Biology subjects

Cea, D.

Publications and source records attributed to Cea, D..

3 recordsLinked to original sources

bioRxiv2026

Repurposing nystatin and taurocholate to target intracellular spore persistence during antibiotic treatment to prevent recurrent Clostridioides difficile infection.

Successful treatment of primary Clostridioides difficile infection (CDI) while preventing its recurrence remains a major clinical challenge, with recurrent CDI (R-CDI) affecting 20-30% of treated patients. Persistence of C. difficile spores within the intestinal mucosa is thought to drive R-CDI following antibiotic treatment. Here, we show that intracellular C. difficile spores remain protected from taurocholate-triggered germination, and that nystatin, an FDA-approved antifungal that blocks spore entry into host cells, reduces this protected intracellular population and redirects spores toward an extracellular, germinating population accessible to antibiotics. In a murine model of R-CDI, oral co-administration of taurocholate with nystatin and antibiotics during primary CDI reduced R-CDI incidence from 100% to 44%. When administered during an active R-CDI episode, the same formulation reduced a second R-CDI from 100% to 62%. To improve bioavailability, we encapsulated nystatin and vancomycin in chitosan nanoparticles. Oral administration of nanoparticle-encapsulated vancomycin, alone or combined with nanoparticle-encapsulated nystatin, reduced R-CDI colonization to 33% and 44%, respectively, compared with 100% in mice receiving free vancomycin. Together, these findings support a therapeutic strategy that repurposes nystatin and taurocholate, in combination with antibiotics and nanoparticle-based delivery, to target intracellular spore persistence and reduce the incidence of C. difficile recurrence..

pharmacology and toxicology↗

bioRxiv2026

A scalable human neuromuscular organoid platform enables lineage-specific analysis of drug responses in spinal muscular atrophy.

Scalable human models that capture interactions between distinct tissues remain limited, constraining mechanistic insight and therapeutic prediction. Here, we established a scalable, automation-compatible human neuromuscular organoid (NMO) platform that enables integrated analysis of neuronal and muscle lineages in spinal muscular atrophy (SMA). Patient-derived NMOs reproducibly self-organise into spinal cord and skeletal muscle compartments and form functional neuromuscular circuits. SMA NMOs recapitulate early disease features, including reduced survival motor neuron (SMN) protein levels and impaired neuromuscular junction (NMJ) maturation. Single-nucleus RNA sequencing identifies lineage-specific transcriptional changes across neuronal and muscle compartments preceding functional deficits. Using this platform, we compared two clinically relevant SMN2 splicing modulators and observed distinct, cell-type-dependent responses. While both compounds increased SMN levels and NMJ number, only one enhanced myofiber growth and improved contractile function. These findings highlight muscle maturation, rather than NMJ number alone, as a key determinant of functional recovery and establish NMOs as a scalable system for studying cell-type-specific therapeutic responses.

bioengineering↗

bioRxiv2025

Guided maturation of human neuromuscular organoids via electrical stimulation

Organoids derived from human pluripotent stem cells (hPSCs) are emerging as powerful models for studying development and disease. Despite their physiological relevance, the predictive power of organoids remains limited by the immature state of the constituent cells, posing a major challenge for mechanistic studies of adult physiology and late-onset diseases and disorders. Here, we establish a strategy for enhancing the maturation status of human neuromuscular organoids (NMOs) through chronic Electrical Pulse Stimulation (EPS). We demonstrate that low-frequency EPS, applied early on during NMO development and maintained over several weeks, promotes structural and functional maturation of neuromuscular junctions (NMJs). Independent of stimulation waveform dynamics, EPS-trained NMOs (EPS-NMOs) displayed stronger and more frequent spontaneous contractions that persisted long after stimulation ceased. Quantitative imaging and transcriptomic analyses revealed a robust improvement in EPS-NMO skeletal muscle and neural tissue morphology, coordinated regulation of lineage-specific biomarkers, and upregulation of gene programmes associated with mature neuromuscular function. Mechanobiological measurements further demonstrated increased EPS-NMO tissue stiffness and faster relaxation dynamics, consistent with advanced excitation-contraction coupling and force generation. Collectively, these findings establish EPS as a powerful, non-invasive, and on-demand modality for driving the morphological and functional maturation of complex organoid systems.

bioengineering↗