Biology subjects

Pio, T.

Publications and source records attributed to Pio, T..

3 recordsLinked to original sources

bioRxiv2026

Temporal RNA splicing dysregulation in a human multicellular model of C9orf72 ALS

Amyotrophic lateral sclerosis (ALS) is a complex and heterogenous disease, comprising of familial and sporadic forms, numerous genetic mutations, and a wide range of affected cell types and proposed dysregulated processes. While the usage of in vitro cell cultures, mouse models, and postmortem patient tissue have advanced our understanding of ALS disease mechanisms, the temporal progression of the disease and how early molecular changes evolve remain poorly understood. Here, we establish human spinal cord organoids (hSpO) derived from C9orf72 patient induced pluripotent stem cells (C9-ALS hiPSCs) as a platform to model longitudinal changes across the disease trajectory. We show that C9-ALS hSpO recapitulate hallmark C9orf72-related pathologies, increased cell death, and progressive neuronal dysfunction. We further identify RNA splicing dysregulation as an early and persistent feature of C9-ALS, with splicing signatures in hSpO closely mirroring those observed in postmortem patient tissue. Finally, prediction of RNA binding proteins (RBPs) that induce early splicing changes in C9-ALS reveals signatures consistent with a broad RBP network dysfunction. Together, this work establishes hSpO as an in vitro system for investigating early disease mechanisms of ALS in a human multicellular context and highlights dysregulated events that precede cell death.

neuroscience↗

bioRxiv2026

Human spinal cord organoids recapitulate developmental and disease-associated oligodendrocyte lineage signatures

Oligodendrocytes play essential roles in central nervous system development and homeostasis, and their dysfunction is a hallmark of numerous neurological disorders. However, human in vitro systems that support oligodendrocyte lineage progression while enabling the study of disease-relevant states remain limited. Here, we establish human spinal cord organoids (hSpO) and cortico-motor assembloids as platforms to model oligodendrocyte development, neuron-glia interactions, and cytokine-induced dysfunction. We show that hSpO generate oligodendrocyte lineage populations that transcriptionally resemble those found in the developing human spinal cord, and oligodendrocyte progenitor cells that exhibit physiologically-relevant functional properties, including migration and monosynaptic input from neurons. Exposure of assembloids to pro-inflammatory cytokines induces transcriptional changes across the oligodendrocyte lineage, characterized by altered lineage progression and acquisition of disease-associated gene expression programs that mirror signatures observed in multiple sclerosis patient tissue. Together, this work establishes hSpO and assembloids as in vitro systems for studying oligodendrocyte lineage development and disease-associated states in a human multi-cellular context.

cell biology↗

bioRxiv2025

Human assembloid model of emergent neurotropic enteroviruses

Enteroviruses (EVs) are the leading cause of viral meningitis in children. Recent outbreaks of non-polio EVs, most notably EV-A71 and EV-D68, have been associated with a polio-like paralysis known as acute flaccid myelitis (AFM). The lack of relevant models that mimic the cellular and functional responses of these human-restricted pathogens has hampered the development of effective treatments. We have previously engineered human stem cell-derived assembloids that recapitulate the neuromuscular connections underlying muscle contractions by integrating human spinal cord/hindbrain organoids (hSpO) and human skeletal muscle. Here, we used organoids and assembloids to investigate polio and non-polio EV pathogenesis. Infection of assembloids with poliovirus (PV), EV-D68 and EV-A71 resulted in loss of muscle contraction for all three viruses, which could be prevented by treatment with an antiviral agent. Yet, despite the convergence on neuronal dysfunction, the cellular targets by which each virus acted differed. More specifically, single cell transcriptomic profiling uncovered divergent cell tropisms between the EVs, and live imaging experiments revealed different modes and kinetics of cell damage. Altogether, we describe a multi-cellular model that captures viral pathogenesis in a human and circuit-relevant context.

neuroscience↗