Speaker
Description
The choroid plexus (ChP), a vascularized structure, plays a pivotal role in cerebrospinal fluid (CSF) production and brain homeostasis by regulating ion transport, nutrient delivery, and waste clearance. Beyond these functions, the ChP acts as a sensor and modulator of environmental signals, influencing brain development and contributing to the pathophysiology of neurodevelopmental disorders. Growing evidence implicates inflammation and immune dysregulation in childhood neuropsychiatric conditions such as schizophrenia and autism, highlighting the ChP as a key amplifier of these pathological processes. Given its anatomical proximity to the subventricular zone, deciphering the mechanisms of ChP function is crucial for understanding brain maturation and exploring its potential as a therapeutic target. Animal models incompletely model human physiology, while in vitro systems lack key components to replicate ChP complexity. To address this, we developed VIChOs (Vascular Immune ChP Organoids) as a novel 3D human ChP model capturing the cellular heterogeneity of the ChP, extending beyond its well-known epithelial barrier function. VIChOs faithfully replicate the histological and ultrastructural features of native ChP tissue. Using single-cell RNA sequencing, we longitudinally characterized the diverse cell-type composition of VIChOs, revealing a dynamic cellular landscape regulated by subtype-specific signaling pathways. The development of VIChOs into tissue with neural, endothelial, and immune cell populations is accompanied by the dynamic secretion of a CSF-like fluid, which contains actively synthesized neurotrophic and signaling molecules. By leveraging the inherent heterogeneity of VIChOs, we conducted hypothesis-driven perturbations to dissect how microenvironmental cues influence ChP cytoarchitecture and secretory profiles. These experiments unveiled robust, context-dependent shifts in cellular organization and secretome composition, underscoring the utility of VIChOs as a platform for mechanistic studies.
Our work establishes VIChOs as a novel human ChP model that captures the tissue’s full complexity. It provides a scalable, physiologically relevant system for exploring ChP biology in health, disease, and therapeutic discovery.
| Author(s) | Vanessa Aragona*1, Illia Simutin1, Sara Mancinelli1, Matteo Miotto2, Giuseppe Martano3, Giulia Guerra4, Elisabetta Venturelli4, Katia Cortese5 and Simona Lodato1,2 |
|---|---|
| Affiliation(s) | "1 . Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Milan, Italy 2. Neuro Center, IRCCS Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano-Milan 3. Institute of Neuroscience, CNR, Via L. Vanvitelli 32, 20129 Milan, Italy 4. Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy 5. Cellular Electron Microscopy Laboratory, DIMES, Department of Experimental Medicine, Human Anatomy, School of Medical and Pharmacological Sciences, University of Genoa, Via Antonio de Toni 14, 16132, Genoa, Italy" |
