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Methods in Molecular Biology (Clifton,... 2021Human pericytes are a perivascular cell population with mesenchymal stem cell properties, present in all vascularized tissues. Human pericytes have a distinct... (Review)
Review
Human pericytes are a perivascular cell population with mesenchymal stem cell properties, present in all vascularized tissues. Human pericytes have a distinct immunoprofile, which may be leveraged for purposes of cell purification. Adipose tissue is the most commonly used cell source for human pericyte derivation. Pericytes can be isolated by FACS (fluorescence-activated cell sorting), most commonly procured from liposuction aspirates. Pericytes have clonal multilineage differentiation potential, and their potential utility for bone regeneration has been described across multiple animal models. The following review will discuss in vivo methods for assessing the bone-forming potential of purified pericytes. Potential models include (1) mouse intramuscular implantation, (2) mouse calvarial defect implantation, and (3) rat spinal fusion models. In addition, the presented surgical protocols may be used for the in vivo analysis of other osteoprogenitor cell types.
Topics: Adipose Tissue; Animals; Bone Marrow Cells; Bone Regeneration; Cell Differentiation; Cell Line; Cell Separation; Humans; Mesenchymal Stem Cells; Mice; Osteogenesis; Pericytes; Rats; Tissue Engineering
PubMed: 33576974
DOI: 10.1007/978-1-0716-1056-5_9 -
International Journal of Cancer Aug 2016The conventional view of tumour vascularization is that tumours acquire their blood supply from neighbouring normal stroma. Additional methods of tumour vascularization... (Review)
Review
The conventional view of tumour vascularization is that tumours acquire their blood supply from neighbouring normal stroma. Additional methods of tumour vascularization such as intussusceptive angiogenesis, vasculogenic mimicry, vessel co-option and vasculogenesis have been demonstrated to occur. However, the origin of the endothelial cells and pericytes in the tumour vasculature is not fully understood. Their origin from malignant cells has been shown indirectly in lymphoma and neuroblastoma by immuno-FISH experiments. It is now evident that tumours arise from a small population of cells called cancer stem cells (CSCs) or tumour initiating cells. Recent data suggest that a proportion of tumour endothelial cells arise from cancer stem cells in glioblastoma. This was demonstrated both in vitro and in vivo. The analysis of chromosomal abnormalities in endothelial cells showed identical genetic changes to those identified in tumour cells. However, another report contradicted these results from the earlier studies in glioblastoma and had shown that CSCs give rise to pericytes and not endothelial cells. The main thrust of this review is the critical analysis of the conflicting data from different studies and the remaining questions in this field of research. The mechanism by which this phenomenon occurs is also discussed in detail. The transdifferentiation of CSCs to endothelial cells/pericytes has many implications in the progression and metastasis of the tumours and hence it would be a novel target for antiangiogenic therapy.
Topics: Animals; Biomarkers; Cell Communication; Cell Transdifferentiation; Cell Transformation, Neoplastic; Endothelial Cells; Humans; Neoplasms; Neoplastic Stem Cells; Neovascularization, Pathologic; Pericytes; Signal Transduction
PubMed: 26934471
DOI: 10.1002/ijc.30067 -
Cell Reports Aug 2023Circular RNAs are generated by backsplicing and control cellular signaling and phenotypes. Pericytes stabilize capillary structures and play important roles in the...
Circular RNAs are generated by backsplicing and control cellular signaling and phenotypes. Pericytes stabilize capillary structures and play important roles in the formation and maintenance of blood vessels. Here, we characterize hypoxia-regulated circular RNAs (circRNAs) in human pericytes and show that the circular RNA of procollagen-lysine,2-oxoglutarate 5-dioxygenase-2 (circPLOD2) is induced by hypoxia and regulates pericyte functions. Silencing of circPLOD2 affects pericytes and increases proliferation, migration, and secretion of soluble angiogenic proteins, thereby enhancing endothelial migration and network capability. Transcriptional and epigenomic profiling of circPLOD2-depleted cells reveals widespread changes in gene expression and identifies the transcription factor krüppel-like factor 4 (KLF4) as a key effector of the circPLOD2-mediated changes. KLF4 depletion mimics circPLOD2 silencing, whereas KLF4 overexpression reverses the effects of circPLOD2 depletion on proliferation and endothelial-pericyte interactions. Together, these data reveal an important function of circPLOD2 in controlling pericyte proliferation and capillary formation and show that the circPLOD2-mediated regulation of KLF4 significantly contributes to the transcriptional response to hypoxia.
Topics: Humans; Hypoxia; Pericytes; RNA, Circular
PubMed: 37481725
DOI: 10.1016/j.celrep.2023.112824 -
Tissue Engineering. Part B, Reviews Feb 2022For the survival and integration of complex large-sized tissue-engineered (TE) organ constructs that exceed the maximal nutrients and oxygen diffusion distance required... (Review)
Review
For the survival and integration of complex large-sized tissue-engineered (TE) organ constructs that exceed the maximal nutrients and oxygen diffusion distance required for cell survival, graft (pre)vascularization to ensure medium or blood supply is crucial. To achieve this, the morphology and functionality of the microcapillary bed should be mimicked by incorporating vascular cell populations, including endothelium and mural cells. Pericytes play a crucial role in microvascular function, blood vessel stability, angiogenesis, and blood pressure regulation. In addition, tissue-specific pericytes are important in maintaining specific functions in different organs, including vitamin A storage in the liver, renin production in the kidneys and maintenance of the blood-brain-barrier. Together with their multipotential differentiation capacity, this makes pericytes the preferred cell type for application in TE grafts. The use of a tissue-specific pericyte cell population that matches the TE organ may benefit organ function. In this review, we provide an overview of the literature for graft (pre)-vascularization strategies and highlight the possible advantages of using tissue-specific pericytes for specific TE organ grafts. Impact statement The use of a tissue-specific pericyte cell population that matches the tissue-engineered (TE) organ may benefit organ function. In this review, we provide an overview of the literature for graft (pre)vascularization strategies and highlight the possible advantages of using tissue-specific pericytes for specific TE organ grafts.
Topics: Cell Differentiation; Humans; Neovascularization, Pathologic; Pericytes; Tissue Engineering
PubMed: 33231500
DOI: 10.1089/ten.TEB.2020.0229 -
Journal of Cerebral Blood Flow and... Jun 2024The blood-brain barrier (BBB) is a complex and dynamic interface that regulates the exchange of molecules and cells between the blood and the central nervous system. It... (Review)
Review
The blood-brain barrier (BBB) is a complex and dynamic interface that regulates the exchange of molecules and cells between the blood and the central nervous system. It undergoes structural and functional changes during aging, which may compromise its integrity and contribute to the pathogenesis of neurodegenerative diseases. In recent years, advances in microscopy and high-throughput bioinformatics have allowed a more in-depth investigation of the aging mechanisms of BBB. This review summarizes age-related alterations of the BBB structure and function from six perspectives: endothelial cells, astrocytes, pericytes, basement membrane, microglia and perivascular macrophages, and fibroblasts, ranging from the molecular level to the human multi-system level. These basic components are essential for the proper functioning of the BBB. Recent imaging methods of BBB were also reviewed. Elucidation of age-associated BBB changes may offer insights into BBB homeostasis and may provide effective therapeutic strategies to protect it during aging.
Topics: Blood-Brain Barrier; Humans; Aging; Animals; Endothelial Cells; Pericytes; Astrocytes
PubMed: 38513138
DOI: 10.1177/0271678X241240843 -
Trends in Pharmacological Sciences Mar 2017Brain pericytes are perivascular cells that regulate capillary function, and this localization puts them in a pivotal position for the regulation of central nervous... (Review)
Review
Brain pericytes are perivascular cells that regulate capillary function, and this localization puts them in a pivotal position for the regulation of central nervous system (CNS) inflammatory responses at the neurovascular unit. Neuroinflammation, driven by microglia and astrocytes or resulting from peripheral leukocyte infiltration, has both homeostatic and detrimental consequences for brain function and is present in nearly every neurological disorder. More recently, brain pericytes have been shown to have many properties of immune regulating cells, including responding to and expressing a plethora of inflammatory molecules, presenting antigen, and displaying phagocytic ability. In this review we highlight the emerging role of pericytes in neuroinflammation and discuss pericyte-mediated neuroinflammation as a potential therapeutic target for the treatment of a range of devastating brain disorders.
Topics: Animals; Brain; Encephalitis; Humans; Pericytes
PubMed: 28017362
DOI: 10.1016/j.tips.2016.12.001 -
Neuroscience Bulletin Jun 2019Cerebral pericytes are perivascular cells that stabilize blood vessels. Little is known about the plasticity of pericytes in the adult brain in vivo. Recently, using... (Review)
Review
Cerebral pericytes are perivascular cells that stabilize blood vessels. Little is known about the plasticity of pericytes in the adult brain in vivo. Recently, using state-of-the-art technologies, including two-photon microscopy in combination with sophisticated Cre/loxP in vivo tracing techniques, a novel role of pericytes was revealed in vascular remodeling in the adult brain. Strikingly, after pericyte ablation, neighboring pericytes expand their processes and prevent vascular dilatation. This new knowledge provides insights into pericyte plasticity in the adult brain.
Topics: Animals; Brain; Brain Diseases; Capillaries; Cellular Microenvironment; Diabetic Retinopathy; Endothelial Cells; Humans; Pericytes; Vascular Remodeling
PubMed: 30367336
DOI: 10.1007/s12264-018-0296-5 -
Advances in Experimental Medicine and... 2018Pericytes wrap blood microvessels and are believed to play important roles in vascular morphogenesis, maturation, and stability. In addition, pericytes have emerged as... (Review)
Review
Pericytes wrap blood microvessels and are believed to play important roles in vascular morphogenesis, maturation, and stability. In addition, pericytes have emerged as candidates for targeting cancer growth and for wound healing. In order to model these processes and test new therapies, it is desirable to have a reliable, scalable source of pericytes. Human pluripotent stem cells (hPSCs), which possess the ability to differentiate into any cell type in the body, have been used to generate pericytes in vitro quickly, consistently, and with high yields. In this chapter, we consider the differentiation of pericytes from hPSCs. We compare the approaches taken by multiple groups and discuss characterization of hPSC-pericytes. Studying pericyte differentiation in vitro provides the opportunity to identify factors influencing pericyte development and to establish the ontogenic relationships between pericytes and similar cells. The development of highly specific, defined pericyte populations from hPSCs will enable downstream applications requiring large quantities of cells, including tissue engineered models and cell therapies.
Topics: Cell Differentiation; Humans; Microvessels; Pericytes; Pluripotent Stem Cells
PubMed: 30523593
DOI: 10.1007/978-3-030-02601-1_9 -
Brain : a Journal of Neurology Mar 2024Incomplete reperfusion of the microvasculature ('no-reflow') after ischaemic stroke damages salvageable brain tissue. Previous ex vivo studies suggest pericytes are...
Incomplete reperfusion of the microvasculature ('no-reflow') after ischaemic stroke damages salvageable brain tissue. Previous ex vivo studies suggest pericytes are vulnerable to ischaemia and may exacerbate no-reflow, but the viability of pericytes and their association with no-reflow remains under-explored in vivo. Using longitudinal in vivo two-photon single-cell imaging over 7 days, we showed that 87% of pericytes constrict during cerebral ischaemia and remain constricted post reperfusion, and 50% of the pericyte population are acutely damaged. Moreover, we revealed ischaemic pericytes to be fundamentally implicated in capillary no-reflow by limiting and arresting blood flow within the first 24 h post stroke. Despite sustaining acute membrane damage, we observed that over half of all cortical pericytes survived ischaemia and responded to vasoactive stimuli, upregulated unique transcriptomic profiles and replicated. Finally, we demonstrated the delayed recovery of capillary diameter by ischaemic pericytes after reperfusion predicted vessel reconstriction in the subacute phase of stroke. Cumulatively, these findings demonstrate that surviving cortical pericytes remain both viable and promising therapeutic targets to counteract no-reflow after ischaemic stroke.
Topics: Humans; Stroke; Pericytes; Brain Ischemia; Ischemic Stroke; Cerebral Infarction
PubMed: 38153327
DOI: 10.1093/brain/awad401 -
Arteriosclerosis, Thrombosis, and... Oct 2023The differentiation of pericytes into myofibroblasts causes microvascular degeneration, ECM (extracellular matrix) accumulation, and tissue stiffening, characteristics...
BACKGROUND
The differentiation of pericytes into myofibroblasts causes microvascular degeneration, ECM (extracellular matrix) accumulation, and tissue stiffening, characteristics of fibrotic diseases. It is unclear how pericyte-myofibroblast differentiation is regulated in the microvascular environment. Our previous study established a novel 2-dimensional platform for coculturing microvascular endothelial cells (ECs) and pericytes derived from the same tissue. This study investigated how ECM stiffness regulated microvascular ECs, pericytes, and their interactions.
METHODS
Primary microvessels were cultured in the TGM2D medium (tubular microvascular growth medium on 2-dimensional substrates). Stiff ECM was prepared by incubating ECM solution in regular culture dishes for 1 hour followed by PBS wash. Soft ECM with Young modulus of ≈6 kPa was used unless otherwise noted. Bone grafts were prepared from the rat skull. Immunostaining, RNA sequencing, RT-qPCR (real-time quantitative polymerase chain reaction), Western blotting, and knockdown experiments were performed on the cells.
RESULTS
Primary microvascular pericytes differentiated into myofibroblasts (NG2αSMA) on stiff ECM, even with the TGFβ (transforming growth factor beta) signaling inhibitor A83-01. Soft ECM and A83-01 cooperatively maintained microvascular stability while inhibiting pericyte-myofibroblast differentiation (NG2αSMA). We thus defined 2 pericyte subpopulations: primary (NG2αSMA) and activated (NG2αSMA) pericytes. Soft ECM promoted microvascular regeneration and inhibited fibrosis in bone graft transplantation in vivo. As integrins are the major mechanosensor, we performed RT-qPCR screening of integrin family members and found Itgb1 (integrin β1) was the major subunit downregulated by soft ECM and A83-01 treatment. Knocking down suppressed myofibroblast differentiation on stiff ECM. Interestingly, ITGB1 phosphorylation (Y783) was mainly located on microvascular ECs on stiff ECM, which promoted EC secretion of paracrine factors, including CTGF (connective tissue growth factor), to induce pericyte-myofibroblast differentiation. CTGF knockdown or monoclonal antibody treatment partially reduced myofibroblast differentiation, implying the participation of multiple pathways in fibrosis formation.
CONCLUSIONS
ECM stiffness and TGFβ signaling cooperatively regulate microvascular stability and pericyte-myofibroblast differentiation. Stiff ECM promotes EC ITGB1 phosphorylation (Y783) and CTGF secretion, which induces pericyte-myofibroblast differentiation.
Topics: Rats; Animals; Pericytes; Paracrine Communication; Endothelial Cells; Cells, Cultured; Transforming Growth Factor beta; Fibrosis; Extracellular Matrix; Myofibroblasts
PubMed: 37650330
DOI: 10.1161/ATVBAHA.123.319119