Attempts to model in vitro the blood-brain barrier during the past twenty years have been quite successful; however, establishment of dynamic models, integrating shear stress and the associated mechanotransduction, has proven to be a challenging aim. To address this important issue, we recently developed a new laminar flow device and demonstrated that, when cultivated in this device, the human hCMEC/D3 brain microvascular endothelial cell line, a validated in vitro model of human BBB, displayed further optimized characteristics of in situ BBB: reduced permeability to Lucifer Yellow (0.31±0.04 x 10-3cm.min-1), enhanced trans-endothelial electrical resistance (155±23 Ω.cm²) and strong activity of P-gp and BCRP ABC-transporters. We believe that this dynamic model will help perform drug screening, design new approaches of drug delivery to the brain and unravel the molecular mechanisms of brain endothelium response to immune dysfunctions or infections by human pathogens.
As an illustration, we recently deciphered the mechanisms of adhesion under flow of Neisseria meningitidis, or meningococcus, onto human brain endothelium. Using the hCMEC/D3 model, we identified the immunoglobulin superfamily member CD147 (also called EMMPRIN or Basigin) as a critical endothelial receptor for meningococcus. Interfering with this interaction under laminar flow by specific anti-CD147 antibodies or by genetic engineering of bacteria potently inhibited the primary attachment of meningococci to hCMEC/D3 cells. These results were validated by the observation that the same treatments also prevented ex vivo colonisation of brain vessels on human cerebral tissue sections.
These findings establish the power of dynamic in vitro models of human BBB for adressing physiologically important issues and for designing new clinically relevant approaches.