Tissue Specific Origin, Development, and Pathological Perspectives of Pericytes

Frontiers in Cardiovascular Medicine, Journal Year: 2018, Volume and Issue: 5

Published: June 27, 2018

Pericytes are mural cells surrounding blood vessels, adjacent to endothelial cells. play critical roles in maturation and maintenance of vascular branching morphogenesis. In the central nervous system (CNS), pericytes necessary for formation regulation blood-brain barrier (BBB) pericyte deficiency accompanies CNS diseases including multiple sclerosis, diabetic retinopathy, neonatal intraventricular hemorrhage, neurodegenerative disorders. Despite importance pericytes, their developmental origins phenotypic diversity remain incompletely understood. express markers origin differs by tissue, which may cause difficulty identification understanding ontogeny pericytes. Also, have potential give rise different tissues vitro but this is not clear vivo. These studies indicate that heterogeneous a tissue- context- dependent manner. This short review focuses on recent about during development adults, differentiation capacity pathological settings.

Language: Английский

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CD146, from a melanoma cell adhesion molecule to a signaling receptor

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: Aug. 11, 2020

Abstract CD146 was originally identified as a melanoma cell adhesion molecule (MCAM) and highly expressed in many tumors endothelial cells. However, the evidence that acts an to mediate homophilic through direct interactions between itself is still lacking. Recent revealed not merely molecule, but also cellular surface receptor of miscellaneous ligands, including some growth factors extracellular matrixes. Through bidirectional with its actively involved numerous physiological pathological processes Overexpression can be observed most malignancies implicated nearly every step development progression cancers, especially vascular lymphatic metastasis. Thus, immunotherapy against would provide promising strategy inhibit metastasis, which accounts for majority cancer-associated deaths. Therefore, deepen understanding CD146, we review reports describing newly ligands discuss implications these findings establishing novel strategies cancer therapy.

Language: Английский

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Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

EMBO Reports, Journal Year: 2019, Volume and Issue: 20(11)

Published: Oct. 16, 2019

Review16 October 2019Open Access Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes Urban Lendahl Department of Cell Molecular Biology, Karolinska Institutet, Stockholm, Sweden Neurobiology, Care Sciences Society, Division Neurogeriatrics, Center Alzheimer Research, Solna, Integrated Cardio Metabolic Centre (ICMC), Huddinge, Search more papers by this author Per Nilsson Christer Betsholtz Corresponding Author [email protected] orcid.org/0000-0002-8494-971X Immunology, Genetics Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Medicine, Information Lendahl1,2,3, Nilsson2 *,3,4,5 1Department 2Department 3Integrated 4Department 5Department *Corresponding author. Tel: +46 709 796690; E-mail: EMBO Reports (2019)20:e48070https://doi.org/10.15252/embr.201948070 See the Glossary abbreviations used in article. PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Neurodegenerative diseases cause considerable human suffering, therapy options these two disease categories are limited or non-existing. It is an emerging notion that linked several ways, review, we discuss current status regarding vascular dysregulation disease, conversely, how associated with central nervous system (CNS) degeneration dysfunction. The reviewed a particular focus on pericytes—important cells ensheath endothelium microvasculature which pivotal blood–brain barrier function cerebral blood flow. Finally, address novel molecular cellular insights into other cell types may open new avenues diagnosis development important diseases. 20-HETE 20-Hydroxyeicosatetraenoic acid AD Alzheimer's ALK5 TGFβ type I receptor kinase ALS amyotrophic lateral sclerosis APOE apolipoprotein E APP amyloid precursor protein Aqp4 aquaporin 4 atp adenosine triphosphate a-v arterio-venous avm arteriovenous malformations aβ β peptide BBB BDNF brain-derived neurotrophic factor CAA angiopathy CADASIL autosomal dominant arteriopathy subcortical infarcts leukoencephalopathy CARASIL recessive CBF flow Cldn claudin CNS CSF cerebrospinal fluid CXCL12 C-X-C motif chemokine 12 CXCR4 ECM extracellular matrix EM electron microscopy FGF fibroblast growth GFAP glial fibrillary acidic Glut1 glucose transporter 1 HD Huntington's ISF interstitial Lam laminin LRP1 low-density lipoprotein receptor-related MCAM melanoma adhesion molecule MCI mild cognitive impairment NG2 neuron-glial antigen 2 NVU neurovascular unit OPC oligodendrocyte progenitor PDGF platelet-derived PDGFR PET positron-emission tomography PVS perivascular space scRNA-seq single-cell RNA sequencing SMA smooth muscle actin SOD1 super oxide dismutase SVD small vessel TBI traumatic brain injury TGF transforming tPA tissue plasminogen activator VSMC WML white matter lesions Introduction its vasculature composed 100 billion neurons connected intricate ways. In addition, there even larger number supporting cells, i.e., astrocytes oligodendrocytes, latter forming myelin sheets around making up large part brain. Another category microglia—macrophage-like scavenging debris aggregates, but when activated they also become players inflammation. While traditionally have been classified sub-categories based morphological anatomical criteria differences neurotransmitter repertoire, fine-grained view sub-types now as result recent transcriptomic analyses at level. Thus, than 500 molecularly distinct classes identified mouse 1, 2, information about composition specific regions increasing rapidly 2-8. Insights developmental trajectories different lineages—proceeding from immature progenitors specialized cells—are generated computational transcriptomes derived stages 8-10. Most data thus far mouse, progress made understanding diversity 10. With available normal unperturbed situation benchmark, gene expression changes related start be elucidated, example, (AD) 11 multiple 12, where single-nuclei technology has capture resolution. expected additional diseases, those can faithfully recapitulated models, will transcriptomically analyzed not too distant future. constitutes ≈2% adult body weight receives 20% cardiac output consumes our oxygen glucose. However, it almost negligible capacity long-term storage energy therefore dependent elaborate continuously fuels nutrients. architecture: Feeding arteries follow outer rim via meninges make branches penetrate perpendicularly parenchyma (sometimes referred penetrating arterioles), further split smaller arterioles eventually capillaries (Fig 1A–C). subsequently join venules collect radially oriented veins drain arachnoid 1D). Figure 1. Overview vasculature(A) Schematic dorsal surface feeding (red) draining (blue). (B) Branches superficial vessels, present subarachnoid space, parenchyma. (C) sagittal section level indicated (A) depicted cortex. (D) High-magnification schematic arteriole capillaries. rejoin organized venules, arachnoid. cross-sections vessels arteriolar, capillary, venous levels indicated, depicting various vessel-associated (as figure), spaces transport veins. longitudinal stretch capillary illustrates single pericyte connects endothelial through peg-socket contacts. Download figure PowerPoint built principal types: inner lining surrounded layer mural cells. phenotypes called names depending type: (VSMC) cover arteries, arterioles, veins, (Figs 1D 2). proportion abluminal covered varies among types. coverage complete whereas incomplete microvessels. least (≈10–20%) observed capillaries, (in brain) typically bipolar tripolar branch points) primary processes along length axis capillary. From processes, short sawtooth-like secondary extend. 2. Pericytes unitIn (BBB), interlocked tight junctions adherens junctions, extensively coated A arterial side side, coating (NVU) middle firing neuron sending signals (unknown their chemical nature) local branch, play receiver, turn exerting effects upstream-propagating regulate contraction/relaxation terminal arteriole. For most part, interface area physically separated basement membrane. sites, often located end membranes come close apposition. These sites contacts plaques. contacts, pericytic cytoplasmic projections (“pegs”) protrude membrane pockets (“sockets”), plaques flat areas contact. An question both contact if one thereby potentially integrating functional behavior. structures mostly ultrastructural transmission scanning analysis animal tissues 13, 14, seem form under vitro conditions during pericyte–endothelial co-culture 15. Little is, however, known physiological intriguing possibility harbor gap possibly moieties involved contact-dependent (“juxtacrine”) signaling 16 Although pericyte:endothelial ratio high compared organs, sometimes claimed order 1:1, own unpublished observations suggest density severalfold lower Therefore, fact tube 100% (i.e., would find every cross-section) follows 1B). Since difficult distinguish using light singular mRNA markers, constitute defining criterion versus types, including fibroblasts macrophages. Progress proteomic provide ideas cytoskeletal proteins reside feature serves separate fluids (interstitial fluid; CSF, respectively) hinders pathogens xenobiotic substances entering non-fenestrated physical barrier. This contrasts in, liver, kidney, endocrine fenestrated freely permeable solutes proteins. To allow efficient, precise, regulated ions, sugars, amino acids, nucleic lipids, proteins, equipped wide range influx transporters, well receptors engage receptor-mediated transcytosis. bounce off unwanted neurotoxic blood, xenobiotics taken gut, expresses efflux transporters nonspecifically recognize export lipophilic molecules. major against low pharmaceuticals poses problem efficient drug delivery Whereas features described above attributed surrounding peri-endothelial roles inducers regulators properties taking active homeostatic functions BBB. suggested many molecules specifically expressed lung 17. Among immune fibroblasts, and—depending organ—epithelial deserve attention because appear ubiquitous obligatory component microvessel wall. As mentioned, harbors higher peripheral skeletal muscle, hundredfold (for see ref. 18). magnitude reported should treated caution since identification remains ambiguous, appears enough (or vast majority of) cell. integrity depends astrocytes, completely encapsulate endfeet 19 1B Regulated across largely driven transcytosis discussed below, underpinnings controlled permeability, pericytes, intense research. Platelet-derived critical recruitment, differentiation, homeostasis 18. Hence, evidence importance mainly provided models hypomorphic 20, 21. One such model, Pdgfbret/ret produces only truncated PDGFB ligand (PDGFB-ret) lacking C-terminal residues retention motif. mediates binding secreted wild-type proteoglycans 22. Truncation makes PDGFB-ret unable bind proteoglycans. retains full activate β-receptor (PDGFR-β), increased diffusion away producer cells—the endothelium—presumably lowers concentration vicinity. Pdgfb Pdgfrb genes fully partially ablated. null mutants (heterozygous homozygous) reduction numbers, coupled dysfunction leakage defects 21, 23. More studies demonstrated mice differs 24. Pericyte loss studied another PDGF-signaling impaired PdgfrbF7/F7 mice, reduces competence 25. affected, breakdown was stage were indicating develops rather due 26. engaged complex cross-talk, understood. There ligand–receptor interactions operating PDGF-PDGFR, Ang1-Tie-2, Notch pathway involved, notably regulating PDGFR-β 27. Accordingly, 27-29. Recent work implicated CD146 (MCAM) co-receptor 30. 31 clearly show impairs formation barriers CNS, perturbed do harm 32. has, ablation causes hemorrhage developing embryos, does so without depleting 33. suggests modulation severe phenotype absence 34. worse consequences dropout. underscored reduced above-mentioned nevertheless develop seemingly stable pericyte-deficient attenuation 20. mechanism(s) process hypoplasia unknown, while mechanisms recently study revealing intracellular tubules control 35, unclear whether affects system. what extent affect aspects BBB, unclear. Tight junction claudins, endothelial-specific 5 (Cldn5) 36, limit paracellular interlocking review 37). Available (caused mutants) leads Cldn5 partly inconsistent 38 topic requires study. needs increase nutrient supply given point time active. (CBF) constantly adjusted regions. (NVU), conglomerate VSMC, neurons, regulator connection neuronal activity CBF, allows adjustment response activity, coupling (a.k.a. hyperemia). regulation understood, coupling. advocating regulatory 39-41 42), (although pericytes) 43 44. Erythrocytes themselves influence sensing deformability 45. divergent views deeper warranted. first maps population 46-48. recently, RNA-sequencing (scRNA-seq) transcriptional profiles all microglia reveal graded zonation matches gradual change diameter presumed biophysical parameters pressure sheer, oxygenation, takes place (A-V) axis. contrast transcription showed pattern A-V Here, quite population, well-separated arteriolar profiles, phenotypic conversion VSMC. finding abrupt transition SMC next border following Previous reports shown exhibit morphologies location: morphologically postcapillary reviews refs. 18, 49; Fig unexpected constituted homogenous signs subtypes apparent discrepancy homogeneity heterogeneity captured dual reporter (fluorescent reporters PDGFRβ elements) 17, although dual-labeled brain, possible some subpopulations efficiently strategy. Alternatively, populations fare less sorting enrichment procedures, leading underrepresentation transcriptome set. advent markers systematically addressed. Furthermore discovery ways stain example Neurotrace 500/52 50, complementary explorations transcriptomes. revealed discrepancies certain species cognate protein. Notably, α-smooth (α-SMA) (Acta2) very adds discussion distribution α-SMA pericytes. fail detect immunoreactivity healthy 44, 51-53 promoter 44 differ closer express levels, center bed 51. proposed degraded sample preparation, reason why detected immunohistochemistry situations 54. explored, putative contractile Paravascular addition proper, second fluid-transporting brain—paravascular flow—regulating 1). choroid plexus, transported meninges, drained connections lymphatic dura mater 55. continuous brain's (PVS), thin cavities surround (parenchymal) 56, 57 water, solute, waste product exchange ISF. How paravascular conduits out 58. Furthermore, report shows experimental damage meningeal accumulation aggregates AD-associated (Aβ) 55 tau 59, lymphatics. alternative glymphatic system, removal products lactate, Aβ, 60. ion buffering ISF, clearance sleep state 61. might required “waste” water channel aquaporin-4 (Aqp4) astrocytic 3A). still discussion. correlated astrocyte endfoot–vascular 62, lines Aqp4-deficient tracer depend intact 63. argued solely responsible transport, support notion, uptake rate unaffected arrest 64. Diffusion-driven injected tracers noted 65-68 69). Tracer connect perivenous drainage, routing enter pial-glial exit membranes, going direction 70. relate sleep–wake cycle 71. Aβ (85%) occurs minority bulk 72, 73, similar findings humans 74. conflicting organized, clear research understand detail diseased states. 3. system(A) model interaction t

Language: Английский

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Postnatal development of cerebrovascular structure and the neurogliovascular unit

Wiley Interdisciplinary Reviews Developmental Biology, Journal Year: 2019, Volume and Issue: 9(2)

Published: Oct. 1, 2019

Abstract The unceasing metabolic demands of brain function are supported by an intricate three‐dimensional network arterioles, capillaries, and venules, designed to effectively distribute blood all neurons provide shelter from harmful molecules in the blood. development maturation this microvasculature involves a complex interplay between endothelial cells with nearly other cell types (pericytes, astrocytes, microglia, neurons), orchestrated throughout embryogenesis first few weeks after birth mice. Both expansion regression vascular networks occur during postnatal period cerebrovascular remodeling. Pial on surface dense at then selectively pruned period, most dramatic changes occurring pial venular network. This is contrasted subsurface capillary through induction angiogenesis. Concurrent structure, integration cross talk neurovascular lead establishment blood–brain barrier integrity coupling ensure precise control macromolecular passage supply. While we still possess limited understanding rules that development, can begin assemble view how process evolves, as well identify gaps knowledge for next steps research. article categorized under: Nervous System Development > Vertebrates: Regional Vertebrate Organogenesis Musculoskeletal Vascular General Principles

Language: Английский

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CD146-HIF-1α hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Aug. 7, 2019

Abstract Pulmonary arterial hypertension (PAH) is a vascular remodeling disease of cardiopulmonary units. No cure currently available due to an incomplete understanding remodeling. Here we identify CD146-hypoxia-inducible transcription factor 1 alpha (HIF-1α) cross-regulation as key determinant in and PAH pathogenesis. CD146 markedly upregulated pulmonary artery smooth muscle cells (PASMCs/SMCs) proportion severity. expression HIF-1α transcriptional program reinforce each other physiologically enable PASMCs adopt more synthetic phenotype. Disruption CD146-HIF-1α cross-talk by genetic ablation Cd146 SMCs mitigates chronic hypoxic mice. Strikingly, targeting this axis with anti-CD146 antibodies alleviates established (PH) enhances cardiac function two rodent models. This study provides mechanistic insights into reprogramming that permits remodeling, thus proof concept for anti-remodeling therapy through direct modulation cross-regulation.

Language: Английский

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The Evolving Concept of the Blood Brain Barrier (BBB): From a Single Static Barrier to a Heterogeneous and Dynamic Relay Center

Frontiers in Cellular Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: Sept. 20, 2019

The blood-brain barrier (BBB) helps maintain a tightly regulated microenvironment for optimal central nervous system (CNS) homeostasis and facilitates communications with the peripheral circulation. brain endothelial cells, lining brain's vasculature, close interactions surrounding e.g., astrocytes, pericytes perivascular macrophages. This function critical intercellular crosstalk, giving rise to concept of neurovascular unit (NVU). steady appropriate communication between all components NVU is essential normal CNS function, dysregulation one its constituents can result in disease. Among different regions, along vascular tree, cellular composition varies. Therefore, differential cues from immediate environment affect BBB phenotype. To support fluctuating metabolic functional needs underlying neuropil, specialized heterogeneity required. achieved by variances expression transporters, receptors, adhesion molecules. mini-review will take you on journey through evolving concepts BBB, beyond. Exploring classical experiments leading new approaches allow us understand that not merely static separation periphery but closely interactive entity. We discuss shifting paradigms, ultimately aim address importance regard within NVU, touch implications neuropathologies.

Language: Английский

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Pericytes augment glioblastoma cell resistance to temozolomide through CCL5-CCR5 paracrine signaling

Cell Research, Journal Year: 2021, Volume and Issue: 31(10), P. 1072 - 1087

Published: July 8, 2021

Abstract Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression frequent recurrence. Excessive outgrowth pericytes in GBM governs the ecology perivascular niche, but their function mediating chemoresistance has not been fully explored. Herein, we uncovered that potentiate DNA damage repair (DDR) cells residing which induces temozolomide (TMZ) chemoresistance. We found increased pericyte proportion correlates accelerated recurrence worse prognosis. Genetic depletion xenografts enhances TMZ-induced cytotoxicity prolongs survival tumor-bearing mice. Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by activates receptor (CCR5) on to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment. Disrupting CCL5-CCR5 paracrine signaling through brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted effectively improves chemotherapeutic efficacy TMZ. patient-derived high CCL5 expression benefit from combined treatment MVC. Our study reveals role as an extrinsic stimulator potentiating suggests targeting could be effective therapeutic strategy improve against GBM.

Language: Английский

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High Mobility Group Box-1 and Blood–Brain Barrier Disruption

Cells, Journal Year: 2020, Volume and Issue: 9(12), P. 2650 - 2650

Published: Dec. 10, 2020

Increasing evidence suggests that inflammatory responses are involved in the progression of brain injuries induced by a diverse range insults, including ischemia, hemorrhage, trauma, epilepsy, and degenerative diseases. During processes inflammation, disruption blood–brain barrier (BBB) may play critical role enhancement initiate damage because BBB constitutes an interface between parenchyma bloodstream containing blood cells plasma. The has distinct structure compared with those peripheral tissues: it is composed vascular endothelial tight junctions, numerous pericytes surrounding cells, astrocytic endfeet, basement membrane structure. Under physiological conditions, should function as important element neurovascular unit (NVU). High mobility group box-1 (HMGB1), nonhistone nuclear protein, ubiquitously expressed almost all kinds cells. HMGB1 plays roles maintenance chromatin structure, regulation transcription activity, DNA repair nuclei. On other hand, considered to be representative damage-associated molecular pattern (DAMP) translocated released extracellularly from different types neurons glia, contributing pathophysiology many diseases central nervous system (CNS). release or neutralization extracellular produces beneficial effects on Alzheimer’s amyloidpathy animal models associated improvement neurological symptoms. In present review, we focus dynamics translocation disease conditions CNS discuss functional inflammation. There might common well for each disease. This review will provide novel insights toward improved understanding pathophysiological process diseases, namely, mediated HMGB1. It proposed excellent target treatment disruption.

Language: Английский

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Targeting pericytes for neurovascular regeneration

Cell Communication and Signaling, Journal Year: 2019, Volume and Issue: 17(1)

Published: March 20, 2019

Pericytes, as a key cellular part of the blood-brain barrier, play an important role in maintenance brain neurovascular unit. These cells participate homeostasis by regulating vascular development and integrity mainly through secreting various factors. Pericytes per se show different restorative properties after barrier injury. Upon occurrence acute chronic diseases, pericytes provoke immune to regulate neuro-inflammatory conditions. Loss distinct neurologic disorders intensifies permeability leads dementia. The therapeutic potential is originated from unique morphological shape, location, their ability providing vast paracrine juxtacrine interactions. A subset possesses multipotentiality exhibit trans-differentiation capacity context damaged tissue. This review article aimed highlight critical restoration injury focusing on dynamics cross-talk with other cell types.

Language: Английский

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Glioblastoma ablates pericytes antitumor immune function through aberrant up-regulation of chaperone-mediated autophagy

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(41), P. 20655 - 20665

Published: Sept. 23, 2019

Significance Glioblastoma (GB) is the most lethal brain malignancy without an effective treatment. In this study, we demonstrate that tumor-induced change in chaperone-mediated autophagy (CMA) host perivascular cells a targetable process to prevent GB progression. CMA regulates pericyte interaction with tumor and sustains acquired immunosuppressive function of pericytes, which required for survival. Blockage results changes protein levels involved cell-to-cell affects secretory phenotype, resulting defective adhesion diminished This work reveals previously unknown capacity modulate assist its own Our highlight possibility targeting treat aggressive disease.

Language: Английский

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