Compartmentalized primary cultures of dorsal root ganglion neurons to model peripheral pathophysiological conditions

Abstract

Neurosensory disorders such as pain and pruritus remain a major health problem greatly impacting the quality of life, and often increasing the risk of mortality. Current pre-clinical models to investigate dysfunction of sensory neurons have shown a limited clinical translation, in part, by failing to mimic the compartmentalized nociceptor anatomy that exhibit a central compartment containing the soma and a peripheral one harboring the axon endings with distinct molecular and cellular environmental composition. Thus, there is a need to validate compartmentalized preclinical neurosensory models for investigating the pathophysiology of peripheral sensory disorders and to test drug candidates. Here, we have addressed this issue and developed a microfluidic-based preclinical nociceptor model and validated it for investigating inflammatory and neuropathic peripheral disorders. We show that this model reproduces the peripheral sensitization and resolution produced by an inflammatory soup and by the chemotherapeutic drug paclitaxel. Furthermore, compartmentalized nociceptor primary cultures were amenable to co-culture with keratinocytes in the axonal compartment. Interaction of axonal endings with keratinocytes modulated neuronal responses, consistent with a crosstalk between both cell types. These findings pave the way towards translational pre-clinical sensory models for skin pathophysiological research and drug development.

Assessment of corneal nerve regeneration after axotomy in a compartmentalized microfluidic chip model with automated 3D high resolution live-imaging

“…Despite these advances, there are currently no available data concerning trigeminal nerve regeneration after axotomy using microfluidic compartmentalized chips. Indeed, only one recent study presented compartmentalized models of primary sensory neurons from dorsal root ganglia (DRG) exposed either to inflammatory mediators (mimicking inflammatory peripheral sensitization) or paclitaxel (chemotherapy sensitization) ( Giorgi et al, 2023 ). We recently developed and validated a microfluidic co-culture between mouse trigeminal sensory neurons (responsible for corneal innervation) and primary mouse corneal epithelial cells to evaluate direct toxicity on nerve endings entangled in epithelial cells and indirect toxicity on somas after acute and repeated exposure to benzalkonium chloride, a commonly used preservative in eyedrops ( Bonneau et al, 2023 ).…”