The NIRL was the first laboratory in the world to successfully isolate, purify, culture and characterize adult primary endoneurial endothelial cells (known as pHEndECs) that form the blood-nerve barrier (BNB) from sciatic nerves of recently decedent individuals, demonstrating retention of essential properties of tight-junction forming cells (published in 2010: Cover article).
pHEndECs, coupled with laser capture microdissected endoneurial microvessels from histologically normal adult sural nerve biopsies, were used to define the first human BNB transcriptome. This provides an extensive library of transcripts expressed by the BNB in health and has created an essential framework for biologically relevant mechanistic studies of the human BNB that incorporates transendothelial electrical resistance, solute permeability to low and high molecular weight molecules and transendothelial water flux (hydraulic conductivity). pHEndECs have been stably transfected and immortalized with simian virus 40 (SV40) large T-antigen, forming a stable cell line called THEndECs that have been shown to retain essential properties of the BNB and are particularly suitable for transporter studies.
Glial-derived neurotrophic factor (GDNF), known to be secreted by Schwann cells (the glial cells of the peripheral nervous system), is a potent and sufficient regulator of the BNB in vitro (human) via GFRα1-RET tyrosine kinase-MAPK kinase signaling. GDNF facilitates cytoskeletal remodeling which serves as the prerequisite for continuous endothelial cell-to-cell contacts prior to restrictive junctional complex formation in vitro, and in vivo, restores microvascular impermeability to large macromolecules following sciatic nerve crush injury, independent of claudin-5 and cadherin-5.
Pathogenic leukocyte trafficking across the blood-nerve barrier in Guillain-Barré syndrome is dependent on CCR2, CD11b (αM integrin) and intercellular adhesion molecule-1 (ICAM-1) via paracellular diapedesis without disruption of BNB integrity in vitro (human), in vivo (murine model) and in situ (human sural nerves)
Pathogenic leukocyte trafficking across the BNB in chronic inflammatory demyelinating polyradiculoneuropathy is dependent on the alternatively spliced fibronectin variant, Type III connecting segment or connecting segment-1 and CD49d (α4 integrin, which also binds to vascular cell adhesion molecule-1 [VCAM-1]) in vitro (human) and in vivo (murine model), supported by in situ data (human sural nerves)
Published Images and Videos
- Human Endoneurial Endothelial cells (in vitro) and Human/ Murine Blood-Nerve Barrier (in situ): Molecular Biology and Biophysics [Immunohistochemistry, Electron microscopy]
- Human peripheral neuropathies (GBS/CIDP/HIV neuropathy) and Murine sciatic nerve crush injury
- Leukocyte Trafficking Videos