Peripheral Nerve Pericytes Modify the Blood-Nerve Barrier Function and Tight Junctional Molecules Through the Secretion of Various Soluble Factors
ABSTRACT 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.
Full-textDOI: · Available from: Tetsuya Terasaki, Jul 17, 2015
- SourceAvailable from: Alexander Birbrair
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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. "
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.Frontiers in Aging Neuroscience 09/2014; 6:245. DOI:10.3389/fnagi.2014.00245 · 2.84 Impact Factor
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- "Yosef et al. reported that primary human PnMECs have higher TEER values than FH-BNBs (Yosef et al., 2010). However, these primary cells inevitably contained a small amount of pericytes, which have been reported to promote barrier integrity of the barrier-derived endothelial cells (Shimizu et al., 2011). "
ABSTRACT: The blood-nerve barrier (BNB) is a highly specialized unit that maintains the microenvironments of the peripheral nervous system. Since the breakdown of the BNB has been considered a key step in autoimmune neuropathies such as Guillain-Barré syndrome and chronic inflammatory demyelinating polyraduculoneuropathy, it is important to understand the cellular properties of the peripheral nerve microvascular endothelial cells (PnMECs) which constitute the BNB. For this purpose, we established an immortalized cell line derived from human PnMECs. The human PnMECs were transduced with retroviral vectors encoding the temperature-sensitive SV40 large T antigen and human telomerase. This cell line, termed FH-BNB, showed a spindle fiber-shaped morphology, expression of von Willebrand factor and uptake of acetylated low density lipoprotein. These cells expressed tight junction proteins including occludin, claudin-5, ZO-1 and ZO-2 at the cell-cell boundaries. P-glycoprotein and GLUT-1 were also detected by a Western blot analysis and the cells exhibited the functional expression of p-glycoprotein. In addition, transendothelial electrical resistance experiments and paracellular permeabilities of sodium fluorescein and fluorescein isothiocyanate-labeled dextran of molecular weight 4 kDa across these cells demonstrated that FH-BNBs had functional tight junctions. These results indicated that FH-BNBs had highly specialized barrier properties and they might therefore be a useful tool to analyze the pathophysiology of various neuropathies.Cell Structure and Function 05/2012; 37(2):89-100. DOI:10.1247/csf.11042 · 2.35 Impact Factor
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- "In our study, Meox2 +/À mice with normal pericyte coverage and an intact BBB, but with a substantial perfusion deficit (Wu et al., 2005) comparable to that in pericyte-deficient mice, showed less pronounced changes in neuronal structure than pericyte-deficient mice, indicating that chronic perfusion alone can cause neuronal injury but not to the extent as when combined with the BBB breakdown. Recent findings have suggested that cultured human brain pericytes express low but comparable levels of neurotrophic factors as cultured astrocytes (Shimizu et al., 2010). Given that the expression and role of pericyte-derived neurotrophic factors in brain in vivo have not been demonstrated and that pericytes do not make direct contacts with neurons (in contrast to astrocytes) (Zlokovic, 2008), it is unclear at present whether pericyte degeneration can increase neuronal susceptibility to injury through diminished neurotrophic support. "
ABSTRACT: Pericytes play a key role in the development of cerebral microcirculation. The exact role of pericytes in the neurovascular unit in the adult brain and during brain aging remains, however, elusive. Using adult viable pericyte-deficient mice, we show that pericyte loss leads to brain vascular damage by two parallel pathways: (1) reduction in brain microcirculation causing diminished brain capillary perfusion, cerebral blood flow, and cerebral blood flow responses to brain activation that ultimately mediates chronic perfusion stress and hypoxia, and (2) blood-brain barrier breakdown associated with brain accumulation of serum proteins and several vasculotoxic and/or neurotoxic macromolecules ultimately leading to secondary neuronal degenerative changes. We show that age-dependent vascular damage in pericyte-deficient mice precedes neuronal degenerative changes, learning and memory impairment, and the neuroinflammatory response. Thus, pericytes control key neurovascular functions that are necessary for proper neuronal structure and function, and pericyte loss results in a progressive age-dependent vascular-mediated neurodegeneration.Neuron 11/2010; 68(3):409-27. DOI:10.1016/j.neuron.2010.09.043 · 15.98 Impact Factor