Biology subjects

Olivier, T.

Publications and source records attributed to Olivier, T..

3 recordsLinked to original sources

bioRxiv2025

Building the blood-brain barrier: a scalable self-assembling 3D model of the brain microvasculature under unidirectional flow

The blood vessels of the central nervous (CNS) system form a tight, protective blood-brain barrier (BBB). This barrier is essential for healthy CNS function but also poses a hurdle in the treatment of increasingly common neurological disorders. Additionally, BBB dysfunction is a hallmark of many neurological diseases, further emphasizing a need for a better understanding of BBB function in health and disease. We present a human self-assembling 3D model of the BBB in a microfluidic cell culture platform that allows culture of 48 models in parallel on one tissue culture plate. Human brain microvascular endothelial cells, pericytes, and astrocytes form highly reproducible BBB vascular networks under unidirectional perfusion and remain viable for a minimum of 14 days. Immunostaining reveals close cell-cell interactions with pericytes and astrocyte end-feet in direct contact with the brain microvasculature. Compared to endothelial monocultures, co-culture with astrocytes or pericytes results in improved barrier function, lower vessel diameters, increased branching, and alignment of the vessels in the direction of fluid flow. These results were most pronounced in tri-cultures containing all three cell types. Unlike similar models previously reported, this brain microvasculature model allows for unidirectional perfusion without the need for pumps and syringes. Combined with its high-throughput nature, this feature renders the model suitable for studies of BBB function in health and disease, and assessment of potential BBB restorative therapies.

neuroscience↗

bioRxiv2025

Modeling Hepatocellular Carcinoma and its microenvironment on a chip

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Its incidence is increasing and is closely related to advanced liver disease. Interactions in the HCC microenvironment between tumor cells and the associated stroma actively regulate tumor initiation, progression, metastasis, and therapy response. Effective drug development increasingly requires advanced models that can be utilized in the earliest stages of compound and target discovery. Here we report a phenotypic screen on an advanced HCC patient-derived chip (PDChip) model. The vascularized HCC PDChip models include relevant cellular players of the HCC microenvironment. We assessed the effect of 28 treatment conditions on a panel of 8 primary HCC tumors and 2 cell lines. Approximately 1200 HCC PDchips were grown under perfusion flow, exposed to treatments, and subsequently assessed for viability, tumor-associated vasculature responses and chemokine and cytokine changes. Although the SoC therapeutics sorafenib and lenvatinib reduced culture viability and produced profound changes in the organization of the vascular beds, they did not affect the tumor cell population in these cultures. Atorvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, reduced tumor viability but did not affect vascular bed organization. Sorafenib, lenvatinib and atorvastatin also affected chemokine and cytokine release. Tocilizumab, galunisertib, and vactosertib decreased the level of IL6, a relevant prognostic marker for HCC, while IL6 was increased by halofuginone. In conclusion, HCC PDChip models enabled a detailed evaluation of drug-induced responses in the tumor and associated microenvironment, highlighting their importance in preclinical research for understanding diseases and developing new drugs.

bioengineering↗

bioRxiv2024

An immunocompetent human kidney on-a-chip model to study renal inflammation and immune-mediated injury

Kidney damage and dysfunction is an emerging health issue worldwide resulting in high morbidity and mortality rates. Numerous renal diseases are recognized to be driven by the immune system. Despite this recognition, the development of targeted therapies has been challenging as knowledge of the underlying mechanism and complex interactions remains insufficient. Recent advancements in the field offer promising avenues for exploring the interplay between renal cells and immune cells and their role in the development of renal inflammation and diseases. This study describes the establishment of a human immunocompetent 3D in vitro co-culture model of the proximal tubule in a high-throughput microfluidic platform that can be used to study renal functionality and inflammatory processes. The model incorporated RPTEC in the top compartment and HUVECs in the bottom compartment cultured under flow and in direct contact with a collagen-I ECM gel resulting in the formation of polarized tubular structures. As an immune component, human primary monocytes of different donors were added to the lumen of the endothelium. Renal inflammation was successfully induced using complement activated serum (CAS) as evident by epithelial morphological changes, increased expression of adhesion molecules, release of pro-inflammatory cytokines, and reduced epithelial viability. Realtime migratory behavior of monocytes showed increased extravasation and migration towards the ECM and Renal compartment upon exposure to CAS with donor-to-donor differences observed. Finally, immune modulatory compounds showed efficacious inhibition of monocyte migration under inflammatory conditions in the microfluidic co-culture model. A successful co-culture model was established and can be applied to study renal functionality in health and disease but also for drug screening due to the compatibility of the platform with automation and relatively high throughput. Overall, the described proximal tubule model has high potential to fill the gap that currently exists to study renal inflammation preclinically.

immunology↗