The interface between the choroid plexus and the CSF (the blood–CSF barrier) regulates the composition of the brain fluid that nourishes, protects, and guides brain development. By controlling the delivery of essential signals to developing neurons, it plays a key role in proper neurodevelopment and contributes to the maintenance of brain homeostasis. Despite its crucial functions, the operation of this dynamic epithelial barrier remains poorly understood. The present study focused on developing a choroid plexus organoid model derived from human pluripotent stem cells. This three-dimensional system faithfully reproduces the choroid plexus epithelium and secretes a fluid similar to human CSF. It therefore represents an innovative and relevant translational tool for directly analyzing the molecular mechanisms involved and identifying biomarkers associated with the pathophysiology of neonatal cerebral hypoxia.
Exposure of choroid plexus organoids to low oxygen levels reveals morphological changes and disruptions in mitochondrial metabolism. Proteomic analysis of the fluid secreted by hypoxia-exposed organoids highlights a major dysregulation of proteins involved in neurogenesis and epigenetic regulation. These proteins may contribute to the alterations in neuronal development observed under hypoxic conditions and could serve as relevant biomarkers of cerebral hypoxia.
The organoid model presented in this study represents a promising tool for investigating the pathophysiological mechanisms underlying certain brain injuries, particularly those related to hypoxia, and for identifying diagnostic biomarkers. Such a system could also enable in vitro evaluation of the effectiveness of new neuroprotective strategies.
Joliot contact : Aloïse Mabondzo (aloise.mabondzo@cea.fr)
- The central nervous system is protected by specialized barriers, notably the blood–brain barrier (BBB), located at the level of cerebral capillaries, and the blood–cerebrospinal fluid barrier (BCSFB), located in the choroid plexus. These barriers regulate nutrient transport, maintain brain homeostasis, and prevent the entry of toxic compounds.
- Hypoxic-ischemic encephalopathy (HIE) is a severe brain injury in newborns caused by a significant reduction in blood flow and oxygen supply at birth. It can lead to long-term neurological deficits, learning and intellectual impairments, as well as cognitive and behavioral developmental disorders. To date, therapeutic hypothermia is the only approved treatment, with limited efficacy and significant constraints. The development of innovative research models, such as the one presented here, is therefore particularly important.