Biology subjects

Bougaran, P.

Publications and source records attributed to Bougaran, P..

4 recordsLinked to original sources

bioRxiv2026

Transmural Single-Nucleus Transcriptomics Nominates Candidate Disease Programs in Human Necrotizing Enterocolitis

Background & Aims: Necrotizing enterocolitis (NEC) is a life-threatening disease of premature infants marked by inflammation, ischemia, mucosal injury, and, in advanced cases, necrosis extending into deeper layers of the intestinal wall. Because NEC affects specialized, interacting cells in a developing intestine, we used single-nucleus transcriptomics to build a transmural, cell-type-resolved map and nominate hypothesis-generating disease programs distinct from maturation. Methods: Full-thickness intestinal specimens from fetal/prenatal controls, acute NEC cases, and infant controls were analyzed by single-nucleus RNA sequencing (snRNA-seq). Fetal and infant samples served as developmental references. Analyses included cell annotation, NEC-versus-infant differential expression, gene ontology (GO), cross-lineage recurrence, cell death signatures, and developmental maturity. Results: We profiled 53,735 nuclei by snRNA-seq and resolved 34 epithelial, stromal, vascular, immune, neuronal, glial, and smooth muscle populations. We used a morphology-based nuclei scoring system for sample selection that predicted high-quality transcript recovery. NEC nuclei were represented across this cellular landscape, with recurrent gene-expression changes suggesting shared inflammatory recruitment, antimicrobial/redox defense, stress adaptation, complement/vascular activation, reduced homeostatic signaling, and cell death-associated regulation. Developmental maturity analysis identified fetal-like expression levels in subsets of NEC-regulated genes. Proliferative crypt populations retained DNA repair/cell-cycle programs with inflammatory, hypoxic, and ER-stress features, while absorptive enterocytes showed reduced digestive, transport, detoxification, and terminal villus-function programs. Secretory-lineage changes implicated goblet mucus-barrier responses with reduced glycosylation, trafficking, and hydration; enteroendocrine changes in epithelial defense, metabolic stress, and neural signaling; and Paneth cell retention of antimicrobial effector transcripts despite altered ER quality control, autophagy, and granule delivery in NEC. Non-epithelial programs implicated stromal Wnt/BMP niche loss, impaired lymphatic drainage/scavenging, macrophage cytokine activation with reduced clearance machinery, neuroglial circuit defects, and altered smooth muscle contraction-relaxation balance. Conclusions: This single nuclear intestinal cell atlas nominates multicellular programs that may govern NEC initiation, progression toward tissue destruction, and resolution toward functional recovery.

pathology↗

bioRxiv2026

Nuclear SUN2 coordinates endothelial cell-matrix interactions to regulate blood vessel homeostasis and barrier function

Vascular endothelial cells respond to environmental forces to remodel vessels during development and to achieve homeostasis, and mis-regulated responses lead to vascular dysfunction and disease. The nucleus participates in force transduction to cell-matrix junctions via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex that resides in the nuclear envelope, but how these forces are regulated and relayed is incompletely understood. We found that the LINC complex protein SUN2 is required for proper endothelial cell-matrix interactions that occur far from the nucleus and affect angiogenic expansion, vascular responses to flow, and barrier integrity. Endothelial cells lacking SUN2 had inappropriate flow responses and reduced expression of flow-mediated transcription factors in vitro and in vivo. Expression of several matrix and adhesion genes was reduced in SUN2-depleted cells, leading to defective extracellular matrix, dysmorphic focal adhesions resistant to dynamic turnover, and disturbed cell-matrix force distribution. Mechanistically, nuclear SUN2 affected dynamic regulation of the microtubule cytoskeleton that correlated with matrix metalloprotease-dependent barrier dysfunction. These findings indicate that nuclear SUN2 establishes and maintains blood vessel homeostasis by controlling microtubule-mediated effects on focal adhesion turnover and extracellular matrix properties, with implications for cardiovascular aging and diseases such as Marfan syndrome that affect vessel wall integrity.

cell biology↗

bioRxiv2024

Resolving the design principles that control postnatal vascular growth and scaling

After birth, tissues grow continuously until reaching adult size, with each organ exhibiting unique cellular dynamics, growth patterns, and (stem or non-stem) cell sources. Using a suite of experimental and computational multiscale approaches, we found that aortic expansion is guided by specific biological principles and scales with the vertebral column rather than animal body weight. Expansion proceeds via two distinct waves of arterial cell proliferation along blood flow that are spatially stochastic, yet temporally coordinated. Each wave exhibits unique cell cycle kinetics and properties, with the first wave exhibiting cell cycle durations as fast as 6 hours. Single-cell RNA sequencing showed changes in fatty acid metabolism concomitant with an increase in cell size. Mathematical modeling and experiments indicated endothelial cell extrusion is essential for homeostatic aortic growth and balancing excess proliferation. In a genetic model of achondroplasia, the aorta achieves proper scaling through enhanced cell extrusion while maintaining normal proliferation dynamics. Collectively, these results provide a blueprint of the principles that orchestrate aortic growth which depends entirely on differentiated cell proliferation rather than resident stem cells.

developmental biology↗

bioRxiv2023

HES1 and ID3 temporally regulate p27 levels and endothelial cell flow-mediated quiescence depth

BackgroundEndothelial cells regulate their cell cycle as blood vessels remodel and transition to quiescence downstream of blood flow-induced mechanotransduction. Laminar blood flow leads to quiescence, but how flow-mediated quiescence is established and maintained is poorly understood. MethodsPrimary human endothelial cells were exposed to laminar flow regimens and gene expression manipulations, and quiescence depth was analyzed via time to cell cycle re-entry after flow cessation. Mouse and zebrafish endothelial expression patterns were examined via scRNA seq analysis, and mutant or morphant fish lacking p27 were analyzed for endothelial cell cycle regulation and in vivo cellular behaviors. ResultsArterial flow-exposed endothelial cells had a distinct transcriptome, and they first entered a deep quiescence, then transitioned to shallow quiescence under homeostatic maintenance conditions. In contrast, venous-flow exposed endothelial cells entered deep quiescence early that did not change with homeostasis. The cell cycle inhibitor p27 (CDKN1B) was required to establish endothelial flow-mediated quiescence, and expression levels positively correlated with quiescence depth. p27 loss in vivo led to endothelial cell cycle upregulation and ectopic sprouting, consistent with loss of quiescence. HES1 and ID3, transcriptional repressors of p27 upregulated by arterial flow, were required for quiescence depth changes and the reduced p27 levels associated with shallow quiescence. ConclusionsEndothelial cell flow-mediated quiescence has unique properties and temporal regulation of quiescence depth that depends on the flow stimulus. These findings are consistent with a model whereby flow-mediated endothelial cell quiescence depth is temporally regulated downstream of p27 transcriptional regulation by HES1 and ID3. The findings are important in understanding endothelial cell quiescence mis-regulation that leads to vascular dysfunction and disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=197 SRC="FIGDIR/small/544403v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1137a1forg.highwire.dtl.DTLVardef@1b6bf1dorg.highwire.dtl.DTLVardef@bd4965org.highwire.dtl.DTLVardef@11dbb9b_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIDifferent quiescence stimuli lead to distinct transcriptional and functional quiescence profiles in endothelial cells C_LIO_LIp27 is required for endothelial cell quiescence and depth is temporally regulated in a flow stimulus-dependent manner that correlates with p27 levels and flow-regulated repressors HES1 and ID3 C_LIO_LIp27 is expressed in endothelial cells according to flow magnitude in vivo and is functionally required for cell cycle regulation and sprouting in vivo C_LI

cell biology↗