Poster – Importance of microenvironment in cerebral in vitro models for phenotypic screening

Ask for high quality link by putting your email below

Aim: About 90% of drug-candidates failed in clinical trials, in particular in neurology, due to a lack of efficacy. That highlights a lack of relevance in preclinical models, including in vitro models, which do not take into account the microenvironment, composed by glial cells and the Extracellular Matrix (ECM). The objective was to study the influence of the microenvironment in cerebral in vitro models, in the frame of Parkinson’s Disease (PD).

Methods: First, we analyzed the influence of astrocytes on Luhmes cell sensitivity, a dopaminergic neuronal cell line, in 2D culture. Then, we developed a hyaluronic acid-based hydroscaffold for 3D cell culture, which mimics the ECM, and study the sensitivity of Luhmes cells in this model. Thirdly, we performed a co-culture of Luhmes cells and astrocytes in this matrix, to form a complex model including both the glial and the matricial microenvironments.

Results: We observed a protective effect of astrocytes in 2D culture. In the hydroscaffold, Luhmes cells displayed a lower sensitivity compared to 2D culture, that was explained by a partial retention of toxic molecules in the matrix, and differences in neuronal protein expression. In the co-culture, we observed spheroids containing both neurons and astrocytes.

Conclusions: This work highlighted that the microenvironment of neurons can modify the neuronal response in vitro, and should thus be considered carefully in academic research and in drug discovery. This model can be now used to study the microenvironment modifications in pathological conditions, and to develop innovative drugs targeting the microenvironment.