Research advances in pericyte function and their roles in diseases

Zhang, Zisen; Zhou, Henan; He, Shuangshuang; Xue, Mingying; Li, Tao; Liu, Liangming

doi:10.1016/j.cjtee.2020.02.006

Cited by 43 publications

(71 citation statements)

References 89 publications

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“…As the ratio of PCs to ECs can vary greatly according to different locations and sources even within the brain [ 3 , 4 , 22 ], barrier function was assessed using different ratios of PCs to ECs (1:1, 1:2 and 1:4), all of which increased the barrier function to a similar extent ( Supplementary Figure S2 ). In subsequent experiments, a ratio of 1:4 (PCs:ECs) was used.…”

Section: Resultsmentioning

confidence: 99%

“…Apart from PC depletion, disturbed signaling between ECs and PCs contributes to barrier leakage and disease states. Communication between the two cell types is known to occur via paracrine signaling involving a plethora of soluble factors, but also direct cell-to-cell contacts in form of so-called peg-socket interactions, gap junctions and adhesion plaques play a significant role [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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Transcryptomic Analysis of Human Brain-Microvascular Endothelial Response to -Pericytes: Cell Orientation Defines Barrier Function

Kurmann

Okoniewski

Ogunshola

et al. 2021

Cells

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Pericytes facilitate blood–brain barrier (BBB) integrity; however, the mechanisms involved remain unclear. Hence, using co-cultures of human cerebral microvascular endothelial cells (ECs) and vascular pericytes (PCs) in different spatial arrangements, as well as PC conditioned media, we investigated the impact of PC-EC orientation and PC-derived soluble factors on EC barrier function. We provide the first evidence that barrier-inducing properties of PCs require basolateral contact with ECs. Gene expression analysis (GEA) in ECs co-cultured with PCs versus ECs alone showed significant upregulation of 38 genes and downregulation of 122 genes. Pathway enrichment analysis of modulated genes showed significant regulation of several pathways, including transforming growth factor-β and interleukin-1 regulated extracellular matrix, interferon and interleukin signaling, immune system signaling, receptor of advanced glycation end products (RAGE), and cytokine–cytokine receptor interaction. Transcriptomic analysis showed a reduction in molecules such as pro-inflammatory cytokines and chemokines, which are known to be induced during BBB disruption. Moreover, cytokine proteome array confirmed the downregulation of key pro-inflammatory cytokines and chemokines on the protein level. Other molecules which influence BBB and were favorably modulated upon EC-PC co-culture include IL-18 binding protein, kallikrein-3, CSF2 CSF3, CXCL10, CXCL11 (downregulated) and IL-1-R4; HGF, PDGF-AB/BB, PECAM, SERPIN E1 (upregulated). In conclusion, we provide the first evidence that (1) basolateral contact between ECs and PCs is essential for EC barrier function and integrity; (2) in ECs co-cultured with PCs, the profile of BBB disrupting pro-inflammatory molecules and cytokines/chemokines is downregulated; (3) PCs significantly modulate EC mechanisms known to improve barrier function, including TGF-β regulated ECM pathway, anti-inflammatory cytokines, growth factors and matrix proteins. This human PC-EC co-culture may serve as a viable in vitro model for investigating BBB function and drug transport.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcryptomic Analysis of Human Brain-Microvascular Endothelial Response to -Pericytes: Cell Orientation Defines Barrier Function

Kurmann

Okoniewski

Ogunshola

et al. 2021

Cells

View full text Add to dashboard Cite

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“…However, it should be noted that the tube formation assay does not reflect the physiological situation in vivo, in which blood vessels are embedded in the stabilizing ECM. In addition, the pericytes are not capable of forming spheroidal structures in vivo, hence ratios of pericytes to endothelial cells from 1:1 to 1:100 can be found depending on the tissue [44].…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase CK2 Regulates Nerve/Glial Antigen (NG)2-Mediated Angiogenic Activity of Human Pericytes

Schmitt

Boewe

Becker

et al. 2020

Cells

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Protein kinase CK2 is a crucial regulator of endothelial cell proliferation, migration and sprouting during angiogenesis. However, it is still unknown whether this kinase additionally affects the angiogenic activity of other vessel-associated cells. In this study, we investigated the effect of CK2 inhibition on primary human pericytes. We found that CK2 inhibition reduces the expression of nerve/glial antigen (NG)2, a crucial factor which is involved in angiogenic processes. Reporter gene assays revealed a 114 bp transcriptional active region of the human NG2 promoter, whose activity was decreased after CK2 inhibition. Functional analyses demonstrated that the pharmacological inhibition of CK2 by CX-4945 suppresses pericyte proliferation, migration, spheroid sprouting and the stabilization of endothelial tubes. Moreover, aortic rings of NG2−/− mice showed a significantly reduced vascular sprouting when compared to rings of NG2+/+ mice, indicating that NG2 is an important regulator of the angiogenic activity of pericytes. In vivo, implanted Matrigel plugs containing CX-4945-treated pericytes exhibited a lower microvessel density when compared to controls. These findings demonstrate that CK2 regulates the angiogenic activity of pericytes through NG2 gene expression. Hence, the inhibition of CK2 represents a promising anti-angiogenic strategy, because it does not only target endothelial cells, but also vessel-associated pericytes.

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“…RNA-seq studies have also investigated PCs and their possible role in NVU heterogeneity [28,35,36]. Therefore, if it is correct to consider CNS PCs as motile, contractile cells, as proposed in Rouget's original description [1], it is also true that heterogeneity and multitasking aptitude of PCs have already been pointed out [36][37][38][39][40][41][42][43][44]. Different subclasses of PCs along the capillary bed and in specific developmental and pathological conditions have been identified [13,45].…”

Section: Pluripotency and Heterogeneity Of Pericytesmentioning

confidence: 99%

Neural crest cell-derived pericytes act as pro-angiogenic cells in human neocortex development and gliomas

Girolamo

Trizio

Errede

et al. 2021

Fluids Barriers CNS

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Central nervous system diseases involving the parenchymal microvessels are frequently associated with a ‘microvasculopathy’, which includes different levels of neurovascular unit (NVU) dysfunction, including blood–brain barrier alterations. To contribute to the understanding of NVU responses to pathological noxae, we have focused on one of its cellular components, the microvascular pericytes, highlighting unique features of brain pericytes with the aid of the analyses carried out during vascularization of human developing neocortex and in human gliomas. Thanks to their position, centred within the endothelial/glial partition of the vessel basal lamina and therefore inserted between endothelial cells and the perivascular and vessel-associated components (astrocytes, oligodendrocyte precursor cells (OPCs)/NG2-glia, microglia, macrophages, nerve terminals), pericytes fulfil a central role within the microvessel NVU. Indeed, at this critical site, pericytes have a number of direct and extracellular matrix molecule- and soluble factor-mediated functions, displaying marked phenotypical and functional heterogeneity and carrying out multitasking services. This pericytes heterogeneity is primarily linked to their position in specific tissue and organ microenvironments and, most importantly, to their ontogeny. During ontogenesis, pericyte subtypes belong to two main embryonic germ layers, mesoderm and (neuro)ectoderm, and are therefore expected to be found in organs ontogenetically different, nonetheless, pericytes of different origin may converge and colonize neighbouring areas of the same organ/apparatus. Here, we provide a brief overview of the unusual roles played by forebrain pericytes in the processes of angiogenesis and barriergenesis by virtue of their origin from midbrain neural crest stem cells. A better knowledge of the ontogenetic subpopulations may support the understanding of specific interactions and mechanisms involved in pericyte function/dysfunction, including normal and pathological angiogenesis, thereby offering an alternative perspective on cell subtype-specific therapeutic approaches.

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Research advances in pericyte function and their roles in diseases

Cited by 43 publications

References 89 publications

Transcryptomic Analysis of Human Brain-Microvascular Endothelial Response to -Pericytes: Cell Orientation Defines Barrier Function

Transcryptomic Analysis of Human Brain-Microvascular Endothelial Response to -Pericytes: Cell Orientation Defines Barrier Function

Protein Kinase CK2 Regulates Nerve/Glial Antigen (NG)2-Mediated Angiogenic Activity of Human Pericytes

Neural crest cell-derived pericytes act as pro-angiogenic cells in human neocortex development and gliomas

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