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Maoz BM, Herland A, FitzGerald EA, Grevesse T, Vidoudez C, Pacheco AR, Sheehy SP, Park TE, Dauth S, Mannix R, Budnik N, Shores K, Cho A, Nawroth JC, Segrè D, Budnik B, Ingber DE, Parker KK. A linked organ-on-chip model of the human neurovascular unit reveals the metabolic coupling of endothelial and neuronal cells. Nat Biotechnol. 2018 Aug 20; PubMed.
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University of British Columbia
University Hospital of Zurich
In this paper in Nature Biotechnology, Kit Parker and colleagues, led by Ben Maoz, Anna Herland, and Edward FitzGerald, describe an elegant platform using three linked organs-on-chips to model the human neurovascular unit (NVU) and the metabolic coupling of endothelial and neuronal cells.
The NVU is unquestionably a critical component of brain health, as it is the interface between central nervous system (CNS) and the rest of the body. The NVU has particular importance to Alzheimer’s disease as several cardiovascular disease risk factors also increase AD risk, and as many elements of AD pathophysiology impinge on the NVU, including Aβ clearance, blood-brain-barrier dysfunction, and neuroinflammation.
However, there are many challenges to study the NVU, as both in vivo and current in vitro approaches have several limitations. Parker’s group now provides an innovative approach to study the individual contributions of brain microvascular endothelial cells, perivascular pericytes, astrocytes, and neurons. His approach connects two blood-brain-barrier (BBB) chips to a brain chip, such that separation of the artificial blood and artificial cerebrospinal fluid (CSF) media is preserved. Essentially, when the chips are coupled, artificial blood flows through the endothelium lumen of the first BBB chip (BBB influx), and metabolic factors that are actively transported or perfuse through the perivascular compartment of the BBB influx chip are transferred to the brain chip, where it contacts a mixed culture of neurons and astrocytes. This fluid is then coupled to the perivascular compartment of the BBB efflux chip, where both artificial CSF and blood components can be sampled after contact with the brain compartment.
Several important studies were performed within this paper to validate the model. First, Maoz and colleagues used proteomic and metabolomic approaches to investigate protein expression in coupled versus uncoupled chips and demonstrated that fluidic coupling upregulated metabolism-associated proteins in all compartments and downregulated proteins associated with proliferation and migration compared to uncoupled chips. These data add considerably to a growing body of literature that cellular phenotypes depend on the microenvironment context, and that the traditional reductionist approaches of modeling individual cells is likely to be fraught with error.
Second, the utility of the linked chip platform for drug modeling studies was confirmed using methamphetamine, which is known to transiently disrupt the BBB after acute administration both in vivo and in vitro.
Finally, metabolomic analyses were performed to characterize the secretome produced by each compartment when coupled versus uncoupled. Here, BBB chips were found to be highly metabolically active and secrete chemical cues to maintain neuronal function, including regulating glutamate and gamma-aminobutyric (GABA) neurotransmitters. Analysis of the metabolic contribution of each compartment to the NVU system to pathways associated with glycolysis, the TCA cycle and the glutamine-glutamate cycle shows that glycolysis occurs in all compartments, glutamine synthesis was observed in all compartments containing astrocytes, and GABA is produced exclusively in the brain chip and is significantly higher in the coupled configuration. These data show that metabolites from the vascular endothelium and perivascular cells can directly affect glutamine production by astrocytes and neurons on the brain chip and influence the metabolism of neurons and astrocytes.
Parker’s multichip system has the potential to study several key topics of importance to AD, including Aβ clearance, the relationship between altered systemic metabolism and brain metabolism, the role of circulating factors in neuronal inflammation and metabolism and vice versa, how neuronal factors might affect BBB physiology, and brain-derived biomarkers.
The limitations of traditional in vitro systems to preserve the metabolic and functional state of cells is increasingly recognized, with several more advanced human multicellular models emerging (Brown et al., 2016; Robert et al., 2017). Although all of these systems have limitations, they represent valuable approaches to investigate human cellular physiology in the appropriate context and complement in vivo studies.
References:
Brown JA, Codreanu SG, Shi M, Sherrod SD, Markov DA, Neely MD, Britt CM, Hoilett OS, Reiserer RS, Samson PC, McCawley LJ, Webb DJ, Bowman AB, McLean JA, Wikswo JP. Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit. J Neuroinflammation. 2016 Dec 12;13(1):306. PubMed.
Robert J, Button EB, Yuen B, Gilmour M, Kang K, Bahrabadi A, Stukas S, Zhao W, Kulic I, Wellington CL. Clearance of beta-amyloid is facilitated by apolipoprotein E and circulating high-density lipoproteins in bioengineered human vessels. Elife. 2017 Oct 10;6 PubMed.
View all comments by Jerome RobertWeill College Medicine, New York
I am impressed by the fact that this model, unlike previous ones, provides the opportunity to study the interactions between different cellular compartments of the neurovascular unit (NVU) at the levels of capillaries. This system seems well-suited to examine transport and metabolic coupling among the different NVU cells at the capillary level, since smooth muscle cells and perivascular cells (macrophages, mast cells, etc.) are not included in the model.
The NVU is not uniform across the cerebrovascular tree. The cellular composition, signaling mechanism, and functional characteristics vary depending on the cerebrovascular segment examined (large arteries, pial arteries, penetrating arterioles, capillaries, venules and veins). It would be desirable if, in future iterations of the model, the basement membranes were also included. Much of the cerebrovascular pathobiology of cognitive impairment has been recently linked to basement membrane proteins and enzymes (CADASIL, CARASIL, small vessel disease, etc.). Overall, this is a step forward in capillary NVU modeling, which, owing to IPS cell technology, affords the opportunity to more faithfully recapitulate selected aspects of human diseases.
View all comments by Costantino IadecolaMake a Comment
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