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Pharmacology & Therapeutics Sep 2023Chronic and neuropathic pain are a widespread burden. Incomplete understanding of underlying pathomechanisms is one crucial factor for insufficient treatment. Recently,... (Review)
Review
Chronic and neuropathic pain are a widespread burden. Incomplete understanding of underlying pathomechanisms is one crucial factor for insufficient treatment. Recently, impairment of the blood nerve barrier (BNB) has emerged as one key aspect of pain initiation and maintenance. In this narrative review, we discuss several mechanisms and putative targets for novel treatment strategies. Cells such as pericytes, local mediators like netrin-1 and specialized proresolving mediators (SPMs), will be covered as well as circulating factors including the hormones cortisol and oestrogen and microRNAs. They are crucial in either the BNB or similar barriers and associated with pain. While clinical studies are still scarce, these findings might provide valuable insight into mechanisms and nurture development of therapeutic approaches.
Topics: Humans; Blood-Nerve Barrier; Neuralgia; Pericytes; MicroRNAs
PubMed: 37390969
DOI: 10.1016/j.pharmthera.2023.108484 -
Current Opinion in Immunology Jun 2020The mesenchymal microenvironment is increasingly recognized as a major player in immunity. Here we focus on mesenchymal cells located within or in proximity to the blood... (Review)
Review
The mesenchymal microenvironment is increasingly recognized as a major player in immunity. Here we focus on mesenchymal cells located within or in proximity to the blood vessels wall, which include pericytes, adventitial fibroblasts and mesenchymal stromal cells. We discuss recent evidence that these cells play a role in tissue homeostasis, immunity and inflammatory pathologies by multiple mechanisms, including vascular modulation, leucocyte migration, activation or survival in the perivascular space and differentiation into specialized 'effector' mesenchymal cells essential for tissue repair and immunity, such as myofibroblasts and lymphoid stromal cells. When dysregulated, these responses contribute to inflammatory and fibrotic diseases.
Topics: Cell Differentiation; Fibroblasts; Humans; Mesenchymal Stem Cells; Pericytes; Stromal Cells
PubMed: 32387900
DOI: 10.1016/j.coi.2020.03.009 -
Biomedicine & Pharmacotherapy =... Dec 2022Pericytes are mural vascular cells covering microvascular capillaries, where they contribute to the formation, maturation, maintenance, stabilisation and remodelling of... (Review)
Review
Pericytes are mural vascular cells covering microvascular capillaries, where they contribute to the formation, maturation, maintenance, stabilisation and remodelling of vasculature. They actively interact and communicate with other cells to maintain the capillary structural integrity, vascular permeability and blood flow. Pericytes are crucial participants in the physiological and pathological processes of cardiovascular disease. In this review, we summarise recent data regarding pericyte metabolism, trans-differentiation, angiogenesis and immunomodulation in connection with different cardiovascular pathologies. Further, we discuss an application of pericytes as a new cell therapy approach to treat coronary artery disease, congenital heart disease, atherosclerotic plaques calcification and calcific valvular heart disease in different in vivo animal models and in vitro studies. Also, we discuss different methods and pharmacological therapies for CVDs treatment with pericyte-mediated effects. Finally, we present a comprehensive overview of the role of pericytes in CVDs and as a pharmacological target for different novel drugs and techniques and highlight the potential application of pericytes to treat CVDs.
Topics: Animals; Pericytes; Cardiovascular Diseases; Capillaries; Neovascularization, Pathologic; Cell Differentiation
PubMed: 36411618
DOI: 10.1016/j.biopha.2022.113928 -
Respiratory Research Jun 2023The origin of αSMA-positive myofibroblasts, key players within organ fibrosis, is still not fully elucidated. Pericytes have been discussed as myofibroblast progenitors...
BACKGROUND
The origin of αSMA-positive myofibroblasts, key players within organ fibrosis, is still not fully elucidated. Pericytes have been discussed as myofibroblast progenitors in several organs including the lung.
METHODS
Using tamoxifen-inducible PDGFRβ-tdTomato mice (PDGFRβ-CreER; R26tdTomato) lineage of lung pericytes was traced. To induce lung fibrosis, a single orotracheal dose of bleomycin was given. Lung tissue was investigated by immunofluorescence analyses, hydroxyproline collagen assay and RT-qPCR.
RESULTS
Lineage tracing combined with immunofluorescence for nitric oxide-sensitive guanylyl cyclase (NO-GC) as marker for PDGFRβ-positive pericytes allows differentiating two types of αSMA-expressing myofibroblasts in murine pulmonary fibrosis: (1) interstitial myofibroblasts that localize in the alveolar wall, derive from PDGFRβ pericytes, express NO-GC and produce collagen 1. (2) intra-alveolar myofibroblasts which do not derive from pericytes (but express PDGFRβ de novo after injury), are negative for NO-GC, have a large multipolar shape and appear to spread over several alveoli within the injured areas. Moreover, NO-GC expression is reduced during fibrosis, i.e., after pericyte-to-myofibroblast transition.
CONCLUSION
In summary, αSMA/PDGFRβ-positive myofibroblasts should not be addressed as a homogeneous target cell type within pulmonary fibrosis.
Topics: Mice; Animals; Pulmonary Fibrosis; Pericytes; Myofibroblasts; Guanylate Cyclase; Fibrosis; Collagen
PubMed: 37349733
DOI: 10.1186/s12931-023-02479-2 -
Glia Aug 2023Cerebral blood flow (CBF) is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer's disease (AD). Microglia...
Cerebral blood flow (CBF) is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer's disease (AD). Microglia associations with capillaries suggest they may play a role in the regulation of CBF or the blood-brain-barrier (BBB). We explored the relationship between microglia and pericytes, a vessel-resident cell type that has a major role in the control of CBF and maintenance of the BBB, discovering a spatially distinct subset of microglia that closely associate with pericytes. We termed these pericyte-associated microglia (PEM). PEM are present throughout the brain and spinal cord in NG2DsRed × CX CR1 mice, and in the human frontal cortex. Using in vivo two-photon microscopy, we found microglia residing adjacent to pericytes at all levels of the capillary tree and found they can maintain their position for at least 28 days. PEM can associate with pericytes lacking astroglial endfeet coverage and capillary vessel width is increased beneath pericytes with or without an associated PEM, but capillary width decreases if a pericyte loses a PEM. Deletion of the microglia fractalkine receptor (CX CR1) did not disrupt the association between pericytes and PEM. Finally, we found the proportion of microglia that are PEM declines in the superior frontal gyrus in AD. In summary, we identify microglia that specifically associate with pericytes and find these are reduced in number in AD, which may be a novel mechanism contributing to vascular dysfunction in neurodegenerative diseases.
Topics: Mice; Humans; Animals; Pericytes; Mice, Transgenic; Microglia; Brain; Blood-Brain Barrier; Alzheimer Disease
PubMed: 36994950
DOI: 10.1002/glia.24371 -
The EMBO Journal May 2022A functional blood-brain barrier relies on a tightly controlled interplay between endothelial cells, pericytes, and astrocytes, which together form the neurovascular...
A functional blood-brain barrier relies on a tightly controlled interplay between endothelial cells, pericytes, and astrocytes, which together form the neurovascular unit. Recent work by Lee et al (2022) discovers endothelial cell-derived lactate as a crucial metabolic fuel for brain pericytes, revealing a new way of CNS vascular communication that links nutrient metabolism to blood-brain barrier function.
Topics: Astrocytes; Blood-Brain Barrier; Brain; Ecosystem; Endothelial Cells; Pericytes
PubMed: 35437788
DOI: 10.15252/embj.2022111189 -
Cellular and Molecular Neurobiology Mar 2023Microvessels in the central nervous system (CNS) have one of the highest populations of pericytes, indicating their crucial role in maintaining homeostasis. Pericytes... (Review)
Review
Microvessels in the central nervous system (CNS) have one of the highest populations of pericytes, indicating their crucial role in maintaining homeostasis. Pericytes are heterogeneous cells located around brain microvessels; they present three different morphologies along the CNS vascular tree: ensheathing, mesh, and thin-strand pericytes. At the arteriole-capillary transition ensheathing pericytes are found, while mesh and thin-strand pericytes are located at capillary beds. Brain pericytes are essential for the establishment and maintenance of the blood-brain barrier, which restricts the passage of soluble and potentially toxic molecules from the circulatory system to the brain parenchyma. Pericytes play a key role in regulating local inflammation at the CNS. Pericytes can respond differentially, depending on the degree of inflammation, by secreting a set of neurotrophic factors to promote cell survival and regeneration, or by potentiating inflammation through the release of inflammatory mediators (e.g., cytokines and chemokines), and the overexpression of cell adhesion molecules. Under inflammatory conditions, pericytes may regulate immune cell trafficking to the CNS and play a role in perpetuating local inflammation. In this review, we describe pericyte responses during acute and chronic neuroinflammation.
Topics: Adult; Humans; Pericytes; Neuroinflammatory Diseases; Brain; Blood-Brain Barrier; Central Nervous System
PubMed: 35195811
DOI: 10.1007/s10571-022-01208-5 -
Pathologie (Heidelberg, Germany) Jul 2022
Topics: Pericytes
PubMed: 35925222
DOI: 10.1007/s00292-022-01085-1 -
Stem Cell Reports Oct 2023The formation of vascular structures is fundamental for in vitro tissue engineering. Vascularization can enable the nutrient supply within larger structures and...
The formation of vascular structures is fundamental for in vitro tissue engineering. Vascularization can enable the nutrient supply within larger structures and increase transplantation efficiency. We differentiated human induced pluripotent stem cells toward endothelial cells in 3D suspension culture. To investigate in vitro neovascularization and various 3D microenvironmental approaches, we designed a comprehensive single-cell transcriptomic study. Time-resolved single-cell transcriptomics of the endothelial and co-evolving mural cells gave insights into cell type development, stability, and plasticity. Transfer to a 3D hydrogel microenvironment induced neovascularization and facilitated tracing of migrating, coalescing, and tubulogenic endothelial cell states. During maturation, we monitored two pericyte subtypes evolving mural cells. Profiling cell-cell interactions between pericytes and endothelial cells revealed angiogenic signals during tubulogenesis. In silico discovered ligands were tested for their capability to attract endothelial cells. Our data, analyses, and results provide an in vitro roadmap to guide vascularization in future tissue engineering.
Topics: Humans; Endothelial Cells; Induced Pluripotent Stem Cells; Neovascularization, Physiologic; Coculture Techniques; Neovascularization, Pathologic; Pericytes
PubMed: 37714147
DOI: 10.1016/j.stemcr.2023.08.008 -
Cells May 2023Multiple biological processes rely on direct intercellular interactions to regulate cell proliferation and migration in embryonic development and cancer processes. Tumor... (Review)
Review
Multiple biological processes rely on direct intercellular interactions to regulate cell proliferation and migration in embryonic development and cancer processes. Tumor development and growth depends on close interactions between cancer cells and cells in the tumor microenvironment. During embryonic development, morphogenetic signals and direct cell contacts control cell proliferation, polarity, and morphogenesis. Cancer cells communicate with cells in the tumor niche through molecular signals and intercellular contacts, thereby modifying the vascular architecture and antitumor surveillance processes and consequently enabling tumor growth and survival. While looking for cell-to-cell signaling mechanisms that are common to both brain development and cancer progression, we have studied the infiltration process in glioblastoma multiforme (GBM), which is the most malignant primary brain tumor and with the worst prognosis. Cell-to-cell contacts, by means of filopodia-like structures, between GBM cells and brain pericytes (PCs) are necessary for adequate cell signaling during cancer infiltration; similarly, contacts between embryonic regions, via cytonemes, are required for embryo regionalization and development. This GBM-PC interaction provokes two important changes in the physiological function of these perivascular cells, namely, (i) vascular co-option with changes in cell contractility and vascular malformation, and (ii) changes in the PC transcriptome, modifying the microvesicles and protein secretome, which leads to the development of an immunosuppressive phenotype that promotes tumor immune tolerance. Moreover, the GTPase Cdc42 regulates cell polarity across organisms, from yeast to humans, playing a central role in GBM cell-PC interaction and maintaining vascular co-option. As such, a review of the molecular and cellular mechanisms underlying the development and maintenance of the physical interactions between cancer cells and PCs is of particular interest.
Topics: Humans; Glioblastoma; Pericytes; Cell Line, Tumor; Brain Neoplasms; Brain; Tumor Microenvironment
PubMed: 37174724
DOI: 10.3390/cells12091324