Biology subjects

Michel, D.

Publications and source records attributed to Michel, D..

9 recordsLinked to original sources

bioRxiv2026

Bidirectional modulation of aging-associated cellular phenotypes by mitochondrial genome replacement

Mitochondrial dysfunction is a hallmark of cellular aging, but whether age-associated cellular decline can be functionally reversed remains unclear. Here, we applied mitochondrial genome replacement to replicative senescent fibroblasts and aged T cells derived from mice and humans. In senescent fibroblasts, replacement with mitochondria from young cells extended proliferative lifespan, whereas replacement with aged mitochondria accelerated proliferative decline, indicating bidirectional modulation of aging-associated phenotypes. In aged mouse T cells, mitochondrial genome replacement restored proliferative capacity and significantly enhanced antitumor activity following adoptive transfer into tumor-bearing mice. Similarly, mitochondrial genome replacement in aged human T cells enhanced cytokine production and shifted the transcriptomic programs toward a more youthful state. Collectively, these findings identify mitochondrial genetic integrity as a functional regulator of aging-associated cellular states and support the emerging view that mitochondria actively influence cellular aging trajectories.

Cell Biology↗

bioRxiv2025

Intracellular autofluorescence enables the isolation of viable, functional human muscle reserve cells with distinct Pax7 levels and stem cell states.

BackgroundHuman muscle reserve cells (MuRC) represent a quiescent MuSC population generated in vitro that exhibit heterogeneous Pax7 expression, with a Pax7High subset in a deeper quiescent state. However, conventional identification of Pax7High cells requires intracellular staining, limiting their viability for functional studies. This study investigates autofluorescence (AF) as a potential biomarker to identify functionally distinct human MuRC subpopulations. MethodsHuman myoblasts (MB) and MuRC were analysed for AF by fluorescence microscopy and flow cytometry. Cellular metabolic composition was assessed by NADH/NADPH quantification and lipid staining. Human MuRC subpopulations were sorted by AF intensity and analysed for Pax7 expression, cell cycle re-entry, proliferation, clonal expansion, and myogenic differentiation. In vivo transplantation of MuRC-AFHigh and MuRC-AFLow populations into immunodeficient mice assessed survival and regenerative potential using bioluminescence imaging and immunohistochemistry. ResultsHuman MuRC showed a 3-fold increase in mean fluorescence intensity compared to MB, with AF peak at 405 nm excitation. Lipid staining revealed a 1.6-fold increase in lipid content in MuRC, while NADH/NADPH levels were similar between MB and MuRC. Flow cytometry identified MuRC-AFHigh as a Pax7High-enriched subpopulation. Functionally, MuRC-AFHigh cells exhibited delayed cell cycle re-entry and slower proliferation but retained differentiation potential. In vivo, both MuRC-AFHigh and MuRC-AFLow survived transplantation with no significant differences in engraftment efficiency. They contributed to the generation of human Pax7 positives MuSC and both subpopulations retain their regenerative capacity upon re-injury. ConclusionAF allows the identification of human MuRC subsets, with the AFHigh subpopulation associated with increased lipid content. MuRC-AFHigh cells are enriched in Pax7High cells and show delayed activation, slower proliferation and comparable engraftment efficiency to the AFLow subpopulation. These findings provide a novel perspective on AF as a potential biomarker to identify functionally distinct muscle progenitor subsets and highlight its relevance in muscle regeneration research.

cell biology↗

bioRxiv2024

Unveiling mechanical interactions between cell division and extracellular matrix in human colonic epithelium organoids: A 4D study using DVC

Cell division is a major event in tissue homeostasis, enabling renewal and regeneration. Stem cells, in particular, play an important role in this homeostasis, thanks to their ability to perform symmetric or asymmetric cell divisions. To study cell division, the human colon epithelium represents a model of choice due to its rapid renewal and therefore high proliferative potential. Currently, studying the live mechanical interactions between the epithelium and its matrix in vivo is challenging due to the lack of suitable methods. 3D human colon organoids seeded in Matrigel(R) are good models for this purpose as, from isolated stem cells, they recapitulate the tissue architecture organization and properties. This culture set-up also allows to study the matrix displacements around the organoid. Here, we studied the impact of cell division within the colonic epithelium on the extracellular matrix. We performed and validated an original experimental and analytical process with a 3D time-lapse confocal microscopy to follow cell mitosis and matrix movements on which we performed Digital Volume Correlation. We showed that these two different types of cell division impact the matrix differently with the asymmetric divisions causing a mainly uniaxial displacement, whereas symmetric ones involved a multiaxial and more important one.

cell biology↗

bioRxiv2024

Detection of Antibodies Against the African Parasite Trypanosoma brucei Using Synthetic glycosylphosphatidylinositol oligosaccharide fragments

Trypanosoma brucei (T. brucei) parasites cause two major infectious diseases in Africa: African trypanosomiasis in humans (HAT) and Nagana in animals. Despite the enormous economic and social impact, vaccines and reliable diagnostic measures are still lacking for these diseases. The main obstacle to developing accurate diagnostic methods and an active vaccine is the parasites ability for antigenic variation and impairment of B cell maturation, which prevents the development of a long-lasting, effective immune response. The antigenic variation is sustained by random gene switching, segmental gene conversion, and altered glycosylation states of solvent-exposed regions of the corresponding variant surface glycoproteins (VSG). These glycoproteins use a glycosylphosphatidylinositol (GPI) anchor for attachment to the membrane. GPIs of T. brucei have specific branched structures that are further heterogeneously galactosylated. We synthesized a glycan fragment library containing T. brucei GPIs most prominent structural features and performed an epitope mapping using mice and human sera of infected specimens using glycan microarrays. The studies indicate that in contrast to VSG, T. brucei GPIs are recognized by both short-lived IgM and long-lasting IgG, indicating a specific immune response against GPI structures. These findings enable the development of diagnostic tests based on synthetic antigens for reliable diagnosis of human African trypanosomiasis and Nagana.

biochemistry↗

bioRxiv2023

An interactive web application for exploring human plasma and fibroblast metabolomics data from patients with inborn errors of metabolism

Metabolomic profiling is instrumental in understanding the systemic and cellular impact of inborn errors of metabolism (IEMs), monogenic disorders caused by pathogenic genomic variants in genes involved in metabolism. This study encompasses untargeted metabolomics analysis of plasma from 474 individuals and fibroblasts from 67 subjects, incorporating healthy controls, patients with 65 different monogenic diseases, and numerous undiagnosed cases. We introduce a web application designed for the in-depth exploration of this extensive metabolomics database. The application offers a user-friendly interface for data review, download, and detailed analysis of metabolic deviations linked to IEMs at the level of individual patients or groups of patients with the same diagnosis. It also provides interactive tools for investigating metabolic relationships and offers comparative analyses of plasma and fibroblast profiles. This tool emphasizes the metabolic interplay within and across biological matrices, enriching our understanding of metabolic regulation in health and disease. As a resource, the application provides broad utility in research, offering novel insights into metabolic pathways and their alterations in various disorders.

bioinformatics↗

bioRxiv2023

Characterization of cannabinoid plasma concentration, maternal health, and cytokine levels in a rat model of prenatal Cannabis smoke exposure

Cannabis sativa has gained popularity as a "natural substance", leading many to falsely assume that it is not harmful. This assumption has been documented amongst pregnant mothers, many of whom consider Cannabis use during pregnancy as benign. The purpose of this study was to validate a Cannabis smoke exposure model in pregnant rats by determining the plasma levels of cannabinoids and associated metabolites in the dams after exposure to either Cannabis smoke or injected cannabinoids. Maternal and fetal cytokine and chemokine profiles were also assessed after exposure. Pregnant Sprague-Dawley rats were treated daily from gestational day 6 - 20 with either room air, i.p. vehicle, inhaled high-{Delta}9-tetrahydrocannabinol (THC) (17.98% THC, 0.1% cannabidiol [CBD]) smoke, inhaled high-CBD (0.1% THC, 12.83% CBD) smoke, 3 mg/kg i.p. THC, or 10 mg/kg i.p. CBD. Our data reveal that THC and CBD, but not their metabolites, accumulate in maternal plasma after repeated exposures. Injection of THC or CBD was associated with fewer offspring and increased uterine reabsorption events. For cytokines and chemokines, injection of THC or CBD up-regulated several pro-inflammatory cytokines compared to control or high-THC smoke or high-CBD smoke in placental and fetal brain tissue, whereas smoke exposure was generally associated with reduced cytokine and chemokine concentrations in placental and fetal brain tissue compared to controls. These results support existing, but limited, knowledge on how different routes of administration contribute to inconsistent manifestations of cannabinoid-mediated effects on pregnancy. Smoked Cannabis is still the most common means of human consumption, and more preclinical investigation is needed to determine the effects of smoke inhalation on developmental and behavioural trajectories.

pharmacology and toxicology↗

bioRxiv2023

Deciphering the interplay between biology and physics: finite element method-implemented vertex organoid model raises the challenge

Understanding the intertwining of biology and mechanics in tissue architecture is a challenging issue, especially when it comes to the 3D tissue organization. Addressing this challenge requires both a biological model allowing multiscale observations from the cell to the tissue, and theoretical and computational approaches allowing the generation of a synthetic model, relevant to the biological model, and allowing access to the mechanical constraints experienced by the tissue. Here, using human colon epithelium monolayer organoid as biological model, and combining vertex and FEM approaches, we generated a comprehensive elastic finite element model of the human colon organoid and demonstrated its flexibility. This FEM model provides a basis for relating cell shape, tissue deformation, and strain at the cellular level due to imposed stresses. In conclusion, we demonstrated that the combination of vertex and FEM approaches allows for better modeling of the alteration of organoid morphology over time and better assessment of the mechanical cues involved in establishing the architecture of the human colon epithelium.

biophysics↗

bioRxiv2019

The thrombopoietin receptor agonist eltrombopag inhibits human cytomegalovirus replication via iron chelation

The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interferes with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after haematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses and synergistically increase the effects of ganciclovir, eltrombopag is also a drug repurposing candidate for the treatment of therapy-refractory HCMV disease.

pharmacology and toxicology↗

bioRxiv2019

The basal level of gene expression associated with chromatin loosening shapes Waddington landscapes and controls cell differentiation

The baseline level of transcription is variable and seriously complicates the normalization of comparative transcriptomic data, but its biological importance remains unappreciated. We show that this ingredient is in fact crucial for the interpretation of molecular biology results. It is correlated to the degree of chromatin loosening measured by DNA accessibility, and systematically leads to cellular dedifferentiation as assessed by transcriptomic signatures, irrespective of the molecular and cellular tools used. A theoretical analysis of gene circuits formally involved in differentiation, reveals that the epigenetic landscapes of Waddington are restructured by the level of non-specific expression, such that the attractors of progenitor and differentiated cells can be mutually exclusive. Together, these results unveil a generic principle of epigenetic landscape remodeling in which the basal gene expression level, notoriously important in pluripotent cells, allows the maintenance of stemness by generating a specific landscape and in turn, its reduction favors multistability and thereby differentiation. This study highlights how heterochromatin maintenance is essential for preventing pathological cellular reprogramming, age-related diseases and cancer.

cell biology↗