Vesicular Transport Machinery in Brain Endothelial Cells: What We Know and What We Do not

Abstract

The vesicular transport machinery regulates numerous essential functions in cells such as cell polarity, signaling pathways, and the transport of receptors and their cargoes. From a pharmaceutical perspective, vesicular transport offers avenues to facilitate the uptake of therapeutic agents into cells and across cellular barriers. In order to improve receptor-mediated transcytosis of biologics across the blood-brain barrier and into the diseased brain, a detailed understanding of intracellular transport mechanisms is essential. The vesicular transport machinery is a highly complex network and involves an array of protein complexes, cytosolic adaptor proteins, and the subcellular structures of the endo-lysosomal system. The endo-lysosomal system includes several types of vesicular entities such as early, late, and recycling endosomes, exosomes, ectosomes, retromer-coated vesicles, lysosomes, trans-endothelial channels, and tubules. While extensive research has been done on the trafficking system in many cell types, little is known about vesicular trafficking in brain endothelial cells. Consequently, assumptions on the transport system in endothelial cells are based on findings in polarised epithelial cells, although recent studies have highlighted differences in the endothelial system. This review highlights aspects of the vesicular trafficking machinery in brain endothelial cells, including recent findings, limitations, and opportunities for further studies.

Exosomal delivery of therapeutic modulators through the blood–brain barrier; promise and pitfalls

“…), paracytosis, and transcytosis [ 69 ]. In the fusion of exosomes with the barrier type ECs, exosomes attach and fuse with these cells to release cargo onto the cytosol [ 70 ]. Exosome membrane proteins and specific receptors on the ECs surface initiate the existence of gap junction-like communications.…”

Similarities and differences in the localization, trafficking, and function of P-glycoprotein in MDR1-EGFP-transduced rat versus human brain capillary endothelial cell lines

“…Except for red blood cells, all eukaryotic cells, including BBB endothelial cells, contain lysosomes, but their structure and number vary depending on the cell type and functional state [ 55 , 56 ]. Lysosomes are highly acidic, membrane-enclosed, intracellular organelles, carrying a battery of hydrolytic enzymes as well as several membrane-associated proteins [ 55 ].…”

Post-capillary venules are the key locus for transcytosis-mediated brain delivery of therapeutic nanoparticles

“…This corresponded to the location of both late endosomes, and lysosomes downstream in the trafficking route 53,54 , which suggests that most nanoparticles converge with the lysosomal degradation pathway 55 , similarly to high-affinity antibodies and nanoparticles targeting TfR 56,57 . However, a fraction of perinuclear nanoparticles might also undergo endosomal recycling, typically located in proximity to the microtubule organizing center, at the spot close to the nucleus membrane 53,58 . This supports the notion that despite segmental differences in RMT dynamics, the microanatomy of the brain surrounding microvessels may play a decisive role in the successful brain entry of nanoparticles.…”