that expresses Hhip, a disease-variant gene downregulated in emphysema. Stromal-specific deletion of Hhip induced the topographic expansion of TRLs in the lung that was mediated by a hyperactive hedgehog-IL-7 axis. 3D immune-stem cell organoids and animal models of viral exacerbations demonstrated that expanded TRLs suppressed alveolar stem cell growth through interferon gamma (IFNγ). Finally, we uncovered an IFNγ-sensitive subset of human alveolar stem cells that was preferentially lost in emphysema. Thus, we delineate a stromal-lymphocyte-epithelial stem cell axis in the lung that is modified by a disease-variant gene and confers host susceptibility to emphysema.
Topics: Humans; Mice; Animals; Pulmonary Emphysema; Lung; Emphysema; Lymphocytes; Stem Cells; Pulmonary Disease, Chronic Obstructive
PubMed: 36822205
DOI: 10.1016/j.immuni.2023.01.032 -
Arterial Sca1 Vascular Stem Cells Generate De Novo Smooth Muscle for Artery Repair and Regeneration.Cell Stem Cell Jan 2020Rapid regeneration of smooth muscle after vascular injury is essential for maintaining arterial function. The existence and putative roles of resident vascular stem...
Rapid regeneration of smooth muscle after vascular injury is essential for maintaining arterial function. The existence and putative roles of resident vascular stem cells (VSCs) in artery repair are controversial, and vessel regeneration is thought to be mediated by proliferative expansion of pre-existing smooth muscle cells (SMCs). Here, we performed cell fate mapping and single-cell RNA sequencing to identify Sca1 VSCs in the adventitial layer of artery walls. After severe injury, Sca1 VSCs migrate into the medial layer and generate de novo SMCs, which subsequently expand more efficiently compared with pre-existing smooth muscle. Genetic lineage tracing using dual recombinases distinguished a Sca1PDGFRa VSC subpopulation that generates SMCs, and genetic ablation of Sca1 VSCs or specific knockout of Yap1 in Sca1 VSCs significantly impaired artery repair. These findings provide genetic evidence of a bona fide Sca1 VSC population that produces SMCs and delineates their critical role in vessel repair.
Topics: Adventitia; Arteries; Cell Differentiation; Myocytes, Smooth Muscle; Stem Cells
PubMed: 31883835
DOI: 10.1016/j.stem.2019.11.010 -
Arteriosclerosis, Thrombosis, and... Mar 2018The vascular system forms as a branching network of endothelial cells that acquire identity as arterial, venous, hemogenic, or lymphatic. Endothelial specification... (Review)
Review
The vascular system forms as a branching network of endothelial cells that acquire identity as arterial, venous, hemogenic, or lymphatic. Endothelial specification depends on gene targets transcribed by Ets domain-containing factors, including Ets variant gene 2 (Etv2), together with the activity of chromatin-remodeling complexes containing Brahma-related gene-1 (Brg1). Once specified and assembled into vessels, mechanisms regulating lumen diameter and axial growth ensure that the structure of the branching vascular network matches the need for perfusion of target tissues. In addition, blood vessels provide important morphogenic cues that guide or direct the development of organs forming around them. As the embryo grows and lumen diameters increase, smooth muscle cells wrap around the nascent vessel walls to provide mechanical strength and vasomotor control of the circulation. Increasing mechanical stretch and wall strain promote smooth muscle cell differentiation via coupling of actin cytoskeletal remodeling to myocardin and serum response factor-dependent transcription. Remodeling of artery walls by developmental signaling pathways reappears in postnatal blood vessels during physiological and pathological adaptation to vessel wall injury, inflammation, or chronic hypoxia. Recent reports providing insights into major steps in vascular development are reviewed here with a particular emphasis on studies that have been recently published in
Topics: Animals; Arteries; Cell Communication; Cell Differentiation; Cell Lineage; Endothelial Cells; Gene Expression Regulation, Developmental; Humans; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Phenotype; Signal Transduction
PubMed: 29467221
DOI: 10.1161/ATVBAHA.118.310223