Heparan sulfate proteoglycan‐mediated dynamin‐dependent transport of neural stem cell exosomes in an in vitro blood–brain barrier model

• Published in: The European journal of neuroscience Vol. 53; no. 3; pp. 706 - 719
• Main Authors: Joshi, Bhagyashree S., Zuhorn, Inge S.
• Format: Journal Article
• Language: English
• Published: France Wiley Subscription Services, Inc 01.02.2021; John Wiley and Sons Inc
• Subjects: Blood-brain barrier; cargo; Drug delivery; Dynamin; Endocytosis; endothelial cell; Endothelial cells; Exosomes; extracellular vesicles; Heparan sulfate; Heparan sulfate proteoglycans; Microvasculature; Molecular and Synaptic Mechanisms; nanocarriers; Neural stem cells; Proteoglycans; Research Report; transcytosis; blood-brain barrier; extracellular vesicles; endothelial cell; exosomes; nanocarriers; transcytosis; cargo; heparan sulfate proteoglycans
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.14974

Drug delivery to the brain is greatly hampered by the presence of the blood–brain barrier (BBB) which tightly regulates the passage of molecules from blood to brain and vice versa. Nanocarriers, in which drugs can be encapsulated, can move across the blood–brain barrier (BBB) via the process of transcytosis, thus showing promise to improve drug delivery to the brain. Here, we demonstrate the use of natural nanovesicles, that is, exosomes, derived from C17.2 neural stem cells (NSCs) to efficiently carry a protein cargo across an in vitro BBB model consisting of human brain microvascular endothelial cells. We show that the exosomes are primarily taken up in brain endothelial cells via endocytosis, while heparan sulfate proteoglycans (HSPGs) act as receptors. Taken together, our data support the view that NSC exosomes may act as biological nanocarriers for efficient passage across the BBB. Nanomedicines that target HSPGs may improve their binding to brain endothelial cells and, possibly, show subsequent transcytosis across the BBB. Neural stem cell‐derived exosomes interact with heparan sulfate proteoglycans on endothelial cells at the apical (blood) side and are taken up by dynamin dependent endocytosis. II. Exosomes are transported across the endothelial cell and reach the basal (brain) side.