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JCI Insight Nov 2023The management of preretinal fibrovascular membranes, a devastating complication of advanced diabetic retinopathy (DR), remains challenging. We characterized the...
The management of preretinal fibrovascular membranes, a devastating complication of advanced diabetic retinopathy (DR), remains challenging. We characterized the molecular profile of cell populations in these fibrovascular membranes to identify potentially new therapeutic targets. Preretinal fibrovascular membranes were surgically removed from patients and submitted for single-cell RNA-Seq (scRNA-Seq). Differential gene expression was implemented to define the transcriptomics profile of these cells and revealed the presence of endothelial, inflammatory, and stromal cells. Endothelial cell reclustering identified subclusters characterized by noncanonical transcriptomics profile and active angiogenesis. Deeper investigation of the inflammatory cells showed a subcluster of macrophages expressing proangiogenic cytokines, presumably contributing to angiogenesis. The stromal cell cluster included a pericyte-myofibroblast transdifferentiating subcluster, indicating the involvement of pericytes in fibrogenesis. Differentially expressed gene analysis showed that Adipocyte Enhancer-binding Protein 1, AEBP1, was significantly upregulated in myofibroblast clusters, suggesting that this molecule may have a role in transformation. Cell culture experiments with human retinal pericytes (HRP) in high-glucose condition confirmed the molecular transformation of pericytes toward myofibroblastic lineage. AEBP1 siRNA transfection in HRP reduced the expression of profibrotic markers in high glucose. In conclusion, AEBP1 signaling modulates pericyte-myofibroblast transformation, suggesting that targeting AEBP1 could prevent scar tissue formation in advanced DR.
Topics: Humans; Diabetic Retinopathy; Retina; Pericytes; Glucose; Gene Expression Profiling; Diabetes Mellitus; Carboxypeptidases; Repressor Proteins
PubMed: 37917183
DOI: 10.1172/jci.insight.172062 -
Cell Reports Jun 2021Tumor vessel co-option is poorly understood, yet it is a resistance mechanism against anti-angiogenic therapy (AAT). The heterogeneity of co-opted endothelial cells...
Tumor vessel co-option is poorly understood, yet it is a resistance mechanism against anti-angiogenic therapy (AAT). The heterogeneity of co-opted endothelial cells (ECs) and pericytes, co-opting cancer and myeloid cells in tumors growing via vessel co-option, has not been investigated at the single-cell level. Here, we use a murine AAT-resistant lung tumor model, in which VEGF-targeting induces vessel co-option for continued growth. Single-cell RNA sequencing (scRNA-seq) of 31,964 cells reveals, unexpectedly, a largely similar transcriptome of co-opted tumor ECs (TECs) and pericytes as their healthy counterparts. Notably, we identify cell types that might contribute to vessel co-option, i.e., an invasive cancer-cell subtype, possibly assisted by a matrix-remodeling macrophage population, and another M1-like macrophage subtype, possibly involved in keeping or rendering vascular cells quiescent.
Topics: Animals; Cell Line, Tumor; Endothelial Cells; Female; Kidney Neoplasms; Lung Neoplasms; Macrophages; Mice, Inbred BALB C; Myeloid Cells; Neoplasms; Pericytes; Single-Cell Analysis; Mice
PubMed: 34133923
DOI: 10.1016/j.celrep.2021.109253 -
Experimental & Molecular Medicine May 2022Subretinal fibrosis remains a major obstacle to the management of neovascular age-related macular degeneration. Choroidal pericytes were found to be a significant source...
Subretinal fibrosis remains a major obstacle to the management of neovascular age-related macular degeneration. Choroidal pericytes were found to be a significant source of subretinal fibrosis, but the underlying mechanisms of pericyte-myofibroblast transition (PMT) remain largely unknown. The goal of this study was to explore the role and potential mechanisms by which PMT contributes to subretinal fibrosis. Choroidal neovascularization (CNV) was induced by laser photocoagulation in transgenic mice with the collagen1α1-green fluorescent protein (Col1α1-GFP) reporter, and recombinant adeno-associated virus 2 (rAAV2)-mediated TGF-β2 (rAAV2-TGF-β2) was administered intravitreally to further induce PMT. Primary mouse choroidal GFP-positive pericytes were treated with TGF-β2 in combination with siRNAs targeting Smad2/3, the Akt inhibitor MK2206 or the mTOR inhibitor rapamycin to examine cell proliferation, migration, and differentiation into myofibroblasts. The involvement of the Akt/mTOR pathway in PMT in subretinal fibrosis was further investigated in vivo. Intraocular TGF-β2 overexpression induced GFP-positive pericyte infiltration and PMT in subretinal fibrosis, which was mimicked in vitro. Knockdown of Smad2/3 or inhibition of Akt/mTOR decreased cell proliferation, PMT and migration in primary mouse pericytes. Combined inhibition of Smad2/3 and mTOR showed synergistic effects on attenuating α-smooth muscle actin (α-SMA) expression and cell proliferation. In mice with laser-induced CNV, the administration of the Akt/mTOR inhibitors suppressed pericyte proliferation and alleviated the severity of subretinal fibrosis. Our results showed that PMT plays a pivotal role in subretinal fibrosis, which was induced by TGF-β2 through the Smad2/3 and Akt/mTOR pathways. Thus, inhibiting PMT may be a novel strategy for the treatment of subretinal fibrosis.
Topics: Animals; Fibrosis; Mice; Myofibroblasts; Pericytes; Proto-Oncogene Proteins c-akt; Smad2 Protein; Smad3 Protein; TOR Serine-Threonine Kinases; Transforming Growth Factor beta2
PubMed: 35624154
DOI: 10.1038/s12276-022-00778-0 -
Animal Models and Experimental Medicine Aug 2023Pericytes are the main cellular components of tiny arteries and capillaries. Studies have found that pericytes can undergo morphological contraction or relaxation under... (Review)
Review
Pericytes are the main cellular components of tiny arteries and capillaries. Studies have found that pericytes can undergo morphological contraction or relaxation under stimulation by cytokines, thus affecting the contraction and relaxation of microvessels and playing an essential role in regulating vascular microcirculation. Moreover, due to the characteristics of stem cells, pericytes can differentiate into a variety of inflammatory cell phenotypes, which then affect the immune function. Additionally, pericytes can also participate in angiogenesis and wound healing by interacting with endothelial cells in vascular microcirculation disorders. Here we review the origin, biological phenotype and function of pericytes, and discuss the potential mechanisms of pericytes in vascular microcirculation disorders, especially in pulmonary hypertension, so as to provide a sound basis and direction for the prevention and treatment of vascular microcirculation diseases.
Topics: Pericytes; Microcirculation; Endothelial Cells; Capillaries; Biology
PubMed: 37317664
DOI: 10.1002/ame2.12334 -
Journal of Hepatology Mar 2024Metabolic dysfunction-associated steatohepatitis (MASH) is linked to insulin resistance and type 2 diabetes and marked by hepatic inflammation, microvascular...
BACKGROUND & AIMS
Metabolic dysfunction-associated steatohepatitis (MASH) is linked to insulin resistance and type 2 diabetes and marked by hepatic inflammation, microvascular dysfunction, and fibrosis, impairing liver function and aggravating metabolic derangements. The liver homeostatic interactions disrupted in MASH are still poorly understood. We aimed to elucidate the plasticity and changing interactions of non-parenchymal cells associated with advanced MASH.
METHODS
We characterized a diet-induced mouse model of advanced MASH at single-cell resolution and validated findings by assaying chromatin accessibility, bioimaging murine and human livers, and via functional experiments in vivo and in vitro.
RESULTS
The fibrogenic activation of hepatic stellate cells (HSCs) led to deterioration of a signaling module consisting of the bile acid receptor NR1H4/FXR and HSC-specific G-protein-coupled receptors (GPCRs) capable of preserving stellate cell quiescence. Accompanying HSC activation, we further observed the attenuation of HSC Gdf2 expression, and a MASH-associated expansion of a CD207-positive macrophage population likely derived from both incoming monocytes and Kupffer cells.
CONCLUSION
We conclude that HSC-expressed NR1H4 and GPCRs of the healthy liver integrate postprandial cues, which sustain HSC quiescence and, through paracrine signals, overall sinusoidal health. Hence HSC activation in MASH not only drives fibrogenesis but may desensitize the hepatic sinusoid to liver homeostatic signals.
IMPACT AND IMPLICATIONS
Homeostatic interactions between hepatic cell types and their deterioration in metabolic dysfunction-associated steatohepatitis are poorly characterized. In our current single cell-resolved study of advanced murine metabolic dysfunction-associated steatohepatitis, we identified a quiescence-associated hepatic stellate cell-signaling module with potential to preserve normal sinusoid function. As expression levels of its constituents are conserved in the human liver, stimulation of the identified signaling module is a promising therapeutic strategy to restore sinusoid function in chronic liver disease.
Topics: Mice; Humans; Animals; Pericytes; Diabetes Mellitus, Type 2; Liver; Signal Transduction; Hepatic Stellate Cells; Fatty Liver; Liver Cirrhosis; Growth Differentiation Factor 2
PubMed: 37972658
DOI: 10.1016/j.jhep.2023.11.001 -
Microcirculation (New York, N.Y. : 1994) Nov 2019Vascular pericytes provide critical contributions to the formation and integrity of the blood vessel wall within the microcirculation. Pericytes maintain vascular... (Review)
Review
Vascular pericytes provide critical contributions to the formation and integrity of the blood vessel wall within the microcirculation. Pericytes maintain vascular stability and homeostasis by promoting endothelial cell junctions and depositing extracellular matrix (ECM) components within the vascular basement membrane, among other vital functions. As their importance in sustaining microvessel health within various tissues and organs continues to emerge, so does their role in a number of pathological conditions including cancer, diabetic retinopathy, and neurological disorders. Here, we review vascular pericyte contributions to the development and remodeling of the microcirculation, with a focus on the local microenvironment during these processes. We discuss observations of their earliest involvement in vascular development and essential cues for their recruitment to the remodeling endothelium. Pericyte involvement in the angiogenic sprouting context is also considered with specific attention to crosstalk with endothelial cells such as through signaling regulation and ECM deposition. We also address specific aspects of the collective cell migration and dynamic interactions between pericytes and endothelial cells during angiogenic sprouting. Lastly, we discuss pericyte contributions to mechanisms underlying the transition from active vessel remodeling to the maturation and quiescence phase of vascular development.
Topics: Animals; Basement Membrane; Cellular Microenvironment; Extracellular Matrix; Humans; Neovascularization, Physiologic; Pericytes
PubMed: 31066166
DOI: 10.1111/micc.12554 -
Hearing Research Oct 2023Pericytes are specialized mural cells surrounding endothelial cells in microvascular beds. They play a role in vascular development, blood flow regulation, maintenance... (Review)
Review
Pericytes are specialized mural cells surrounding endothelial cells in microvascular beds. They play a role in vascular development, blood flow regulation, maintenance of blood-tissue barrier integrity, and control of angiogenesis, tissue fibrosis, and wound healing. In recent decades, understanding of the critical role played by pericytes in retina, brain, lung, and kidney has seen significant progress. The cochlea contains a large population of pericytes. However, the role of cochlear pericytes in auditory pathophysiology is, by contrast, largely unknown. The present review discusses recent progress in identifying cochlear pericytes, mapping their distribution, and defining their role in regulating blood flow, controlling the blood-labyrinth barrier (BLB) and angiogenesis, and involvement in different types of hearing loss.
Topics: Humans; Pericytes; Endothelial Cells; Hearing Loss; Deafness; Cochlea
PubMed: 37651921
DOI: 10.1016/j.heares.2023.108877 -
Biomedicine & Pharmacotherapy =... Jan 2020Pericytes, as mural cells of microvessels, are important regulators of vascular structure formation and function maintenance in the process of cerebrovascular... (Review)
Review
Pericytes, as mural cells of microvessels, are important regulators of vascular structure formation and function maintenance in the process of cerebrovascular maturation, cerebrovascular homeostasis and disease. In the recent years, they have gradually become the hot spot of the research. In fact, pericytes are not isolated cells. Their functions can't be played without the cooperation with surrounding cells. In the neurovascular unit (NVU), they communicate with other cells by direct contact or through signaling pathways to regulate cerebral vascular function and the state of blood vessels in response to changes in neural activity. Pericytes are closely related to the cerebrovascular and central nervous system disease. Currently, a large number of clinical and animal studies have confirmed that pericytes biological function is related to cerebral blood flow, blood-brain barrier permeability, cerebral vascular formation maintenance, and neuroinflammation. The objective of this review is to highlight the role of pericytes in cerebral microvessels as well as their relationships with stroke, dementia, and brain tumor disease. The possible pathogenic mechanisms between pericytes and these diseases will also be described. As a matter of fact, the role of pericytes in the brain-associated vascular disease may provide new ideas for clinical treatment.
Topics: Animals; Blood-Brain Barrier; Brain; Central Nervous System Diseases; Cerebrovascular Circulation; Humans; Microvessels; Pericytes; Signal Transduction
PubMed: 31743876
DOI: 10.1016/j.biopha.2019.109633 -
Frontiers in Bioscience (Landmark... Apr 2024Pericytes, a specific type of mesenchymal cell that surround the basement membrane of pulmonary venules and capillaries. They are crucial pathological features observed... (Review)
Review
Pericytes, a specific type of mesenchymal cell that surround the basement membrane of pulmonary venules and capillaries. They are crucial pathological features observed in individuals with the severe lung disease of pulmonary fibrosis (PF). The presence of pericytes leads to inflammation and fibrosis in the lung interstitium and alveolar space due to the release of various cytokines and chemokines. Pericytes also stimulate the proliferation and activation of fibroblasts, thereby promoting the progression of PF. Previous studies examining the mechanism of action of pericytes have primarily focused on cell signal transduction pathways, cell growth and death processes, and the synthesis and breakdown of extracellular matrix (ECM). Notably, the transforming growth factor-β (TGF-β) and Wnt signaling pathways have been associated with the action of pericytes in driving the progression of PF. It is therefore clear that pericytes play an essential role in the development of PF, while also offering possible avenues for targeted therapeutic intervention against this condition. The current article provides a comprehensive review on how pericytes contribute to inflammatory responses, as well as their importance for understanding the mechanism of PF. In addition, this review discusses the potential use of pericyte-targeted approaches for the treatment of patients affected by this debilitating lung disease.
Topics: Pericytes; Humans; Pulmonary Fibrosis; Animals; Transforming Growth Factor beta; Signal Transduction; Extracellular Matrix; Wnt Signaling Pathway
PubMed: 38682199
DOI: 10.31083/j.fbl2904141 -
Cells Mar 2021Pericytes, as mural cells covering microvascular capillaries, play an essential role in vascular remodeling and maintaining vascular functions and blood flow. Pericytes... (Review)
Review
Pericytes, as mural cells covering microvascular capillaries, play an essential role in vascular remodeling and maintaining vascular functions and blood flow. Pericytes are crucial participants in the physiological and pathological processes of cardiovascular disease. They actively interact with endothelial cells, vascular smooth muscle cells (VSMCs), fibroblasts, and other cells via the mechanisms involved in the secretome. The secretome of pericytes, along with diverse molecules including proinflammatory cytokines, angiogenic growth factors, and the extracellular matrix (ECM), has great impacts on the formation, stabilization, and remodeling of vasculature, as well as on regenerative processes. Emerging evidence also indicates that pericytes work as mesenchymal cells or progenitor cells in cardiovascular regeneration. Their capacity for differentiation also contributes to vascular remodeling in different ways. Previous studies primarily focused on the roles of pericytes in organs such as the brain, retina, lung, and kidney; very few studies have focused on pericytes in the heart. In this review, following a brief introduction of the origin and fundamental characteristics of pericytes, we focus on pericyte functions and mechanisms with respect to heart disease, ending with the promising use of cardiac pericytes in the treatment of ischemic heart failure.
Topics: Cell Differentiation; Endothelial Cells; Humans; Myocytes, Cardiac; Pericytes
PubMed: 33806335
DOI: 10.3390/cells10030548