Biomedical subjects

Silvia Cappello

Publications and source records attributed to Silvia Cappello.

3 recordsLinked to original sources

PubMed2026

Defective EV-mediated transport of SHH alters neural fate specification in EPM1 epilepsy.

The extracellular milieu, including extracellular vesicles (EVs), plays a pivotal role in brain development. In this study, we sought to elucidate the pathogenesis of progressive myoclonus epilepsy type 1 (EPM1), a disease caused by mutations in the CSTB gene, using cerebral organoids (COs) derived from patient cells. The results demonstrate that EPM1 COs display increased electrophysiological activity and disrupted excitatory/inhibitory (E/I) balance. Single-cell RNA sequencing analysis of ventral EPM1-COs revealed an abnormal specification of progenitor fate, with a shift toward dorsal neuron identities. We demonstrated that this misspecification is driven by a functional alteration of the ventral signaling niche, resulting from impaired EV dynamics and altered protein cargo. Mechanistically, we identified Sonic Hedgehog (SHH) as a direct physical interactor of CSTB and demonstrated that CSTB deficiency leads to reduced SHH content and secretion. Our findings establish CSTB as a safeguard of ventral patterning and identify the CSTB-SHH-EV axis as a potential therapeutic target for mitigating the E/I imbalance associated with EPM1.

Hedgehog Proteins↗

PubMed2026

A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes.

Stem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions, but limitations in reproducibility, maturation and cell-type diversity persist. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. Here, we developed a human induced pluripotent stem cell-based three-dimensional cortical brain tissue model (3BTM) containing neurons, astrocytes and microglia with high reproducibility, maturity and viability. 3BTMs show morphological, functional and proteomic maturation of all cell types, leading to high similarity to their in vivo counterparts. Incorporated microglia survive for over 6 months and display mature morphology, functions and gene expression. Importantly, when engineered to model Alzheimer's disease pathology, 3BTMs recapitulate key disease hallmarks, including amyloid deposition, increased phospho-tau levels and neuroinflammation, with microglia shifting their transcriptional landscape to disease-relevant signatures. Treatment of Alzheimer's disease 3BTMs with anti-Aβ immunotherapy cleared deposits and largely reversed disease signatures in glia. Together, our microglia-containing model provides a platform for studying physiological and pathological states of human brain tissue.

Humans↗

PubMed2025

Astrocytic glutamate regulation is shaped by adversity and glucocorticoid signalling.

Astrocytes are a brain cell type vulnerable to the effects of stress and the development of psychiatric-like phenotypes in animals, yet how this translates to humans is unclear. Here, we probed the diversity of ~145,000 total human cortical astrocytes with single nucleus and spatial transcriptomics, showing that human astrocytes comprise a molecularly and anatomically diverse cell population. In individuals with psychiatric disorders and high adversity exposure, we identified distinct alterations to glutamate-related synaptic functions, supported by histological quantification of >20,000 astrocytes. Early-life adversity exposure produced more pronounced cellular changes than adversity experienced later in life, and female cases displayed stronger transcriptomic associations than males with adversity exposure. Human pluripotent stem cell-derived astrocytes from both two- and three-dimensional models confirmed that glutamate signalling is directly impacted by glucocorticoid activation. Our findings highlight astrocytes as crucial players in how exposure to severe adversity raises risk to psychopathology and position them as strategic pharmacological targets for future intervention strategies.

Journal Article↗