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JCI Insight Jul 2023Pericytes are multipotent mesenchymal precursor cells that demonstrate tissue-specific properties. In this study, by comparing human adipose tissue- and...
Pericytes are multipotent mesenchymal precursor cells that demonstrate tissue-specific properties. In this study, by comparing human adipose tissue- and periosteum-derived pericyte microarrays, we identified T cell lymphoma invasion and metastasis 1 (TIAM1) as a key regulator of cell morphology and differentiation decisions. TIAM1 represented a tissue-specific determinant between predispositions for adipocytic versus osteoblastic differentiation in human adipose tissue-derived pericytes. TIAM1 overexpression promoted an adipogenic phenotype, whereas its downregulation amplified osteogenic differentiation. These results were replicated in vivo, in which TIAM1 misexpression altered bone or adipose tissue generation in an intramuscular xenograft animal model. Changes in pericyte differentiation potential induced by TIAM1 misexpression correlated with actin organization and altered cytoskeletal morphology. Small molecule inhibitors of either small GTPase Rac1 or RhoA/ROCK signaling reversed TIAM1-induced morphology and differentiation in pericytes. In summary, our results demonstrate that TIAM1 regulates the cellular morphology and differentiation potential of human pericytes, representing a molecular switch between osteogenic and adipogenic cell fates.
Topics: Animals; Humans; Actins; Pericytes; Guanine Nucleotide Exchange Factors; Osteogenesis; Cell Differentiation; Adipose Tissue; T-Lymphoma Invasion and Metastasis-inducing Protein 1
PubMed: 37219951
DOI: 10.1172/jci.insight.159141 -
International Journal of Molecular... Mar 2023The brain needs sufficient oxygen in order to function normally. This is achieved by a large vascular capillary network ensuring that oxygen supply meets the changing... (Review)
Review
The brain needs sufficient oxygen in order to function normally. This is achieved by a large vascular capillary network ensuring that oxygen supply meets the changing demand of the brain tissue, especially in situations of hypoxia. Brain capillaries are formed by endothelial cells and perivascular pericytes, whereby pericytes in the brain have a particularly high 1:1 ratio to endothelial cells. Pericytes not only have a key location at the blood/brain interface, they also have multiple functions, for example, they maintain blood-brain barrier integrity, play an important role in angiogenesis and have large secretory abilities. This review is specifically focused on both the cellular and the molecular responses of brain pericytes to hypoxia. We discuss the immediate early molecular responses in pericytes, highlighting four transcription factors involved in regulating the majority of transcripts that change between hypoxic and normoxic pericytes and their potential functions. Whilst many hypoxic responses are controlled by hypoxia-inducible factors (HIF), we specifically focus on the role and functional implications of the regulator of G-protein signaling 5 (RGS5) in pericytes, a hypoxia-sensing protein that is regulated independently of HIF. Finally, we describe potential molecular targets of RGS5 in pericytes. These molecular events together contribute to the pericyte response to hypoxia, regulating survival, metabolism, inflammation and induction of angiogenesis.
Topics: Humans; Pericytes; Endothelial Cells; Brain; Hypoxia; Blood-Brain Barrier; Oxygen
PubMed: 36982744
DOI: 10.3390/ijms24065671 -
FEBS Open Bio Apr 2022As a potential source of myofibroblasts, pericytes may play a role in human peritoneal fibrosis. The culture of primary vascular pericytes in animals has previously been...
As a potential source of myofibroblasts, pericytes may play a role in human peritoneal fibrosis. The culture of primary vascular pericytes in animals has previously been reported, most of which are derived from cerebral and retinal microvasculature. Here, in the field of peritoneal dialysis, we describe a method to isolate and characterize mouse peritoneal microvascular pericytes. The mesenteric tissues of five mice were collected and digested by type II collagenase and type I DNase. After cell attachment, the culture fluid was replaced with pericyte-conditioned medium. Pericytes with high purity (99.0%) could be isolated by enzymatic disaggregation combined with conditional culture and magnetic activated cell sorting. The primary cells were triangular or polygonal with protrusions, and confluent cell culture could be established in 3 days. The primary pericytes were positive for platelet-derived growth factor receptor-β, α-smooth muscle actin, neuron-glial antigen 2, and CD13. Moreover, they promoted formation of endothelial tubes, and pericyte-myofibroblast transition occurred after treatment with transforming growth factor-β1. In summary, we describe here a reproducible isolation protocol for primary peritoneal pericytes, which may be a powerful tool for in vitro peritoneal fibrosis studies.
Topics: Animals; Mice; Myofibroblasts; Pericytes; Receptor, Platelet-Derived Growth Factor beta
PubMed: 35226797
DOI: 10.1002/2211-5463.13386 -
The Journal of Physiology Jun 2023The brain is an energetically demanding tissue which, to function adequately, requires constant fine tuning of its supporting blood flow, and hence energy supply. Whilst... (Review)
Review
The brain is an energetically demanding tissue which, to function adequately, requires constant fine tuning of its supporting blood flow, and hence energy supply. Whilst blood flow was traditionally believed to be regulated only by vascular smooth muscle cells on arteries and arterioles supplying the brain, recent work has suggested a critical role for capillary pericytes, which are also contractile. This concept has evoked some controversy, especially over the relative contributions of arterioles and capillaries to the control of cerebral blood flow. Here we outline why pericytes are in a privileged position to control cerebral blood flow. First we discuss the evidence, and fundamental equations, which describe how the small starting diameter of capillaries, compared to upstream arterioles, confers a potentially greater control by capillary pericytes than by arterioles over total cerebral vascular resistance. Then we suggest that the faster time frame over which low branch order capillary pericytes dilate in response to local energy demands provides a niche role for pericytes to regulate blood flow compared to slower responding arterioles. Finally, we discuss the role of pericytes in capillary stalling, whereby pericyte contraction appears to facilitate a transient stall of circulating blood cells, exacerbating the effect of pericytes upon cerebral blood flow.
Topics: Arterioles; Pericytes; Brain; Capillaries; Muscle Contraction
PubMed: 37036208
DOI: 10.1113/JP284207 -
Cells Sep 2022Angiogenesis is a vital endogenous brain self-repair processes for neurological recovery after intracerebral hemorrhage (ICH). Increasing evidence suggests that leptin...
Angiogenesis is a vital endogenous brain self-repair processes for neurological recovery after intracerebral hemorrhage (ICH). Increasing evidence suggests that leptin potentiates angiogenesis and plays a beneficial role in stroke. However, the proangiogenic effect of leptin on ICH has not been adequately explored. Moreover, leptin triggers post-ICH angiogenesis through pericyte, an important component of forming new blood vessels, which remains unclear. Here, we reported that exogenous leptin infusion dose-dependent promoted vascular endothelial cells survival and proliferation at chronic stage of ICH mice. Additionally, leptin robustly ameliorated pericytes loss, enhanced pericytes proliferation and migration in ICH mice in vivo, and in ICH human brain microvascular pericytes (HBVPC) in vitro. Notably, we showed that pericytes-derived pro-angiogenic factors were responsible for enhancing the survival, proliferation and tube formation followed leptin treatment in human brain microvascular endothelial cells (HCMEC/D3)/HBVPC co-culture models. Importantly, considerable improvements in neurobehavioral function and hostile microenvironment were observed in leptin treatment ICH mice, indicating that better vascular functionality post ICH improves outcome. Mechanistically, this study unveiled that leptin boost post-ICH angiogenesis potentially through modulation of leptin receptor (leptinR)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in pericyte. Thus, leptin may be a lucrative option for the treatment of ICH.
Topics: Animals; Cerebral Hemorrhage; Endothelial Cells; Humans; Leptin; Mice; Neovascularization, Physiologic; Pericytes; STAT3 Transcription Factor
PubMed: 36078162
DOI: 10.3390/cells11172755 -
American Journal of Physiology. Cell... Apr 2023Pericytes are mural cells that play an important role in regulation of angiogenesis and endothelial function. Cadherins are a superfamily of adhesion molecules mediating...
Pericytes are mural cells that play an important role in regulation of angiogenesis and endothelial function. Cadherins are a superfamily of adhesion molecules mediating Ca-dependent homophilic cell-cell interactions that control morphogenesis and tissue remodeling. To date, classical N-cadherin is the only cadherin described on pericytes. Here, we demonstrate that pericytes also express T-cadherin (H-cadherin, CDH13), an atypical glycosyl-phosphatidylinositol (GPI)-anchored member of the superfamily that has previously been implicated in regulation of neurite guidance, endothelial angiogenic behavior, and smooth muscle cell differentiation and progression of cardiovascular disease. The aim of the study was to investigate T-cadherin function in pericytes. Expression of T-cadherin in pericytes from different tissues was performed by immunofluorescence analysis. Using lentivirus-mediated gain-of-function and loss-of-function in cultured human pericytes, we demonstrate that T-cadherin regulates pericyte proliferation, migration, invasion, and interactions with endothelial cells during angiogenesis in vitro and in vivo. T-cadherin effects are associated with the reorganization of the cytoskeleton, modulation of cyclin D1, α-smooth muscle actin (αSMA), integrin β3, metalloprotease MMP1, and collagen expression levels, and involve Akt/GSK3β and ROCK intracellular signaling pathways. We also report the development of a novel multiwell 3-D microchannel slide for easy analysis of sprouting angiogenesis from a bioengineered microvessel in vitro. In conclusion, our data identify T-cadherin as a novel regulator of pericyte function and support that it is required for pericyte proliferation and invasion during active phase of angiogenesis, while T-cadherin loss shifts pericytes toward the myofibroblast state rendering them unable to control endothelial angiogenic behavior.
Topics: Humans; Pericytes; Endothelial Cells; Cadherins; Morphogenesis; Neovascularization, Physiologic
PubMed: 36802732
DOI: 10.1152/ajpcell.00326.2022 -
Genes Jan 2024Pericytes (PCs) are located surrounding the walls of small blood vessels, particularly capillaries and microvessels. In addition to their functions in maintaining... (Review)
Review
Pericytes (PCs) are located surrounding the walls of small blood vessels, particularly capillaries and microvessels. In addition to their functions in maintaining vascular integrity, participating in angiogenesis, and regulating blood flow, PCs also serve as a reservoir for multi-potent stem/progenitor cells in white, brown, beige, and bone marrow adipose tissues. Due to the complex nature of this cell population, the identification and characterization of PCs has been challenging. A comprehensive understanding of the heterogeneity of PCs may enhance their potential as therapeutic targets for metabolic syndromes or bone-related diseases. This mini-review summarizes multiple PC markers commonly employed in lineage-tracing studies, with an emphasis on their contribution to adipogenesis and functions in different adipose depots under diverse metabolic conditions.
Topics: Adipogenesis; Pericytes; Adipose Tissue; Stem Cells; Capillaries
PubMed: 38275607
DOI: 10.3390/genes15010126 -
Nature Communications Nov 2022Neutrophil diapedesis is an immediate step following infections and injury and is driven by complex interactions between leukocytes and various components of the blood...
Neutrophil diapedesis is an immediate step following infections and injury and is driven by complex interactions between leukocytes and various components of the blood vessel wall. Here, we show that perivascular mast cells (MC) are key regulators of neutrophil behaviour within the sub-endothelial space of inflamed venules. Using confocal intravital microscopy, we observe directed abluminal neutrophil motility along pericyte processes towards perivascular MCs, a response that created neutrophil extravasation hotspots. Conversely, MC-deficiency and pharmacological or genetic blockade of IL-17A leads to impaired neutrophil sub-endothelial migration and breaching of the pericyte layer. Mechanistically, identifying MCs as a significant cellular source of IL-17A, we establish that MC-derived IL-17A regulates the enrichment of key effector molecules ICAM-1 and CXCL1 in nearby pericytes. Collectively, we identify a novel MC-IL-17A-pericyte axis as modulator of the final steps of neutrophil diapedesis, with potential translational implications for inflammatory disorders driven by increased neutrophil diapedesis.
Topics: Transendothelial and Transepithelial Migration; Neutrophils; Pericytes; Interleukin-17; Mast Cells
PubMed: 36396641
DOI: 10.1038/s41467-022-34695-7 -
Scientific Reports Oct 2022Parkinson's disease (PD) is characterised by the progressive loss of midbrain dopaminergic neurons and the presence of aggregated α-synuclein (α-syn). Pericytes and...
Parkinson's disease (PD) is characterised by the progressive loss of midbrain dopaminergic neurons and the presence of aggregated α-synuclein (α-syn). Pericytes and microglia, two non-neuronal cells contain α-syn in the human brain, however, their role in disease processes is poorly understood. Pericytes, found surrounding the capillaries in the brain are important for maintaining the blood-brain barrier, controlling blood flow and mediating inflammation. In this study, primary human brain pericytes and microglia were exposed to two different α-synuclein aggregates. Inflammatory responses were assessed using immunocytochemistry, cytometric bead arrays and proteome profiler cytokine array kits. Fixed flow cytometry was used to investigate the uptake and subsequent degradation of α-syn in pericytes. We found that the two α-syn aggregates are devoid of inflammatory and cytotoxic actions on human brain derived pericytes and microglia. Although α-syn did not induce an inflammatory response, pericytes efficiently take up and degrade α-syn through the lysosomal pathway but not the ubiquitin-proteasome system. Furthermore, when pericytes were exposed the ubiquitin proteasome inhibitor-MG132 and α-syn aggregates, there was profound cytotoxicity through the production of reactive oxygen species resulting in apoptosis. These results suggest that the observed accumulation of α-syn in pericytes in human PD brains likely plays a role in PD pathogenesis, perhaps by causing cerebrovascular instability, under conditions of cellular stress.
Topics: Apoptosis; Cytokines; Humans; Parkinson Disease; Pericytes; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteome; Reactive Oxygen Species; Ubiquitin; alpha-Synuclein
PubMed: 36243723
DOI: 10.1038/s41598-022-20261-0 -
Science Signaling Mar 2022The dense network of capillaries composed of capillary endothelial cells (cECs) and pericytes lies in close proximity to all neurons, ideally positioning it to sense...
The dense network of capillaries composed of capillary endothelial cells (cECs) and pericytes lies in close proximity to all neurons, ideally positioning it to sense neuron- and glial-derived compounds that enhance regional and global cerebral perfusion. The membrane potential () of vascular cells serves as the physiological bridge that translates brain activity into vascular function. In other beds, the ATP-sensitive K (K) channel regulates in vascular smooth muscle, which is absent in the capillary network. Here, with transgenic mice that expressed a dominant-negative mutant of the pore-forming Kir6.1 subunit specifically in brain cECs or pericytes, we demonstrated that K channels were present in both cell types and robustly controlled . We further showed that the signaling nucleotide adenosine acted through A receptors and the Gα/cAMP/PKA pathway to activate capillary K channels. Moreover, K channel stimulation in vivo increased cerebral blood flow (CBF), an effect that was blunted by expression of the dominant-negative Kir6.1 mutant in either capillary cell type. These findings establish an important role for K channels in cECs and pericytes in the regulation of CBF.
Topics: Adenosine; Adenosine Triphosphate; Animals; Capillaries; Endothelial Cells; KATP Channels; Mice; Pericytes
PubMed: 35349300
DOI: 10.1126/scisignal.abl5405