Biology subjects

Davidzohn, N.

Publications and source records attributed to Davidzohn, N..

4 recordsLinked to original sources

bioRxiv2026

TLR2-mediated microbial sensing by intestinal stem cells coordinates epithelial antimicrobial defense.

Intestinal regeneration and host defense require adaptation to environmental cues, but the mechanisms underlying this coordination remain unclear. We show that intestinal Lgr5 stem cells act as luminal sensors via apically localized Toll-like receptor 2 (TLR2), enabling direct detection of microbiota-derived signals. We identify apical TLR2 activation as a mechanism of luminal sensing in adult stem cells and show that it controls epithelial differentiation, antimicrobial peptide production, and crypt organization, with a particularly strong influence on Paneth cell maturation. Genetic ablation of constitutive, epithelial, or stem cell-specific TLR2 disrupts these processes, leading to impaired antimicrobial defense and altered epithelial composition. Using germ-free mice and human intestinal organoids, we demonstrate that this pathway is microbiota-dependent and evolutionarily conserved, respectively. These findings support a model in which stem cells act as active integrators of environmental information and suggest a broader principle by which barrier tissues couple microbial sensing to regeneration and host protection.

immunology↗

bioRxiv2025

Persistent ECM Scarring Reprograms Intestinal Stem Cells to Drive Chronic Inflammation

Tissue regeneration is conventionally viewed as a return to homeostasis. Here, we uncover that the extracellular matrix (ECM) in the colon undergoes a lasting pathological reprogramming following inflammation, forming a remodeled niche--modECM--that persistently disrupts intestinal stem cell (ISC) identity. Using temporal multi-omics, biomechanical profiling, and spatial fate mapping in murine colitis models, we show that modECM, characterized by Collagen XVIII accumulation and immune-driven proteolysis, redirects ISCs toward a wound-associated, squamous-like epithelial state with pro-inflammatory transcriptional signatures. Ex vivo, modECM alone reprograms ISC fate by suppressing Wnt signaling and activating immune recruitment pathways. In vivo, modECM-rich zones sustain T cell infiltration and KRT14 epithelial cell emergence from Lgr5 progenitors. This aberrant epithelial program is mirrored in inflamed rectal biopsies from ulcerative colitis patients. Our findings redefine the ECM as a long-lived instructive compartment that encodes injury memory and promotes maladaptive regeneration, positioning it as a potential therapeutic target in chronic inflammatory disease.

immunology↗

bioRxiv2024

Elucidating early intestinal stem cell response to bacterial infection

Intestinal stem cells (ISCs) are the regenerative force of the gut epithelium. Lgr5+-ISC have been shown to respond to changes in their microenvironment by coping with different metabolites, adapting to caloric changes, and recovering from injury and inflammation. However, how pathogenic bacteria affect adult stem cell regeneration and, as a consequence, the overall tissue adaption to infection has yet to be explored in depth. Here, we interrogated early Lgr5+ ISC responses to an enteric intracellular pathogen by profiling individual IECs from the mouse small intestine. Utilizing GFP-labeled Salmonella enterica, we isolated intracellular invaded cells to elucidate invasion programs of epithelial cell subsets. In particular, we identified a Salmonella-specific infection signature comprised of antimicrobial peptide (AMP) genes, including the Defensin gene family. Our findings demonstrate that Salmonella enterica targets differentiated Paneth, enterocytes, and stem/progenitor cells at these early stages of infection. In response, a rapid Lg5+ ISC-driven cellular remodeling to enterocyte and Paneth lineages expressing AMP genes is initiated to combat the intruders. Importantly, we uncovered an ISC differentiation program via inflammasome activation to protect the crypt environment, while eliminating infected stem cells from the overall stem cell pool. This novel Lgr5+ stem cell defense mechanism not only protects the gut epithelium from persistent bacterial infection but also promotes tissue regeneration. We propose epithelial remodeling to AMP-secreting cells as a novel innate immune response to handle different gut stresses mediated by Lgr5+ ISCs to maintain organizational principles of gut homeostasis and physiology.

immunology↗

bioRxiv2021

Dendritic cell ICAM-1 strengthens immune synapses but is dispensable for effector and memory responses

Lymphocyte priming in lymph nodes (LNs) depends on the formation of functional TCR specific immune synapses (ISs) with antigen (Ag) presenting dendritic cells. The high affinity LFA-1 ligand ICAM-1 has been implicated in different ISs studied in vitro. The in vivo roles of DC ICAM-1 in Ag stimulated T cell differentiation have been unclear. In newly generated DC conditional ICAM-1 knockout mice, we report that under Th1 polarizing conditions, ICAM-1 deficient DCs could not engage in stable conjugates with newly generated CD8 blasts. Nevertheless, these DCs triggered normal lymphocyte priming, proliferation and differentiation into functional cytotoxic T cells (CTLs) and central memory lymphocytes (Tcm) in both vaccinated and virus infected skin. Single cell RNAseq analysis confirmed that Tcm were normally generated in these mice and gave rise to normal T effectors during a recall skin response. Our results suggest that although CD8 T cell blasts tightly bind DC-ICAM-1, strongly adhesive DC-T ISs are not necessary for functional TCR dependent DC mediated CD8 T cell proliferation and differentiation into productive effector and memory lymphocytes. SummarySapoznikov et al generated a new genetic murine model deficient in dendritic cell expression of the key adhesion molecule ICAM-1 and found that CD8 lymphocytes do not require strong adhesion to dendritic cells for antigen-dependent differentiation into effector and memory T cells.

immunology↗