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.

Advanced glycation end-products induce basement membrane hypertrophy in endoneurial microvessels and disrupt the blood–nerve barrier by stimulating the release of TGF-β and vascular endothelial growth factor (VEGF) by pericytes

“…The level of the receptor of AGE (RAGE) in peripheral nerve pericytes was observed to increase significantly after incubation with AGEs in a dose-dependent manner (Table 1). We previously reported that our peripheral nerve pericytes released several growth factors, including VEGF, TGF-β and bFGF, to maintain peripheral nerve homeostasis at the BNB [15]. We also quantified the change of these growth factors in peripheral nerve pericytes after incubation with AGEs (100 and 200 μg/ml) by a western blot analysis (Fig.…”

“…We have successfully established PnMEC and peripheral nerve pericyte cell lines of human origin [15,16]. Therefore, our in vitro BNB model is considered suitable for the analysis of the production of basement-membrane-related molecules, because it is difficult to identify cells that synthesise these molecules in vivo.…”

“…Cell culture The immortalised human PnMECs, and brain and peripheral nerve pericyte cell lines were generated as described previously by our group [15,16]. The study protocol for human tissue was approved by the ethics committee of the Medical Faculty, University of Yamaguchi Graduate School, and was conducted in accordance with the Declaration of Helsinki, as amended in Somerset West in 1996.…”

Pericyte-derived Glial Cell Line-derived Neurotrophic Factor Increase the Expression of Claudin-5 in the Blood–brain Barrier and the Blood-nerve Barrier

“…The BBB is comprised of brain microvascular endothelial cells (BMECs), astrocytes and pericytes of microvascular origin, whereas the BNB comprises peripheral nerve microvascular endothelial cells (PnMECs) and pericytes of endoneurial microvascular origin [1,3]. Astrocytes have been demonstrated to strengthen the barrier function of the BBB via their secretion of soluble factors, as demonstrated in in vitro BBB models [4,5], although pericytes have also been shown to have this effect in in vitro BBB and BNB models [6,7]). …”

Neuron-Derived Semaphorin 3A is an Early Inducer of Vascular Permeability in Diabetic Retinopathy

“…Pericyte involvement has also been suggested in the development of peripheral neuropathy, since these cells contribute to the strengthening of the BNB through the secretion of growth factors such as basic fibroblast growth factor (bFGF), which upregulate tight junction claudin-5 expression in peripheral nerve microvascular ECs (162).…”