Peripheral Nerve Pericytes Modify the Blood-Nerve Barrier Function and Tight Junctional Molecules Through the Secretion of Various Soluble Factors

Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
Journal of Cellular Physiology (Impact Factor: 3.84). 01/2011; 226(1):255-66. DOI: 10.1002/jcp.22337
Source: PubMed


The objectives of this study were to establish pure blood-nerve barrier (BNB) and blood-brain barrier (BBB)-derived pericyte cell lines of human origin and to investigate their unique properties as barrier-forming cells. Brain and peripheral nerve pericyte cell lines were established via transfection with retrovirus vectors incorporating human temperature-sensitive SV40 T antigen (tsA58) and telomerase. These cell lines expressed several pericyte markers such as α-smooth muscle actin, NG2, platelet-derived growth factor receptor β, whereas they did not express endothelial cell markers such as vWF and PECAM. In addition, the inulin clearance was significantly lowered in peripheral nerve microvascular endothelial cells (PnMECs) through the up-regulation of claudin-5 by soluble factors released from brain or peripheral nerve pericytes. In particular, bFGF secreted from peripheral nerve pericytes strengthened the barrier function of the BNB by increasing the expression of claudin-5. Peripheral nerve pericytes may regulate the barrier function of the BNB, because the BNB does not contain cells equivalent to astrocytes which regulate the BBB function. Furthermore, these cell lines expressed several neurotrophic factors such as NGF, BDNF, and GDNF. The secretion of these growth factors from peripheral nerve pericytes might facilitate axonal regeneration in peripheral neuropathy. Investigation of the characteristics of peripheral nerve pericytes may provide novel strategies for modifying BNB functions and promoting peripheral nerve regeneration.

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Available from: Tetsuya Terasaki, Jul 17, 2015
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    • "Again, whether selective ablation of pericytes from skeletal muscle will prevent or otherwise affect regeneration will clarify whether they can be replaced by other cell types with myogenic capacity. We propose that due to their ability to secrete several growth factors, pericytes may be required to induce other cell types to adopt a myogenic fate (Sato and Rifkin, 1989; Shepro and Morel, 1993; Davis et al., 1996; Yamagishi et al., 1999; Brown et al., 2001; Reinmuth et al., 2001; Hirschi et al., 2003; Niimi, 2003; Armulik et al., 2005; Paquet- Fifield et al., 2009; Shimizu et al., 2011). A global analysis of candidate growth factors secreted by skeletal muscle pericytes that promote skeletal muscle regeneration is required. "
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    ABSTRACT: Pericytes are perivascular cells that envelop and make intimate connections with adjacent capillary endothelial cells. Recent studies show that they may have a profound impact in skeletal muscle regeneration, innervation, vessel formation, fibrosis, fat accumulation, and ectopic bone formation throughout life. In this review, we summarize and evaluate recent advances in our understanding of pericytes' influence on adult skeletal muscle pathophysiology. We also discuss how further elucidating their biology may offer new approaches to the treatment of conditions characterized by muscle wasting.
    Full-text · Article · Sep 2014 · Frontiers in Aging Neuroscience
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    • "We have shown that αSMA positive pericytes secrete chemokines and cytokines into media in response to pro-inflammatory cues in the absence of microglia or astrocytes. Other groups have also shown that pericytes can secrete factors that are essential for proper BBB functioning and can affect gene and protein expression in surrounding endothelial cells [78,79]. Co-culture studies of brain pericytes and endothelial cells indicate an important role in maintenance of hemostasis as well as BBB permeability to pathogens, such as HIV-1, in human and mouse cells, respectively [80,81]. "
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    ABSTRACT: Background Brain inflammation plays a key role in neurological disease. Although much research has been conducted investigating inflammatory events in animal models, potential differences in human brain versus rodent models makes it imperative that we also study these phenomena in human cells and tissue. Methods Primary human brain cell cultures were generated from biopsy tissue of patients undergoing surgery for drug-resistant epilepsy. Cells were treated with pro-inflammatory compounds IFNγ, TNFα, IL-1β, and LPS, and chemokines IP-10 and MCP-1 were measured by immunocytochemistry, western blot, and qRT-PCR. Microarray analysis was also performed on late passage cultures treated with vehicle or IFNγ and IL-1β. Results Early passage human brain cell cultures were a mixture of microglia, astrocytes, fibroblasts and pericytes. Later passage cultures contained proliferating fibroblasts and pericytes only. Under basal culture conditions all cell types showed cytoplasmic NFκB indicating that they were in a non-activated state. Expression of IP-10 and MCP-1 were significantly increased in response to pro-inflammatory stimuli. The two chemokines were expressed in mixed cultures as well as cultures of fibroblasts and pericytes only. The expression of IP-10 and MCP-1 were regulated at the mRNA and protein level, and both were secreted into cell culture media. NFκB nuclear translocation was also detected in response to pro-inflammatory cues (except IFNγ) in all cell types. Microarray analysis of brain pericytes also revealed widespread changes in gene expression in response to the combination of IFNγ and IL-1β treatment including interleukins, chemokines, cellular adhesion molecules and much more. Conclusions Adult human brain cells are sensitive to cytokine challenge. As expected ‘classical’ brain immune cells, such as microglia and astrocytes, responded to cytokine challenge but of even more interest, brain pericytes also responded to such challenge with a rich repertoire of gene expression. Immune activation of brain pericytes may play an important role in communicating inflammatory signals to and within the brain interior and may also be involved in blood brain barrier (BBB) disruption . Targeting brain pericytes, as well as microglia and astrocytes, may provide novel opportunities for reducing brain inflammation and maintaining BBB function and brain homeostasis in human brain disease.
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    • "Rare pathological studies have reported perivascular lymphocytic infiltration in the endoneurial microvessels of the BNB [9–12]. The presence of circulating cytokines, such as VEGF, TNF-α, and IL-1β, appears to be linked to dysfunction of the BNB in MMN patients [37]. A recent study using an in vitro BNB model, consisting of conditionally immortalised human BNB-derived endothelial cells, has suggested that VEGF is the main effector molecule linked to the pathogenesis of the BNB breakdown [38]. "
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    ABSTRACT: Multifocal motor neuropathy (MMN) is a rare inflammatory neuropathy characterized by progressive, asymmetric distal limb weakness and conduction block (CB). Clinically MMN is a pure motor neuropathy, which as such can mimic motor neuron disease. GM1-specific IgM antibodies are present in the serum of approximately half of all MMN patients, and are thought to play a key role in the immune pathophysiology. Intravenous immunoglobulin (IVIg) treatment has been shown to be effective in MMN in five randomized placebo-controlled trials. Despite long-term treatment with intravenous immunoglobulin (IVIg), which is efficient in the majority of patients, slowly progressive axonal degeneration and subsequent muscle weakness cannot be fully prevented. In this review, we will discuss the current understanding of the immune pathogenesis underlying MMN and how this may cause CB, available treatment strategies and future therapeutic targets.
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