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Results for “intestinal stem cells”

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At least 19 recordsLinked to original sources
PubMed2026

Co-targeting Deregulated WNT and MAPK Signaling Pathways Limits Phenotypic Reprogramming of Intestinal Stem Cell Progeny in KRAS-Hyperactivated Colorectal Cancer.

In their recent article, Moore and colleagues demonstrate that, upon KRAS hyperactivation, colorectal cancer growth is driven by a reprogramming of Lgr5+ intestinal stem cell (ISC) progeny towards the acquisition of a regenerative phenotype. They find that this phenotype is regulated by a balance between WNT-related ISCs and MAPK-related regenerative and proliferative transcriptional programs. By targeting both pathways, they are able to suppress this dynamic plasticity and achieve tumor regression in cell line and mouse models. The antagonistic relationship between these central pathways defined here provides key insights into genomic patterns of colorectal cancer and targeted therapy strategies.

Colorectal Neoplasms↗
PubMed1979

[Irreversibility of intestinal epithelium stem cell conversion into semi-stem enterocytes and the ability of the latter to reproduce themselves].

The analysis of literature experimental data on cell kinetics of the generating intestinal epithelium of rats and mice suggested the irreversibility of transformation of intestinal epithelium stem cells into non-stem proliferating enterocytes and the ability of the latter for self-reproduction. This property of half-stem enterocytes enabled us to assume that the daughter cells immediately after their appearance are always in the G1-phase of the mother cell mitotic cycle.

Animals↗
PubMed2026

A conserved Notch-Meis1-Pbx cascade specifies secretory progenitors into spatially diverse intestinal best4 + cells.

best4 + cells are a recently described vertebrate intestinal epithelial cell type. best4 + cells are altered in inflammatory bowel disease and colorectal cancer, suggesting that stimulation of their homeostatic replenishment may have therapeutic potential. However, the development and function of best4 + cells remain unclear. Since mice lack best4 + cells, we established zebrafish as a tractable in vivo model to observe, manipulate, and remove best4 + cells in an organismal context. We dissected best4 + cell developmental regulation in vivo from birth to differentiation and specialization, focusing on factors conserved in best4 + cells across vertebrates. Lineage tracing demonstrated that best4 + cells arise from secretory progenitors, where Notch/Dll4 signaling mediates a decision between best4 + and enterochromaffin cells by triggering meis1b expression. Following specification by meis1b, pbx3a spatially diversifies best4 + cells, which develop regional heterogeneity in gene expression, intracellular pH, and function. In vivo live imaging and removal of best4 + cells showed that best4+ cells sense luminal pH changes and extend dynamic luminal and stromal projections, but are not required to restore global luminal pH after challenge. Altogether, this study experimentally delineates best4 + cell developmental regulation and develops a genetic toolkit to examine their function in vivo, both of which will aid investigating how best4 + cells are altered or can be restored during disease.

Animals↗
PubMed1979

Cytotoxic effects of colcemid or high specific activity tritiated thymidine on clonogenic cell survival in B6CF1 mice.

High specific activity tritiated thymidine (HSA-[3H]TdR) and colcemid were given in cytotoxic doses and regimens to B6CF1/Anl mice. The number of cells per intestinal crypt was reduced by the S-phase-specific (HSA-[3H]TdR and the metaphase blocking and cytotoxic effect of multiple injections of colcemid. In 50-day-old mice, the cytotoxic effect of multiple injections of colcemid reduced both the number of cells per crypt and the clonogenic cell survival. However, the number of surviving intestinal clonogenic or stem cells, assayed by the microcolony technique, did not change in 110--130-day old mice. These data suggest that most of the cells at risk from these cytotoxic agents are not clonogenic in adult 110--130-day old mice but are the cells in amplification division. However, since the stem cells of young mice are more susceptible to colcemid, they are apparently in a more rapid cell cycle than those of older mice. The clonogenic cell survival measured in 110--130-day old mice after a single radiation dose of 14 Gy (1400 rad) responded in a non-linear way to increasing time of continuous colcemid cytotoxicity. These data suggest that the intestinal stem cells can respond to amplification compartment cell death by a shortening of their cell cycle and thus, over time, the number of stem cells at risk to colcemid cytotoxicity increases.

Animals↗
PubMed2026

Spatiotemporal single-cell profiling reveals T cell clonal dynamics and phenotypic plasticity in human graft-versus-host disease.

Allogeneic hematopoietic cell transplantation cures hematologic diseases but is limited by acute graft‑versus‑host disease. How human T cell clones drive epithelial injury remains poorly mapped. We studied 31 transplant recipients, integrating longitudinal T cell antigen receptor (TCR) profiling with single-cell RNA sequencing/TCR sequencing and spatial transcriptomics to track T cell clonal dynamics. We developed DecompTCR to resolve temporal dynamics and adapted computational tools to map clone phenotypes and niches in tissue. Our analyses revealed that cyclophosphamide selectively depletes alloreactive clones, although insufficient early expansion leads to incomplete depletion and severe disease. Severe graft‑versus‑host disease is marked by persistent expansion of alloreactive clones, rewiring of homeostatic cell types and diversification of donor-derived CD8+ clonotypes that acquire Hobit (ZNF683)+ tissue‑resident memory T (TRM) cell programs during migration to epithelium. Spatial deconvolution identified CD8+ effector/Hobit+ TRM hubs near intestinal stem‑cell-rich crypt bases and crypt‑loss regions. This clonotype‑resolved framework links tissue‑instructed TRM cell remodeling to localized epithelial injury, nominating early-repertoire dynamics and spatial hub burden as biomarkers.

Journal Article↗
PubMed1979

Time factors in total body irradiation.

The role of time dose factors in the irradiation effect of the bone marrow has been investigated in mice by assessing the lethal dose 50% as a function of fraction number and dose rate. It is compared to the time dose effect in intestinal mucosa and lung, considered as critical tissues, for discussing the differential effect between these tissues.

Animals↗
PubMed2023

Bacteroides ovatus alleviates dysbiotic microbiota-induced intestinal graft-versus-host disease.

Acute gastrointestinal intestinal GVHD (aGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation, and the intestinal microbiota is known to impact on its severity. However, an association between treatment response of aGI-GVHD and the intestinal microbiota has not been well-studied. In a cohort of patients with aGI-GVHD (n=37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and loss of Bacteroides ovatus from the microbiome. In a mouse model of carbapenem-aggravated GVHD, introducing Bacteroides ovatus reduced severity of GVHD and improved survival. Bacteroides ovatus reduced degradation of colonic mucus by another intestinal commensal, Bacteroides thetaiotaomicron, via its ability to metabolize dietary polysaccharides into monosaccharides, which then inhibit mucus degradation by Bacteroides thetaiotaomicron and reduce GVHD-related mortality.

Bacteroides ovatus↗
PubMed2025

Fetal-like reversion in the regenerating intestine is regulated by mesenchymal asporin.

Mesenchymal cells and the extracellular matrix (ECM) support epithelium during homeostasis and regeneration. However, the role of the mesenchyme in epithelial conversion into a fetal-like regenerative state after damage is not known. We modeled epithelial regeneration by culturing intestinal epithelium on decellularized small intestinal scaffolds (iECM) and identify asporin (Aspn), an ECM-bound proteoglycan, as a critical mediator of epithelial fetal-like reprogramming. After damage, transient increase in Aspn expression by the pericryptal fibroblasts induces epithelial transforming growth factor β (TGF-β)-signaling via CD44 and promotes timely epithelial reprogramming. Temporal control of Aspn is lost in old mice, and after damage, the persistently high level of Aspn stagnates epithelium in the regenerative state. Increase in Wnt signaling can resolve the stagnated regenerative program of the old epithelium, promoting restoration of tissue function. In summary, we establish a platform for modeling epithelial injury responses ex vivo and show that the mesenchymal Aspn-producing niche modulates tissue repair by regulating epithelial fetal-like reprogramming.

Animals↗
PubMed2024

Bacteroides ovatus alleviates dysbiotic microbiota-induced graft-versus-host disease.

Acute lower gastrointestinal GVHD (aLGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Although the intestinal microbiota is associated with the incidence of aLGI-GVHD, how the intestinal microbiota impacts treatment responses in aLGI-GVHD has not been thoroughly studied. In a cohort of patients with aLGI-GVHD (n = 37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and a disrupted fecal microbiome characterized by reduced abundances of Bacteroides ovatus. In a murine GVHD model aggravated by carbapenem antibiotics, introducing B. ovatus reduced GVHD severity and improved survival. These beneficial effects of Bacteroides ovatus were linked to its ability to metabolize dietary polysaccharides into monosaccharides, which suppressed the mucus-degrading capabilities of colonic mucus degraders such as Bacteroides thetaiotaomicron and Akkermansia muciniphila, thus reducing GVHD-related mortality. Collectively, these findings reveal the importance of microbiota in aLGI-GVHD and therapeutic potential of B. ovatus.

Graft vs Host Disease↗
PubMed2024

In vivo editing of lung stem cells for durable gene correction in mice.

In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)-sgR553X LNPs mediated >95% cystic fibrosis transmembrane conductance regulator (CFTR) DNA correction, restored CFTR function in primary patient-derived bronchial epithelial cells equivalent to Trikafta for F508del, corrected intestinal organoids and corrected R553X nonsense mutations in 50% of lung stem cells in CF mice. These findings introduce LNP-enabled tissue stem cell editing for disease-modifying genome correction.

Animals↗