Self-maintenance of zonal hepatocytes during adult homeostasis and their complex plasticity upon distinct liver injuries.

Hepatocytes are organized into distinct zonal subsets across the liver lobule, yet their contributions to liver homeostasis and regeneration remain controversial. Here, we developed multiple genetic lineage-tracing mouse models to systematically address this. We found that the liver lobule can be divided into two major zonal and molecular hepatocyte populations marked by Cyp2e1 or Gls2.

Maternal gut microbiota influence stem cell function in offspring.

The maternal microbiome influences child health. However, its impact on a given offspring's stem cells, which regulate development, remains poorly understood. To investigate the role of the maternal microbiome in conditioning the offspring's stem cells, we manipulated maternal microbiota using Akkermansia muciniphila.

Lgr5 + intestinal stem cells are required for organoid survival after genotoxic injury.

Progenitors and mature cells can maintain the intestinal epithelium by dedifferentiation and facultative intestinal stem cell (fISC) function when active ISCs (aISCs) are lost to damage. Here, we modeled fISC activation in mouse intestinal organoids with doxorubicin (DXR) treatment, a chemotherapeutic known to ablate Lgr5+ aISCs in vivo. Similar fISC gene activation was observed between organoids treated with low versus high DXR, despite significantly decreased survival at the higher dose.

Lgr5 marks stem/progenitor cells contributing to epithelial and muscle development in the mouse esophagus.

The existence and function of Lgr5 cells within the developing esophagus remains unknown. Here, we document multiple discrete Lgr5 populations in the developing mouse esophagus, predominantly within nascent epithelial and external muscle layers. Lgr5 expression initially emerges in the developing proximal embryonic epithelium, but progressively extends distally and persists within the distal epithelium of neonates.

Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis.

The circadian clock regulates daily rhythms of numerous physiological activities through tightly coordinated modulation of gene expression and biochemical functions. Circadian disruption is associated with enhanced tumor formation and metastasis via dysregulation of key biological processes and modulation of cancer stem cells (CSCs) and their specialized microenvironment. Here, we review how the circadian clock influences CSCs and their local tumor niches in the context of different stages of tumor metastasis.

+ intestinal stem cells are required for organoid survival after genotoxic injury.

Progenitors and mature cells can maintain the intestinal epithelium by dedifferentiation and facultative intestinal stem cell (fISC) function when active ISCs (aISCs) are lost to damage. Here, we sought to model fISC activation in intestinal organoids with doxorubicin (DXR), a chemotherapeutic known to ablate + aISCs . We identified low and high doses of DXR compatible with long-term organoid survival.

Minimum intervention oral care - incentivising preventive management of high-needs/high caries-risk patients using phased courses of treatment.

This paper demonstrates how person-focused, prevention-based, risk/needs-related, team-delivered, minimum intervention oral care (MIOC) principles and approaches can be integrated into the dental profession for the delivery of environmentally sustainable, optimal care to high-needs and high caries-risk/susceptibility patients. It highlights the potential for NHS remuneration for prevention-based, phased, personalised care pathways/plans (PCPs) within a reformed NHS dental contract system. It emphasises the importance of comprehensive and longitudinal patient risk/susceptibility assessments, prevention and stabilisation of the oral environment before considering more complex, definitive restorative work.

A Mutation-driven oncofetal regression fuels phenotypic plasticity in colorectal cancer.

Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment . However, the molecular mechanisms underlying resistance to LGR5 CSCs depletion in colorectal cancer (CRC) remain largely elusive. Here, we unveil the existence of a primitive cell state dubbed the oncofetal (OnF) state, which works in tandem with the LGR5 stem cells (SCs) to fuel tumor evolution in CRC.

Serrated colorectal cancer: preclinical models and molecular pathways.

Serrated lesions are histologically heterogeneous, and detection can be challenging as these lesions have subtle features that may be missed by endoscopy. Furthermore, while approximately 30% of colorectal cancers (CRCs) arise from serrated lesions, only 8-10% of invasive serrated CRCs exhibit serrated morphology at presentation, suggesting potential loss of apparent characteristics with increased malignancy. Thus, understanding the genetic basis driving serrated CRC initiation and progression is critical to improve diagnosis and identify therapeutic biomarkers and targets to guide disease management.

Gastric epithelial stem cells in development, homeostasis and regeneration.

The stem/progenitor cell pool is indispensable for the development, homeostasis and regeneration of the gastric epithelium, owing to its defining ability to self-renew whilst supplying the various functional epithelial lineages needed to digest food efficiently. A detailed understanding of the intricacies and complexities surrounding the behaviours and roles of these stem cells offers insights, not only into the physiology of gastric epithelial development and maintenance, but also into the pathological consequences following aberrations in stem cell regulation. Here, we provide an insightful synthesis of the existing knowledge on gastric epithelial stem cell biology, including the in vitro and in vivo experimental techniques that have advanced such studies.

Unveiling the Influence of Tumor Microenvironment and Spatial Heterogeneity on Temozolomide Resistance in Glioblastoma Using an Advanced Human In Vitro Model of the Blood-Brain Barrier and Glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain cancer in adults with a dismal prognosis. Temozolomide (TMZ) is the first-in-line chemotherapeutic; however, resistance is frequent and multifactorial. While many molecular and genetic factors have been linked to TMZ resistance, the role of the solid tumor morphology and the tumor microenvironment, particularly the blood-brain barrier (BBB), is unknown.

The CagA oncoprotein disrupts Wnt/PCP signaling and promotes hyperproliferation of pyloric gland base cells.

strains that deliver the oncoprotein CagA into gastric epithelial cells are the major etiologic agents of upper gastric diseases including gastric cancer. CagA promotes gastric carcinogenesis through interactions with multiple host proteins. Here, we show that CagA also disrupts Wnt-dependent planar cell polarity (Wnt/PCP), which orients cells within the plane of an epithelium and coordinates collective cell behaviors such as convergent extension to enable epithelial elongation during development.

Role of Wnt signaling in the maintenance and regeneration of the intestinal epithelium.

The intestinal epithelium plays a key role in digestion and protection against external pathogens. This tissue presents a high cellular turnover with the epithelium being completely renewed every 5days, driven by intestinal stem cells (ISCs) residing in the crypt bases. To sustain this dynamic renewal of the intestinal epithelium, the maintenance, proliferation, and differentiation of ISCs must be precisely controlled.

Proteasome inhibitor bortezomib stabilizes and activates p53 in hematopoietic stem/progenitors and double-negative T cells in vivo.

We have previously shown that proteasome inhibitor bortezomib stabilizes p53 in stem and progenitor cells within gastrointestinal tissues. Here, we characterize the effect of bortezomib treatment on primary and secondary lymphoid tissues in mice. We find that bortezomib stabilizes p53 in significant fractions of hematopoietic stem and progenitor cells in the bone marrow, including common lymphoid and myeloid progenitors, granulocyte-monocyte progenitors, and dendritic cell progenitors.

The East of England dental trauma service.

Background: Current evidence suggests traumatic dental injuries can be difficult to manage in primary care due to uncommon occurrence and challenging patient presentations. Such factors may contribute to general dental practitioners lacking experience and confidence in the assessment, treatment and management of traumatic dental injuries. Furthermore, there are anecdotal accounts of patients presenting to accident and emergency (A&E) services with a traumatic dental injury, which could be placing avoidable strain on secondary care services.

Targeted ablation of Lgr5-expressing intestinal stem cells in diphtheria toxin receptor-based mouse and organoid models.

Intestinal cells marked by Lgr5 function as tissue-resident stem cells that sustain the homeostatic replenishment of the epithelium. By incorporating a diphtheria toxin receptor (DTR) cassette linked to the Lgr5 coding region, native Lgr5-expressing cells are susceptible to ablation upon DT administration . A similar strategy can be used for Lgr5-expressing cells within organoids established from DTR models.

Cell transcriptomic atlas of the non-human primate Macaca fascicularis.

Studying tissue composition and function in non-human primates (NHPs) is crucial to understand the nature of our own species. Here we present a large-scale cell transcriptomic atlas that encompasses over 1 million cells from 45 tissues of the adult NHP Macaca fascicularis. This dataset provides a vast annotated resource to study a species phylogenetically close to humans.

A constant pool of Lgr5 intestinal stem cells is required for intestinal homeostasis.

Lgr5 crypt base columnar cells, the operational intestinal stem cells (ISCs), are thought to be dispensable for small intestinal (SI) homeostasis. Using a Lgr5-2A-DTR (diphtheria toxin receptor) model, which ablates Lgr5 cells with near-complete efficiency and retains endogenous levels of Lgr5 expression, we show that persistent depletion of Lgr5 ISCs in fact compromises SI epithelial integrity and reduces epithelial turnover in vivo. In vitro, Lgr5-2A-DTR SI organoids are unable to establish or survive when Lgr5 ISCs are continuously eliminated by adding DT to the media.

A genome-scale CRISPR screen reveals factors regulating Wnt-dependent renewal of mouse gastric epithelial cells.

An ability to safely harness the powerful regenerative potential of adult stem cells for clinical applications is critically dependent on a comprehensive understanding of the underlying mechanisms regulating their activity. Epithelial organoid cultures accurately recapitulate many features of in vivo stem cell-driven epithelial renewal, providing an excellent ex vivo platform for interrogation of key regulatory mechanisms. Here, we employed a genome-scale clustered, regularly interspaced, short palindromic repeats (CRISPR) knockout (KO) screening assay using mouse gastric epithelial organoids to identify modulators of Wnt-driven stem cell-dependent epithelial renewal in the gastric mucosa.

Lgr5 Marks Adult Progenitor Cells Contributing to Skeletal Muscle Regeneration and Sarcoma Formation.

Regeneration of adult skeletal muscle is driven largely by resident satellite cells, a stem cell population increasingly considered to display a high degree of molecular heterogeneity. In this study, we find that Lgr5, a receptor for Rspo and a potent mediator of Wnt/β-catenin signaling, marks a subset of activated satellite cells that contribute to muscle regeneration. Lgr5 is found to be rapidly upregulated in purified myogenic progenitors following acute cardiotoxin-induced injury.