The neurovasculaire unit (NVU) is composed of brain microvascular endothelial cells (BMECs) that form the Blood-Brain-Barrier (BBB), pericytes, neurons and glial cells. It regulates substance transport between blood and brain. BBB and NVU dysfonctions are associated with numerous neurological pathologies.
Animal models are traditionally used in medical research but the complexity of in vivo models make uneasy the understanding of some mechanisms, and there can be biomolecular inter-species differences with humans. Development of human NVU models are needed to better understand pathological mechanisms and to accelerate drug discovery.
However, primary human cells are difficult to isolate and are obtained in a low yield. Moreover there are genetic differences between donors and often come from unhealthy tissue. Immortalized human cell lines provide a high yield but have poor barrier properties. Face to these issues Lippmann et al. previously developed in 2012 an iPSC-derived BBB model which exhibited BBB markers and active efflux transport activity.
Recent advances in biomaterial and microfluidic systems allowed 3D cell culture to better mimic tissue organization. Lippmann’s team have then developed a new 3D model of iPSC-derived BMECs. They cultivated iPSC-derived BMECs in porcine gelatin hydrogel under perfusion conditions. They analyzed cell-cell junctions and they showed that BMECs maintained barrier properties and efflux transport activity during 21 days.
Fig. 1 Morphology comparison between Calcein AM-stained BMECs cultured in 2D tissue culture plates (i and ii) and in gelatin channels (iii and iv). Source: Faley and Neal, et al. 2019
Fig.2 HUVECs, µVas, and IMR90-4-derived BMECs labeled for VE-cadherin and claudin-5 at day 7 under perfused conditions.
Source: Faley and Neal, et al. 2019
This work confirms the importance of 3D culture to improve model relevance and increase cell survival. It lays the foundation for development of a representative 3D in vitro model of the human NVU constructed from iPSCs.
In the objective to have more and more relevant model, HCS Pharma will develop a 3D BBB model in BIOMIMESYS® hydroscaffolf, which mimics the extracellular matrix thanks to its physiological composition. This model will be adapted for High Content Screening to accelerate drug discovery!
Feel free to contact us if you want more information about our in vitro cerebral models!
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