Biology subjects

Paccalet, A.

Publications and source records attributed to Paccalet, A..

4 recordsLinked to original sources

bioRxiv2025

Bone marrow mesenchymal stromal cells mediate cellular inflammation in HFpEF

During the genesis of heart failure, the myocardium recruits an abundance of bone marrow-derived leukocytes, primarily monocytes, with various disease-promoting functions. Increased hematopoiesis fuels these unfavorable changes in cardiac leukocyte origin, number and phenotype. Here we examine hematopoietic niche cells, which regulate blood progenitor proliferation and systemic monocyte supply, in obese, hypertensive mice that develop heart failure with preserved ejection fraction (HFpEF). Single cell transcriptomics revealed that in HFpEF, stromal bone marrow niche cells expand and respond strongly to IFN{gamma}. Deleting the IFN{gamma} receptor in stromal cells of Prrx1CreERT2;Ifngr1fl/fl mice reduced hematopoietic progenitor proliferation and systemic monocytes in both the steady state and HFpEF and also increased the canonical hematopoietic maintenance factor CXCL12, resulting in reduced fibrosis and improved diastolic function. CD8+ T cells in adipose tissue were a major source of IFN{gamma} in mice with HFpEF; their depletion restored CXCL12 expression and lowered monocyte numbers. ScRNA-seq in mice with ischemic heart disease uncovered a diverging marrow response. These data indicate that in HFpEF, adipose tissue, bone marrow and adaptive and innate immune cells conspire to expand harmful macrophage subsets in the heart.

immunology↗

bioRxiv2024

Therapeutic Spp1 silencing in TREM2+ cardiac macrophages suppresses atrial fibrillation

Atrial fibrillation (AFib) and the risk of its lethal complications are propelled by fibrosis, which induces electrical heterogeneity and gives rise to reentry circuits. Atrial TREM2+ macrophages secrete osteopontin (encoded by Spp1), a matricellular signaling protein that engenders fibrosis and AFib. Here we show that silencing Spp1 in TREM2+ cardiac macrophages with an antibody-siRNA conjugate reduces atrial fibrosis and suppresses AFib in mice, thus offering a new immunotherapy for the most common arrhythmia.

immunology↗

bioRxiv2023

Oxidation-reduction imaging of myoglobin unveils two-phase oxidation in the reperfused myocardium.

Myocardial infarction (MI) is a serious cardiovascular problem that causes myocardial injury due to blood flow obstruction to a specific myocardial area. Under ischemic-reperfusion settings, a burst of reactive oxygen species is generated, leading to redox imbalance that could be attributed to several molecules, including myoglobin. Myoglobin is dynamic and exhibits various oxidation-reduction states that have been a subject of attention in the food industry, specifically for meat consumers. However, rarely if ever, have the myoglobin optical properties been used to understand the pathology of MI. In the current study, we develop a novel imaging pipeline that integrates tissue clearing, confocal and light sheet fluorescence microscopy, combined with imaging analysis, and processing tools to investigate and characterize the oxidation-reduction states of myoglobin in the ischemic area of the myocardium post-MI. Using spectral imaging, we have characterized the endogenous fluorescence of the myocardium and demonstrated that it aligns with the spectral profile of myoglobin. Under ischemia-reperfusion experimental settings, we report that the infarcted myocardium spectral signature is similar to that of oxidized myoglobin signal that peaks 3 hours post-reperfusion and decreases with cardioprotection. These results were correlated with MI measurements by Late Gadolinium Enhancement MRI. In conclusion, this seminal work suggests that the redox state of myoglobin can be used as a promising imaging biomarker for characterizing and estimating the size of the MI during early phases of reperfusion.

pathology↗

bioRxiv2021

Brain virtual histology with X-ray phase-contrast tomography Part I: whole-brain myelin mapping in white-matter injury models

White-matter injury leads to severe functional loss in many neurological diseases. Myelin staining on histological samples is the most common technique to investigate white-matter fibers. However, tissue processing and sectioning may affect the reliability of 3D volumetric assessments. The purpose of this study was to propose an approach that enables myelin fibers to be mapped in the whole rodent brain with microscopic resolution and without the need for strenuous staining. With this aim, we coupled inline (propagation-based) X-ray phase-contrast tomography (XPCT) to ethanol-induced brain sample dehydration. We here provide the proof-of-concept that this approach enhances myelinated axons in rodent and human brain tissue. In addition, we demonstrated that white-matter injuries could be detected and quantified with this approach, using three animal models: ischemic stroke, premature birth and multiple sclerosis. Furthermore, in analogy to diffusion tensor imaging (DTI), we retrieved fiber directions and DTI-like diffusion metrics from our XPCT data to quantitatively characterize white-matter microstructure. Finally, we showed that this non-destructive approach was compatible with subsequent complementary brain sample analysis by conventional histology. In-line XPCT might thus become a novel gold-standard for investigating white-matter injury in the intact brain. This is Part I of a series of two articles reporting the value of in-line XPCT for virtual histology of the brain; Part II shows how in-line XPCT enables the whole-brain 3D morphometric analysis of amyloid-{beta} (A{beta}) plaques. HighlightsO_LIX-ray phase-contrast tomography (XPCT) enables myelin mapping of the whole brain C_LIO_LIXPCT detects and quantifies white-matter injuries in a range of diseases C_LIO_LIFiber directions and anisotropy metrics can be retrieved from XPCT data C_LIO_LIXPCT is compatible with subsequent conventional histology of brain samples C_LIO_LIXPCT is a powerful virtual histology tool that requires minimal sample preparation C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/436852v3_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@1b06ba6org.highwire.dtl.DTLVardef@16b8d4aorg.highwire.dtl.DTLVardef@91cfborg.highwire.dtl.DTLVardef@4dcbca_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗