Biology subjects

Benveniste, O.

Publications and source records attributed to Benveniste, O..

3 recordsLinked to original sources

bioRxiv2025

Defective plasticity in dermatomyositis patients muscle stem cells is associated with sustained intrinsic inflammatory signaling and disruption of the histone H3.3 chromatin loading pathway

Skeletal muscle regeneration is driven by muscle stem cells (MuSCs), which proliferate, differentiate and fuse to reform myofibers and restore muscle function. This myogenesis process is driven both by intrinsic MuSC properties and extrinsic cues. While coordinated inflammatory signals are necessary for healthy regeneration, chronic inflammation participates in various pathologies affecting the skeletal muscle. In the idiopathic inflammatory myopathy dermatomyositis (DM), MuSCs exhibit impaired myogenesis in vitro, indicating that they may have acquired intrinsic defects, contributing to the disease and providing a mechanism for sustained patient muscle weakness despite efficient anti-inflammatory treatments. Here, we investigated the transcriptomic regulation of DM-derived MuSCs, with a focus on the H3.3 histone variant which regulates myogenesis progression. DM-derived MuSCs were unable to effectively execute the myogenic transcriptional program during in vitro differentiation. They exhibited an activated canonical TNF- signaling. They also showed reduced expression of H3.3 and its chaperone genes, coupled with a decrease in H3.3 deposition across the entire genome, and particularly at myogenic regulatory factor loci. The loss of H3.3 combined with elevated TNF- signaling was associated with a failure of DM-derived MuSCs to achieve myogenesis, suggesting a mechanistic link between epigenetic dysregulation and defective muscle regeneration in humans.

molecular biology↗

bioRxiv2024

Distinct pathogenic influence of anti-HMGCR+ and anti-SRP+ immune-mediated necrotizing myopathy autoantibodies on engineered muscle function

Immune-mediated necrotizing myopathy (IMNM) is a subgroup of idiopathic inflammatory myopathies associated with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies. However, the demonstration of a direct pathogenic effect of IMNM patient autoantibodies on skeletal muscle contractile force, independent of the downstream activation of the complement pathway, has yet to be reported. Thus, the goal of this study was to leverage a custom 3D-human skeletal muscle microtissue (hMMT) culture platform, that enables muscle cell contractile apparatus maturation and the analysis of contractile function, to evaluate the direct effect of total immunoglobulins (IgGs) isolated from IMNM patients with amplification of anti-SRP+ or anti-HMGCR+ autoantibodies. hMMTs capable of force generation were treated with total IgGs, isolated from 3 SRP+ and 3 HMGCR+ patients plasma, and delivered in complement inactivated media for 4 days. hMMT health was then evaluated by quantifying the peak force and contraction kinetics in response to electrical field stimulation and by performing histological analysis of sarcomere and myotube structures. Treating hMMTs with total IgGs from anti-HMGCR+ patients resulted in a decline in tetanus contractile force, though sarcomere Z-line architecture analysis revealed no significant influences on sarcomere organization. hMMT treatment with total IgGs from anti-SRP+ patients induced muscle atrophy, observed via significantly smaller myotube diameter, but this did not translate to a decline in contractile function. This study demonstrates that anti-SRP and anti-HMGCR autoantibodies exert direct, but distinct influences on IMNM-associated skeletal muscle pathogenesis, which may inform IMNM therapy development.

bioengineering↗

bioRxiv2018

Clinical data specification and coding for cross-analyses with omics data in autoimmune disease trials

ObjectivesAutoimmune and inflammatory diseases (AIDs) form a continuum of autoimmune and inflammatory diseases, yet AIDs nosology is based on syndromic classification. The TRANSIMMUNOM trial (NCT02466217) was designed to re-evaluate AIDs nosology through clinic-biological and multi-omics investigations of patients with one of 19 selected AIDs. To allow cross-analyses of clinic-biological data together with omics data, we needed to integrate clinical data in a harmonized database.\n\nMaterials and MethodsWe assembled a clinical expert consortium (CEC) to select relevant clinic-biological features to be collected for all patients and a cohort management team comprising biologists, clinicians and computer scientists to design an electronic case report form (eCRF). The eCRF design and implementation has been done on OpenClinica, an open-source CFR-part 11 compliant electronic data capture system.\n\nResultsThe CEC selected 865 clinical and biological parameters. The CMT selected coded the items using CDISC standards into 5835 coded values organized in 28 structured eCRFs. Examples of such coding are check boxes for clinical investigation, numerical values with units, disease scores as a result of an automated calculations, and coding of possible treatment formulas, doses and dosage regimens per disease.\n\nDiscussion21 CRFs were designed using OpenClinica v3.14 capturing the 5835 coded values per patients. Technical adjustment have been implemented to allow data entry and extraction of this amount of data, rarely achieved in classical eCRFs designs.\n\nConclusionsA multidisciplinary endeavour offers complete and harmonized CRFs for AID clinical investigations that are used in TRANSIMMUNOM and will benefit translational research team.

clinical trials↗