Biology subjects

Besson-Girard, S.

Publications and source records attributed to Besson-Girard, S..

7 recordsLinked to original sources

bioRxiv2026

Matched single-cell chromatin, transcriptome, and surface marker profiling captures in vivo epigenomic reprogramming during basal-to-luminal transition in the mammary gland

Single-cell multi-omics methods enable simultaneous mapping of chromatin states and transcriptomes, offering deep insights into gene regulation. Yet, the full potential of these approaches remains untapped for rare cell populations, as most methods require thousands of cells and are limited in their ability to capture multiple molecular layers comprehensively within the same cell. Here, we introduce OneCell CUT&Tag a user-friendly method that provides matched high-resolution epigenome, full-transcriptome, and surface marker quantification from every cell, with input as low as one cell. Using this approach, we uncovered epigenomic priming of basal cells in the mammary gland and captured the dynamics of basal-to-luminal transdifferentiation. We identified a transitional cell population with intermediate epigenomic profiles--absent in reference populations--and demonstrated a continuous epigenomic progression from basal to luminal states, while transcriptomes exhibited a binary switch. Adaptable to diverse samples and tissues, this method also revealed the role of H3K27me3 in shaping zygotic expression programs. By matching multiple layers of molecular information at single-cell resolution, OneCell CUT&Tag dissects the complementary roles of each omics layer in shaping cellular identity and function, opening new avenues to study rare and complex biological systems.

genomics↗

bioRxiv2023

Innate immune memory after brain injury drives inflammatory cardiac dysfunction

The enormous medical burden of stroke is not only due to the brain injury itself and the acute systemic effects, but is largely determined by chronic comorbidities that develop secondarily after stroke. We hypothesized that the high rate of comorbidity developing after a stroke might have a shared immunological cause, however, the chronic effects of brain injury on systemic immunity have so far been barely investigated. Here, we identified myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Using single-cell sequencing, we identified persistent pro-inflammatory transcriptomic changes in resident monocytes/macrophages in multiple organs one month after experimental ischemic brain injury, which was particularly abundant in the heart and associated with the development of cardiac fibrosis and diastolic dysfunction. A similar phenotype was seen in myocardial autopsy samples from stroke versus control patients. We observed chronic functional changes in myeloid hematopoiesis driven by post-stroke IL-1{beta}-mediated epigenetic changes. These alterations could be transplanted to naive recipient mice and were sufficient to induce cardiac dysfunction. By effectively blocking the trafficking of pro-inflammatory monocytes from the bone marrow to the heart using a dual CCR2/5 inhibitor, we successfully prevented post-stroke cardiac dysfunction. This approach holds promising potential as a novel immune-targeted secondary prevention therapy. We anticipate that the epigenetic immune reprogramming mechanisms detailed here for the brain-heart axis could be generalized to provide a novel framework for explaining the development of various comorbidities after acute tissue injury in remote organs.

immunology↗

bioRxiv2023

Continued dysfunction of capillary pericytes promotes no-reflow after experimental stroke in vivo

Incomplete reperfusion of the microvasculature ("no-reflow") after ischemic stroke damages salvageable brain tissue. Previous ex-vivo studies suggest pericytes are vulnerable to ischemia and may exacerbate no-reflow, but the viability of pericytes and their association with no-reflow remains underexplored in vivo. Using longitudinal in vivo 2-photon single-cell imaging over seven days we show 87% of pericytes constrict during cerebral ischemia, remain constricted post-reperfusion and 50% of the pericyte population are acutely damaged. Moreover, we reveal ischemic pericytes are fundamentally implicated in capillary no-reflow by limiting and arresting blood flow within the first 24 hours post-stroke. Despite sustaining acute membrane damage, we observe up to 80% of cortical pericytes survive ischemia, upregulate unique transcriptomic profiles and replicate. Finally, we demonstrate delayed recovery of capillary diameter by ischemic pericytes after reperfusion predicts vessel reconstriction in the sub-acute phase of stroke. Cumulatively, these findings demonstrate surviving cortical pericytes remain both viable and promising therapeutic targets to counteract no-reflow after ischemic stroke.

neuroscience↗

bioRxiv2022

Spatial Transcriptomics-correlated Electron Microscopy

Current spatial transcriptomics methods identify cell states in a spatial context but lack morphological information. Scanning electron microscopy, in contrast, provides structural details at nanometer resolution but lacks molecular decoding of the diverse cellular states. To address this, we correlated MERFISH spatial transcriptomics with large area volume electron microscopy using adjacent tissue sections. We applied our technology to characterize the damage-associated microglial identities in mouse brain, allowing us, for the first time, to link the morphology of foamy microglia and interferon-response microglia with their transcriptional signatures.

neuroscience↗

bioRxiv2022

T cells induce interferon-responsive oligodendrocytes during white matter aging

A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. Here, we found age-related alterations of oligodendrocytes with a reduction of total oligodendrocyte density in the aging murine white matter. Using single-cell RNA sequencing, we identify interferon-responsive oligodendrocytes, which localize in proximity of CD8+ T cells in the aging white matter. Absence of functional lymphocytes decreased oligodendrocyte reactivity and rescued oligodendrocyte loss, while T-cell checkpoint inhibition worsened the aging affect. In summary, we provide evidence that T cells induced interferon-responsive oligodendrocytes are important modifiers of white matter aging.

neuroscience↗

bioRxiv2021

Multi-omics and 3D-imaging reveal bone heterogeneity and unique calvaria cells in neuroinflammation

The meninges of the brain are an important component of neuroinflammatory response. Diverse immune cells move from the calvaria marrow into the dura mater via recently discovered skull-meninges connections (SMCs). However, how the calvaria bone marrow is different from the other bones and whether and how it contributes to human diseases remain unknown. Using multi-omics approaches and whole mouse transparency we reveal that bone marrow cells are highly heterogeneous across the mouse body. The calvaria harbors the most distinct molecular signature with hundreds of differentially expressed genes and proteins. Acute brain injury induces skull-specific alterations including increased calvaria cell numbers. Moreover, TSPO-positron-emission-tomography imaging of stroke, multiple sclerosis and neurodegenerative disease patients demonstrate disease-associated uptake patterns in the human skull, mirroring the underlying brain inflammation. Our study indicates that the calvaria is more than a physical barrier, and its immune cells may present new ways to control brain pathologies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/473988v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@978194org.highwire.dtl.DTLVardef@bc45e8org.highwire.dtl.DTLVardef@91afdborg.highwire.dtl.DTLVardef@b06bc6_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBone marrow across the mouse body display heterogeneity in their molecular profile C_LIO_LICalvaria cells have a distinct profile that is relevant to brain pathologies C_LIO_LIBrain native proteins are identified in calvaria in pathological states C_LIO_LITSPO-PET imaging of the human skull can be a proxy of neuroinflammation in the brain C_LI Supplementary Videos can be seen at: http://discotechnologies.org/Calvaria/

cell biology↗

bioRxiv2021

T cells modulate the microglial response to brain ischemia

Neuroinflammation after stroke is characterized by the activation of resident microglia and the invasion of circulating leukocytes into the brain. Although lymphocytes infiltrate the brain in small number, they have been consistently demonstrated to be the most potent leukocyte subpopulation contributing to secondary inflammatory brain injury. However, the exact mechanism how this minimal number of lymphocytes can profoundly affect stroke outcome is still largely elusive. Here, using a mouse model for ischemic stroke, we demonstrated that early activation of microglia in response to stroke is differentially regulated by distinct T cell subpopulations. Acute treatment with engineered T cells overexpressing IL-10 administered into the cisterna magna after stroke induces a switch of microglial gene expression to a profile associated with pro-regenerative functions. These findings substantiate the role of T cells in stroke with large impact on the cerebral inflammatory milieu by polarizing the microglial phenotype. Targeting T cell-microglia interactions can have direct translational relevance for further development of immune-targeted therapies for stroke and other neuroinflammatory conditions. SummaryThe crosstalk between brain infiltrating T cells and microglia in response to stroke remains elusive. Benakis et al. report that transcriptional signature of the stroke-associated microglia is reprogrammed by distinct T cell subpopulations. Engineered T cells overexpressing IL-10 administered four hours after stroke reinitiate microglial function inducing a pro-regenerative environment.

immunology↗