Biology subjects

Torrente, Y.

Publications and source records attributed to Torrente, Y..

4 recordsLinked to original sources

bioRxiv2024

A synthetic potassium channel reduces oxidative stress 1 via cellular adaptronics

Aerobic metabolism is crucial for human life but reactive oxygen species (ROS) byproducts cause cellular toxicity. Although antioxidant defenses usually maintain ROS levels within a safe range, ROS production can exceed the buffering capacity of cells, causing oxidative stress and disease. Inspired by the principle of adaptronics, we created a synthetic potassium channel that senses cellular ROS levels and mitigates oxidative stress by modulating membrane potential. Engineered from TASK1 channel, ROSTASK1 is sensitive to supraphysiological ROS levels, imposing restorative membrane potential changes on cells or organelles under oxidative stress. We also engineered a blue-light sensitive ROSTASK1 to achieve optogenetic control. In proof-of-concept experiments, mitochondrially-delivered ROSTASK1 rescued ROS overproduction in myoblasts from a Leigh syndrome patient and ROSTASK1 abolished chronic pain-like behavior in mouse models of inflammation and nerve injury. Thus, by functioning as both a sensor and modulator of ROS levels, ROSTASK1 provides a self-healing system during oxidative stress.

biophysics↗

bioRxiv2024

CD90 identifies distinct fractions of muscle stem cells with different modalities of activation and quiescence maintenance

Stem cell transition from quiescence to activation is crucial to guarantee productive tissue regeneration. Here we show that CD90 diversifies quiescent muscle stem cells (MuSCs) in murine and human muscle into two subpopulations differing in the kinetics of activation, CD90+ve MuSCs exhibiting a faster exit quiescence and predominating the initial phases of regeneration compared to CD90-ve MuSCs. In the absence of injury, the CD90+ve fraction is primed toward activation through an active CD90-AMPK axis but is maintained in quiescence through signals from the extracellular matrix. Our studies show that Collagen VI, which is preferentially expressed by CD90+ve MuSCs, binds to the Calcitonin receptor and plays a role in this context. Moreover, while the number of CD90+ve and CD90-ve subpopulations is similar in healthy muscles, the CD90-ve fraction predominates in the muscles of murine models of Duchenne and Ullrich congenital muscular dystrophies. These findings provide novel insights into the mechanistic determinants of MuSCs functional heterogeneity and have implications for understanding the stimulation of repair in dystrophic muscle.

cell biology↗

bioRxiv2023

Porphyromonas gingivalis fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion

The interaction between the gut microbiota and invariant Natural Killer T (iNKT) cells plays a pivotal role in colorectal cancer (CRC). Porphyromonas gingivalis is a keystone oral pathogen associated with CRC. The oral pathobiont Fusobacterium nucleatum influences the anti-tumour functions of CRC-infiltrating iNKT cells. However, the impact of other oral bacteria, like P. gingivalis, on their activation status remains unexplored. In this study, we demonstrate that mucosa-associated P. gingivalis induces a protumour phenotype in iNKT cells, subsequently influencing the composition of mononuclear-phagocyte cells within the tumour microenvironment in CRC. Mechanistically, in vivo and in vitro experiments show that P. gingivalis reduces the cytotoxic functions of iNKT cells, hampering the iNKT cell lytic machinery though increased expression of chitinase 3-like-1 protein (CHI3L1). Neutralization of CHI3L1 effectively restores iNKT cell cytotoxic functions suggesting a therapeutic potential to reactivate iNKT cell-mediated antitumour immunity. In conclusion, our data demonstrate how P. gingivalis accelerates CRC progression by inducing iNKT cells to upregulate CHI3L1, thus impairing iNKT cell cytotoxicity and promoting host tumour immune evasion.

immunology↗

bioRxiv2023

Native extracellular matrix promotes human neuromuscular organoid morphogenesis and function.

Human neuromuscular organoids (NMOs) derived from induced pluripotent stem cells (hiPSCs) hold a great potential to study (dys)functional human skeletal muscle (SkM) in vitro. The three-dimensional (3D) self-assembly of NMOs leads to the generation of spheroids, whose 3D organization cannot be controlled. Indeed, proper development, maturation and function of the innervated SkM require a well-defined multiscale 3D organization of the cells in a tissue-specific extracellular matrix (ECM) context. We hypothesized that extracellular structural imprinting along with hiPSC small-molecule-based differentiation could provide self-assembly guidance driving NMO morphogenesis and promoting the maturation and function of the human neuronal-coupled SkM in vitro models. We found that SkM ECM, provided as decellularized skeletal muscle, is able to reproducibly guide the morphogenesis of differentiating hiPSC toward multiscale structured tissue-like NMOs (t-NMOs). T-NMOs show contractile activity and possess functional neuromuscular junctions (NMJs), with mature neuromuscular system upon 30 days of hiPSC differentiation. We found that t-NMO could mimic altered muscle contraction upon administration of neurotoxins that act at NMJ level. Finally, we used hiPSCs derived from patients affected by Duchenne Muscular Dystrophy (DMD) to produce DMD t-NMOs that, upon neuronal stimulation, were able to mimic the altered SkM contractility and calcium dynamics typical of the disease. Altogether, our data confirm the ability of t-NMO platform to model in vitro human neuromuscular system (patho)physiology.

cell biology↗