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Cytoplasmic divisions are thought to rely on nuclear divisions and mitotic signals. We demonstrate in Drosophila embryos that cytoplasm can divide repeatedly without nuclei and mitotic CDK/cyclin complexes. Cdk1 normally slows an otherwise faster cytoplasmic division cycle, coupling it with nuclear divisions, and when uncoupled, cytoplasm starts dividing before mitosis. In developing embryos where CDK/cyclin activity can license mitotic microtubule (MT) organizers like the spindle, cytoplasmic divisions can occur without the centrosome, a principal organizer of interphase MTs. However, centrosomes become essential in the absence of CDK/cyclin activity, implying that the cytoplasm can employ either the centrosome-based interphase or CDK/cyclin-dependent mitotic MTs to facilitate its divisions. Finally, we present evidence that autonomous cytoplasmic divisions occur during unperturbed fly embryogenesis and that they may help extrude mitotically stalled nuclei during blastoderm formation. We postulate that cytoplasmic divisions occur in cycles governed by a yet-to-be-uncovered clock mechanism autonomous from CDK/cyclin complexes.

Airway epithelium represents a physical barrier against toxic substances and pathogens but also presents pattern recognition receptors on the epithelial cells that detect pathogens leading to molecule release and sending signals that activate both the innate and adaptive immune responses. Thus, impaired airway epithelial function and poor integrity may increase the recurrence of infections. Probiotic use in respiratory diseases as adjuvant of traditional therapy is increasingly widespread. There is growing interest in the use of non-viable heat-killed bacteria, such as tyndallized bacteria (TB), due to safety concerns and to their immunomodulatory properties. This study explores in vitro the effects of a TB blend on the immune activation of airway epithelium. 16HBE bronchial epithelial cells were exposed to different concentrations of TB. Cell viability, TB internalization, TLR2 expression, IL-6, IL-8 and TGF-βl expression/release, E-cadherin expression and wound healing were assessed. We found that TB were tolerated, internalized, increased TLR2, E-cadherin expression, IL-6 release and wound healing but decreased both IL-8 and TGF-βl release. In conclusion, TB activate TLR2 pathway without inducing a relevant pro-inflammatory response and improve barrier function, leading to the concept that TB preserve epithelial homeostasis and could be used as strategy to prevent and to manage respiratory infection, exacerbations included. [ABSTRACT FROM AUTHOR]

Rationale: Pharmacological improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes in patients with cystic fibrosis (CF). However, ETI effects on impaired mucosal homeostasis and host defense at the molecular and cellular levels in the airways of patients with CF remain unknown. Objectives: To investigate effects of ETI on the transcriptome of nasal epithelial and immune cells from children with CF at the single-cell level. Methods: Nasal swabs from 13 children with CF and at least one F508del allele aged 6 to 11 years were collected at baseline and 3 months after initiation of ETI, subjected to single-cell RNA sequencing, and compared with swabs from 12 age-matched healthy children. Measurements and Main Results: Proportions of CFTR-positive cells were decreased in epithelial basal, club, and goblet cells, but not in ionocytes, from children with CF at baseline and were restored by ETI therapy to nearly healthy levels. Single-cell transcriptomics revealed an impaired IFN signaling and reduced expression of major histocompatibility complex classes I and II encoding genes in epithelial cells of children with CF at baseline, which was partially restored by ETI. In addition, ETI therapy markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages. Conclusions: Pharmacological improvement of CFTR function improves innate mucosal immunity and reduces immune cell inflammatory responses in the upper airways of children with CF at the single-cell level, highlighting the potential to restore epithelial homeostasis and host defense in CF airways by early initiation of ETI therapy. [ABSTRACT FROM AUTHOR]

Epithelial cells form a resilient barrier and orchestrate defensive and reparative mechanisms to maintain tissue stability. This review focuses on gut and airway epithelia, which are positionedwhere the body interfaces with the outside world. We review themany signaling pathways andmechanisms by which epithelial cells at the interface respond to invading pathogens to mount an innate immune response and initiate adaptive immunity and communicate with other cells, including resident microbiota, to heal damaged tissue and maintain homeostasis. We compare and contrast how airway and gut epithelial cells detect pathogens, release antimicrobial effectors, collaborate withmacrophages, Tregs and epithelial stem cells tomount an immune response and orchestrate tissue repair. We also describe advanced research models for studying epithelial communication and behaviors during inflammation, tissue injury and disease. [ABSTRACT FROM AUTHOR]

Basal progenitor cells serve as a stem cell pool to maintain the homeostasis of the epithelium of the foregut, including the esophagus and the forestomach. Aberrant genetic regulation in these cells can lead to carcinogenesis, such as squamous cell carcinoma (SCC). However, the underlying molecular mechanisms regulating the function of basal progenitor cells remain largely unknown. Here, we use mouse models to reveal that Hippo signaling is required for maintaining the homeostasis of the foregut epithelium and cooperates with p53 to repress the initiation of foregut SCC. Deletion of Mst1/2 in mice leads to epithelial overgrowth in both the esophagus and forestomach. Further molecular studies find that Mst1/2-deficiency promotes epithelial growth by enhancing basal cell proliferation in a Yes-associated protein (Yap)-dependent manner. Moreover, Mst1/2 deficiency accelerates the onset of foregut SCC in a carcinogen-induced foregut SCC mouse model, depending on Yap. Significantly, a combined deletion of Mst1/2 and p53 in basal progenitor cells sufficiently drives the initiation of foregut SCC. Therefore, our studies shed light on the collaborative role of Hippo signaling and p53 in maintaining squamous epithelial homeostasis while suppressing malignant transformation of basal stem cells within the foregut. [ABSTRACT FROM AUTHOR]

Epithelial cells form a resilient barrier and orchestrate defensive and reparative mechanisms to maintain tissue stability. This review focuses on gut and airway epithelia, which are positioned where the body interfaces with the outside world. We review the many signaling pathways and mechanisms by which epithelial cells at the interface respond to invading pathogens to mount an innate immune response and initiate adaptive immunity and communicate with other cells, including resident microbiota, to heal damaged tissue and maintain homeostasis. We compare and contrast how airway and gut epithelial cells detect pathogens, release antimicrobial effectors, collaborate with macrophages, Tregs and epithelial stem cells to mount an immune response and orchestrate tissue repair. We also describe advanced research models for studying epithelial communication and behaviors during inflammation, tissue injury and disease.

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. We highlight the contributions of stem/progenitor cells towards patterning the developing stomach, specification of the differentiated cell lineages and maintenance of the mature epithelium during homeostasis and following injury. Finally, we discuss gaps in our understanding and identify key research areas for future work. [ABSTRACT FROM AUTHOR]

The epithelial lining of the stomach undergoes rapid turnover to preserve its structural and functional integrity, a process driven by long-lived stem cells residing in the antral and corpus glands. Several subpopulations of gastric stem cells have been identified and their phenotypic and functional diversities linked to spatiotemporal specification of stem cells niches. Here, we review the biological features of gastric stem cells at various locations of the stomach under homeostatic conditions, as demonstrated by reporter mice, lineage tracing, and single cell sequencing. We also review the role of gastric stem cells in epithelial regeneration in response to injury. Moreover, we discuss emerging evidence demonstrating that accumulation of oncogenic drivers or alteration of stemness signaling pathways in gastric stem cells promotes gastric cancer. Given a fundamental role of the microenvironment, this review highlights the role reprogramming of niche components and signaling pathways under pathological conditions in dictating stem cell fate. Several outstanding issues are raised, such as the relevance of stem cell heterogeneity and plasticity, and epigenetic regulatory mechanisms, to Helicobacter pylori infection-initiated metaplasia-carcinogenesis cascades. With the development of spatiotemporal genomics, transcriptomics, and proteomics, as well as multiplexed screening and tracing approaches, we anticipate that more precise definition and characterization of gastric stem cells, and the crosstalk with their niche will be delineated in the near future. Rational exploitation and proper translation of these findings may bring forward novel modalities for epithelial rejuvenation and cancer therapeutics. [ABSTRACT FROM AUTHOR]

• CFTR dysfunction " per se " perturbs epithelial homeostasis. • Alternative approaches to high efficiency modulator therapy are promising for CF. • Airway rehydration is a Host-Directed Strategies alternative approach for CF. • Phage therapy is a Pathogen-Directed Strategies (PDS) alternative approach for CF. Cystic fibrosis (CF), the most common life-threatening genetic disorder in Caucasians, is caused by recessive mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene encoding a chloride ion channel. Aberrant function of CFTR involves mucus- and sweat-producing epithelia affecting multiple organs, including airways and lungs. This condition facilitates the colonization of fungi, bacteria, or viruses. Recurrent antibiotic administration is commonly used to treat pathogen infections leading to the insurgence of resistant bacteria and to a chronic inflammatory state that jeopardizes airway epithelium repair. The phenotype of patients carrying CFTR mutations does not always present a strict correlation with their genotype, suggesting that the disease may occur because of multiple additive effects. Among them, the frequent microbiota dysbiosis observed in patients affected by CF, might be one cause of the discrepancy observed in their genotype-phenotype correlation. Interestingly, the abnormal polarity of the CF airway epithelium has been observed also under non-infectious and non-inflammatory conditions, suggesting that CFTR dysfunction " per se " perturbs epithelial homeostasis. New pathogen- or host-directed strategies are thus needed to counteract bacterial infections and restore epithelial homeostasis in individuals with CF. In this review, we summarized alternative cutting-edge approaches to high-efficiency modulator therapy that might be promising for these patients. [ABSTRACT FROM AUTHOR]

Epithelial malignant transformation and tumorous development were believed to be closely associated with the loss of its microenvironment integrity and homeostasis. The tumor-suppressive molecules Maspin and p53 were demonstrated to play a crucial role in body epithelial and immune homeostasis. Downregulation of Maspin and mutation of p53 were frequently associated with malignant transformation and poor prognosis in various human cancers. In this review, we focused on summarizing the progress of the molecular network of Maspin in studying epithelial tumorous development and its response to clinic treatment and try to clarify the underlying antitumor mechanism. Notably, Maspin expression was reported to be transcriptionally activated by p53, and the transcriptional activity of p53 was demonstrated to be enhanced by its acetylation through inhibition of HDAC1. As an endogenous inhibitor of HDAC1, Maspin possibly potentiates the transcriptional activity of p53 by acetylating the p53 protein. Hereby, it could form a “self-propelling” antitumor mechanism. Thus, we summarized that, upon stimulation of cellular stress and by integrating with p53, the aroused Maspin played the epigenetic surveillant role to prevent the epithelial digressional process and retune the epithelial homeostasis, which is involved in activating host immune surveillance, regulating the inflammatory factors, and fine-tuning its associated cell signaling pathways. Consequentially, in a normal physiological condition, activation of the above “self-propelling” antitumor mechanism of Maspin and p53 could reduce cellular stress (e.g., chronic infection/inflammation, oxidative stress, transformation) effectively and achieve cancer prevention. Meanwhile, designing a strategy of mimicking Maspin’s epigenetic regulation activity with integrating p53 tumorsuppressive activity could enhance the chemotherapy efficacy theoretically in a pathological condition of cancer. [ABSTRACT FROM AUTHOR]

The mammalian intestine is a self-renewing tissue that ensures nutrient absorption while acting as a barrier against environmental insults. This is achieved by mature intestinal epithelial cells, the renewing capacity of intestinal stem cells at the base of the crypts, the development of immune tolerance, and the regulatory functions of stromal cells. Upon intestinal injury or inflammation, this tightly regulated mucosal homeostasis is disrupted and is followed by a series of events that lead to tissue repair and the restoration of organ function. It is now well established that fibroblasts play significant roles both in the maintenance of epithelial and immune homeostasis in the intestine and the response to tissue damage mainly through the secretion of a variety of soluble mediators and ligands and the remodeling of the extracellular matrix. In addition, recent advances in single-cell transcriptomics have revealed an unexpected heterogeneity of fibroblasts that comprise distinct cell subsets in normal and inflammatory conditions, indicative of diverse functions. However, there is still little consensus on the number, terminology, and functional properties of these subsets. Moreover, it is still unclear how individual fibroblast subsets can regulate intestinal repair processes and what is their impact on the pathogenesis of inflammatory bowel disease. In this mini-review, we aim to provide a concise overview of recent advances in the field, that we believe will help clarify current concepts on fibroblast heterogeneity and functions and advance our understanding of the contribution of fibroblasts in intestinal damage and repair. [ABSTRACT FROM AUTHOR]

The mammalian intestine is a self-renewing tissue that ensures nutrient absorption while acting as a barrier against environmental insults. This is achieved by mature intestinal epithelial cells, the renewing capacity of intestinal stem cells at the base of the crypts, the development of immune tolerance, and the regulatory functions of stromal cells. Upon intestinal injury or inflammation, this tightly regulated mucosal homeostasis is disrupted and is followed by a series of events that lead to tissue repair and the restoration of organ function. It is now well established that fibroblasts play significant roles both in the maintenance of epithelial and immune homeostasis in the intestine and the response to tissue damage mainly through the secretion of a variety of soluble mediators and ligands and the remodeling of the extracellular matrix. In addition, recent advances in single-cell transcriptomics have revealed an unexpected heterogeneity of fibroblasts that comprise distinct cell subsets in normal and inflammatory conditions, indicative of diverse functions. However, there is still little consensus on the number, terminology, and functional properties of these subsets. Moreover, it is still unclear how individual fibroblast subsets can regulate intestinal repair processes and what is their impact on the pathogenesis of inflammatory bowel disease. In this mini-review, we aim to provide a concise overview of recent advances in the field, that we believe will help clarify current concepts on fibroblast heterogeneity and functions and advance our understanding of the contribution of fibroblasts in intestinal damage and repair.

Papillomaviruses exclusively infect stratified epithelial tissues and cause chronic infections. To achieve this, infected cells must remain in the epithelial basal layer alongside their uninfected neighbors for years or even decades. To examine how papillomaviruses achieve this, we used the in vivo MmuPV1 (Mus musculus papillomavirus 1) model of lesion formation and persistence. During early lesion formation, an increased cell density in the basal layer, as well as a delay in the infected cells’ commitment to differentiation, was apparent in cells expressing MmuPV1 E6/E7 RNA. Using cell culture models, keratinocytes exogenously expressing MmuPV1 E6, but not E7, recapitulated this delay in differentiation postconfluence and also grew to a significantly higher density. Cell competition assays further showed that MmuPV1 E6 expression led to a preferential persistence of the cell in the first layer, with control cells accumulating almost exclusively in the second layer. Interestingly, the disruption of MmuPV1 E6 binding to MAML1 protein abrogated these phenotypes. This suggests that the interaction between MAML1 and E6 is necessary for the lower (basal)-layer persistence of MmuPV1 E6- expressing cells. Our results indicate a role for E6 in lesion establishment by facilitating the persistence of infected cells in the epithelial basal layer, a mechanism that is most likely shared by other papillomavirus types. Interruption of this interaction is predicted to impede persistent papillomavirus infection and consequently provides a novel treatment target. IMPORTANCE Persistent infection with high-risk HPV types can lead to development of HPV-associated cancers, and persistent low-risk HPV infection causes problematic diseases, such as recurrent respiratory papillomatosis. The management and treatment of these conditions pose a considerable economic burden. Maintaining a reservoir of infected cells in the basal layer of the epithelium is critical for the persistence of infection in the host, and our studies using the mouse papillomavirus model suggest that E6 gene expression leads to the preferential persistence of epithelial cells in the lower layers during stratification. The E6 interaction with MAML1, a component of the Notch pathway, is required for this phenotype and is linked to E6 effects on cell density and differentiation. These observations are likely to reflect a common E6 role that is preserved among papillomaviruses and provide us with a novel therapeutic target for the treatment of recalcitrant lesions. [ABSTRACT FROM AUTHOR]

Cell competition in epithelial tissue eliminates transformed cells expressing activated oncoproteins to maintain epithelial homeostasis. Although the process is now understood to be of mechanochemical origin, direct mechanical characterization and associated biochemical underpinnings are lacking. Here, we employ tissue-scale stress and compressibility measurements and theoretical modeling to unveil a mechanical imbalance between normal and transformed cells, which drives cell competition. In the mouse intestinal epithelium and epithelial monolayer, transformed cells get compacted during competition. Stress microscopy reveals an emergent compressive stress at the transformed loci leading to this compaction. A cell-based self-propelled Voronoi model predicts that this compressive stress originates from a difference in the collective compressibility of the competing populations. A new collective compressibility measurement technique named gel compression microscopy then elucidates a two-fold higher compressibility of the transformed population than the normal population. Mechanistically, weakened cell-cell adhesions due to reduced junctional abundance of E-cadherin in the transformed cells render them collectively more compressible than normal cells. Taken together, our findings unveil a mechanical basis for epithelial homeostasis against oncogenic transformations with implications in epithelial defense against cancer., Competing Interests: Competing interests The authors declare no competing interests.

Our world is filled with microbes. Each multicellular organism has developed ways to interact with this microbial environment. Microbes do not always pose a threat; they can contribute to many processes that benefit the host. Upon colonization both host and microbes adapt resulting in dynamic ecosystems in different host niches. Regulatory processes develop within the host to prevent overt inflammation to beneficial microbes, yet keeping the possibility to respond when pathogens attempt to adhere and invade tissues. This review will focus on microbial colonization and the early (innate) host immune response, with special emphasis on the microbiota-modifying roles of IL-10 and IL-22 in the intestine. IL-10 knock out mice show an altered microbial composition, and spontaneously develop enterocolitis over time. IL-22 knock out mice, although not developing enterocolitis spontaneously, also have an altered microbial composition and increase of epithelial-adherent bacteria, mainly caused by a decrease in mucin and anti-microbial peptide production. Recently interesting links have been found between the IL-10 and IL-22 pathways. While IL-22 can function as a regulatory cytokine at the mucosal surface, it also has inflammatory roles depending on the context. For example, lack of IL-22 in the IL-10–/– mice model prevents spontaneous colitis development. Additionally, the reduced microbial diversity observed in IL-10–/– mice was also reversed in IL-10/IL-22 double mutant mice (Gunasekera et al., 2020). Since in early life, host immunity develops in parallel and in interaction with colonizing microbes, there is a need for future studies that focus on the effect of the timing of colonization in relation to the developmental phase of the host. To illustrate this, examples from zebrafish research will be compared with studies performed in mammals. Since zebrafish develop from eggs and are directly exposed to the outside microbial world, timing of the development of host immunity and subsequent control of microbial composition, is different from mammals that develop in utero and only get exposed after birth. Likewise, colonization studies using adult germfree mice might yield different results from those using neonatal germfree mice. Lastly, special emphasis will be given to the need for host genotype and environmental (co-housing) control of experiments. [ABSTRACT FROM AUTHOR]

Our world is filled with microbes. Each multicellular organism has developed ways to interact with this microbial environment. Microbes do not always pose a threat; they can contribute to many processes that benefit the host. Upon colonization both host and microbes adapt resulting in dynamic ecosystems in different host niches. Regulatory processes develop within the host to prevent overt inflammation to beneficial microbes, yet keeping the possibility to respond when pathogens attempt to adhere and invade tissues. This review will focus on microbial colonization and the early (innate) host immune response, with special emphasis on the microbiota-modifying roles of IL-10 and IL-22 in the intestine. IL-10 knock out mice show an altered microbial composition, and spontaneously develop enterocolitis over time. IL-22 knock out mice, although not developing enterocolitis spontaneously, also have an altered microbial composition and increase of epithelial-adherent bacteria, mainly caused by a decrease in mucin and anti-microbial peptide production. Recently interesting links have been found between the IL-10 and IL-22 pathways. While IL-22 can function as a regulatory cytokine at the mucosal surface, it also has inflammatory roles depending on the context. For example, lack of IL-22 in the IL-10–/– mice model prevents spontaneous colitis development. Additionally, the reduced microbial diversity observed in IL-10–/– mice was also reversed in IL-10/IL-22 double mutant mice (Gunasekera et al., 2020). Since in early life, host immunity develops in parallel and in interaction with colonizing microbes, there is a need for future studies that focus on the effect of the timing of colonization in relation to the developmental phase of the host. To illustrate this, examples from zebrafish research will be compared with studies performed in mammals. Since zebrafish develop from eggs and are directly exposed to the outside microbial world, timing of the development of host immunity and subsequent control of microbial composition, is different from mammals that develop in utero and only get exposed after birth. Likewise, colonization studies using adult germfree mice might yield different results from those using neonatal germfree mice. Lastly, special emphasis will be given to the need for host genotype and environmental (co-housing) control of experiments.

The intestinal autophagy and barrier function are crucial for maintaining the epithelium homeostasis and tightly regulated through well-controlled mechanisms. RNA-binding proteins (RBPs) and long noncoding RNAs (lncRNAs) modulate gene expression at the posttranscription level and are intimately involved in different physiological processes and diverse human diseases. In this review, we first highlight the roles of several RBPs and lncRNAs in the regulation of intestinal epithelial autophagy and barrier function, particularly focusing on the emerging evidence of RBPs and lncRNAs in the control of mRNA stability and translation. We additionally discuss recent findings that the interactions between RBPs and lncRNAs alter the fate of their target transcripts and thus influence gut epithelium host defense in response to stressful environments. These exciting advances in understanding the posttranscriptional control of the epithelial autophagy and barrier function by RBPs and lncRNAs provide a strong rationale for developing new effective therapeutics based on targeting RBPs and/or lncRNAs to preserve the intestinal epithelial integrity in patients with critical illnesses. [ABSTRACT FROM AUTHOR]

Epithelia are structurally integral elements in the fabric of oral mucosa with significant functional roles. Similarly, the gingival epithelium performs uniquely critical tasks in responding to a variety of external stimuli and dangers through the regulation of specific built-in molecular mechanisms in a context-dependent fashion at cellular levels. Gingival epithelial cells form an anatomic architecture that confers defense, robustness, and adaptation toward external aggressions, most critically to colonizing microorganisms, among other functions. Accordingly, recent studies unraveled previously uncharacterized response mechanisms in gingival epithelial cells that are constructed to rapidly exert biocidal effects against invader pathobiotic bacteria, such as Porphyromonas gingivalis, through small danger molecule signaling. The host-adapted bacteria, however, have developed adroit strategies to 1) exploit the epithelia as privileged growth niches and 2) chronically target cellular bactericidal and homeostatic metabolic pathways for successful bacterial persistence. As the overgrowth of colonizing microorganisms in the gingival mucosa can shift from homeostasis to dysbiosis or a diseased state, it is crucial to understand how the innate modulatory molecules are intricately involved in antibacterial pathways and how they shape susceptibility versus resistance in the epithelium toward pathogens. Thus, in this review, we highlight recent discoveries in gingival epithelial cell research in the context of bacterial colonizers. The current knowledge outlined here demonstrates the ability of epithelial cells to possess highly organized defense machineries, which can jointly regulate host-derived danger molecule signaling and integrate specific global responses against opportunistic bacteria to combat microbial incursion and maintain host homeostatic balance. These novel examples collectively suggest that the oral epithelia are equipped with a dynamically robust and interconnected defense system encompassing sensors and various effector molecules that arrange and achieve a fine-tuned and advanced response to diverse bacteria. [ABSTRACT FROM AUTHOR]

Basal progenitor cells serve as a stem cell pool to maintain the homeostasis of the epithelium of the foregut, including the esophagus and the forestomach. Aberrant genetic regulation in these cells can lead to carcinogenesis, such as squamous cell carcinoma (SCC). However, the underlying molecular mechanisms regulating the function of basal progenitor cells remain largely unknown. Here, we use mouse models to reveal that Hippo signaling is required for maintaining the homeostasis of the foregut epithelium and cooperates with p53 to repress the initiation of foregut SCC. Deletion of Mst1/2 in mice leads to epithelial overgrowth in both the esophagus and forestomach. Further molecular studies find that Mst1/2 -deficiency promotes epithelial growth by enhancing basal cell proliferation in a Yes-associated protein (Yap)-dependent manner. Moreover, Mst1/2 deficiency accelerates the onset of foregut SCC in a carcinogen-induced foregut SCC mouse model, depending on Yap. Significantly, a combined deletion of Mst1/2 and p53 in basal progenitor cells sufficiently drives the initiation of foregut SCC. Therefore, our studies shed light on the collaborative role of Hippo signaling and p53 in maintaining squamous epithelial homeostasis while suppressing malignant transformation of basal stem cells within the foregut., Competing Interests: Competing interests statement:The authors declare no competing interest.

Intestinal epithelial autophagy is crucial for host defense against invasive pathogens and its defects occur frequently in patients with inflammatory bowel disease (IBD) and other mucosal disorders, but the exact mechanism that activates autophagy is poorly defined. Here, we investigated the role of RNA-binding protein HuR (human antigen R) in the posttranscriptional control of autophagy related genes (ATGs) in the intestinal epithelium. We found that targeted deletion of HuR in intestinal epithelial cells (IECs) specifically decreased the levels of ATG16L1 in the intestinal mucosa. Intestinal mucosa from patients with IBD exhibited reduced levels of both HuR and ATG16L1. HuR directly interacted with Atg16l1 mRNA via its 3'-untranslated region and enhanced ATG16L1 translation, without affecting Atg16l1 mRNA stability. Circular RNA circPABPN1 blocked HuR binding to Atg16l1 mRNA and lowered ATG16L1 production. HuR silencing in cultured IECs also prevented rapamycin-induced autophagy, which was abolished by overexpressing ATG16L1. These findings indicate that HuR regulates autophagy by modulating ATG16L1 translation via interaction with circPABPN1 in the intestinal epithelium. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are important hormones involved in the regulation of multiple physiologic functions. GCs are also widely used in anti-inflammatory/immunosuppressant drugs. GCs are synthesized by the adrenal cortex as part of the hypothalamus-pituitary-adrenal axis and also by intestinal epithelial cells, among other peripheral sites. GCs are one of the main therapy choices for the exacerbations of inflammatory bowel disease, but they are not useful to prolong remission, and development of tolerance with secondary treatment failure is frequent. Thus, GC actions at the intestinal epithelial level are of great importance, both physiologically and pharmacologically. We generated a tamoxifen-inducible nuclear receptor subfamily 3 group C member 1 (NR3C1)?IEC mouse model to study the effects of GCs on epithelial cells in vivo. Nr3c1 deletion in epithelial cells of the small intestine and colon was associated with limited colonic inflammation at 1 wk postdeletion, involving augmented epithelial proliferation and mucus production, plus local and systemic immune/inflammatory changes. This phenotype regressed substantially, but not completely, after 2 wk. The mechanism may involve augmented inflammatory signaling by epithelial cells or defective barrier function. We conclude that the epithelial GC receptor plays a significant role in colonic homeostasis in basal conditions, but its deficiency can be compensated in the short term. Future studies are required to assess the impact of Nr3c1 deletion in other conditions such as experimental colitis. [ABSTRACT FROM AUTHOR]

Apoptosis is traditionally considered to be an immunologically silent form of cell death. Multiple mechanisms exist to ensure that apoptosis does not stimulate the immune system to cause inflammation or autoimmunity. Against this expectation, we now report that epithelia are programmed to provoke, rather than suppress, inflammation in response to apoptosis. We found that an acute inflammatory response led by neutrophils occurs in zebrafish and cell culture when apoptotic epithelial cells cannot be expelled from the monolayer by apical extrusion. This reflects an intrinsic circuit where ATP released from apoptotic cells stimulates epithelial cells in the immediate vicinity to produce interleukin-8 (IL-8). Apical extrusion therefore prevents inappropriate epithelial inflammation by physically eliminating apoptotic cells before they can activate this pro-inflammatory circuit. This carries the implication that epithelia may be predisposed to inflammation, elicited by sporadic or induced apoptosis, if apical extrusion is compromised. [Display omitted] • Apoptotic epithelial cells provoke inflammation if extrusion fails • ATP from retained apoptotic cells stimulates P2Y11 receptor on the neighboring cells • Activated P2Y11 stimulates IL-8 production in the neighboring cells • IL-8 recruits neutrophils toward retained apoptotic epithelial cells Duszyc et al. report that apoptotic epithelial cells provoke inflammation if they are not eliminated by apical extrusion. This is driven by paracrine signaling, where ATP from retained apoptotic cells triggers their epithelial neighbors to produce IL-8 and thus recruit neutrophils of the innate immune system. [ABSTRACT FROM AUTHOR]

The vertebrate adult intestinal epithelium has a high self-renewal rate driven by intestinal stem cells (ISCs) in the crypts, which play central roles in maintaining intestinal integrity and homeostasis. However, the underlying mechanisms remain elusive. Here we showed that protein arginine methyltransferase 1 (PRMT1), a major arginine methyltransferase that can also function as a transcription co-activator, was highly expressed in the proliferating cells of adult mouse intestinal crypts. Intestinal epithelium-specific knockout of PRMT1, which ablates PRMT1 gene starting during embryogenesis, caused distinct, region-specific effects on small intestine and colon: increasing and decreasing the goblet cell number in the small intestinal and colonic crypts, respectively, leading to elongation of the crypts in small intestine but not colon, while increasing crypt cell proliferation in both regions. We further generated a tamoxifen-inducible intestinal epithelium-specific PRMT1 knockout mouse model and found that tamoxifen-induced knockout of PRMT1 in the adult mice resulted in the same region-specific intestinal phenotypes. Thus, our studies have for the first time revealed that the epigenetic enzyme PRMT1 has distinct, region-specific roles in the maintenance of intestinal epithelial architecture and homeostasis, although PRMT1 may influence intestinal development., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Paneth cells secrete antimicrobial proteins including lysozyme via secretory autophagy as part of the mucosal protective response. The ELAV like RNA-binding protein 1 (ELAVL1, also called HuR) regulates stability and translation of messenger RNAs (mRNAs) and many aspects of mucosal physiology. We studied the posttranscriptional mechanisms by which HuR regulates Paneth cell function. Intestinal mucosal tissues were collected from mice with intestinal epithelium (IE)-specific disruption of HuR (IE- HuR –/–), HuR fl/fl-Cre– mice (controls), and patients with inflammatory bowel diseases and analyzed by histology and immunohistochemistry. Paneth cell functions were determined by lysozyme-immunostaining assays. We isolated primary enterocytes from IE- HuR –/– and control mice and derived intestinal organoids. HuR and the chaperone CNPY3 were overexpressed from transgenes in intestinal epithelial cells (IECs) or knocked down with small interfering RNAs. We performed RNA pulldown assays to investigate interactions between HuR and its target mRNAs. Intestinal tissues from IE- HuR –/– mice had reduced numbers of Paneth cells, and Paneth cells had fewer lysozyme granules per cell, compared with tissues from control mice, but there were no effects on Goblet cells or enterocytes. Intestinal mucosa from patients with inflammatory bowel diseases had reduced levels of HuR and fewer Paneth cells. IE- HuR –/– mice did not have the apical distribution of TLR2 in the intestinal mucosa as observed in control mice. IECs from IE- HuR –/– mice expressed lower levels of CNPY3. Intestinal organoids from IE- HuR –/– mice were smaller and contained fewer buds compared with those generated from controls, and had fewer lysozyme-positive cells. In IECs, knockdown of HuR decreased levels of the autophagy proteins LC3-I and LC3-II, compared with control cells, and prevented rapamycin-induced autophagy. We found HuR to interact directly with the Cnpy3 mRNA coding region and increase levels of CNPY3 by increasing the stability and translation of Cnpy3 mRNA. CNPY3 bound TLR2, and cells with knockdown of CNPY3 or HuR lost membrane localization of TLR2, but increased cytoplasmic levels of TLR2. In studies of mice, IECs, and human tissues, we found HuR to increase expression of CNPY3 at the posttranscriptional level. CNPY3 is required for membrane localization of TLR2 and Paneth cell function. [ABSTRACT FROM AUTHOR]

Glucocorticoid hormones affect gene expression via activation of glucocorticoid receptor NR3C1, causing modulation of inflammation and autoimmune activation. The glucocorticoid Dexamethasone is an important pharmaceutical for the treatment of colitis and other inflammatory bowel diseases. While suppressive effects of glucocorticoids on activated immune cells is significant, their effects upon epithelial cells are less well studied. Previous research shows that the effects of Dexamethasone treatment on polarized Caco-2 cell layer permeability is delayed for >10 treatment days (as measured by transepithelial electrical resistance). In vivo intestinal epithelial cells turn over every 3–5 days; we therefore hypothesized that culture age may produce marked effects on gene expression, potentially acting as a confounding variable. To investigate this issue, we cultured polarized Caco-2 monolayers during a 30-day timecourse with ~15 days of continuous Dexamethasone exposure. We collected samples during the timecourse and tested differential expression using a 250-plex gene expression panel and Nanostring nCounter® system. Our custom panel was selectively enriched for KEGG annotations for tight-junction, actin cytoskeleton regulation, and colorectal cancer-associated genes, allowing for focused gene ontology-based pathway enrichment analyses. To test for confounding effects of time and Dexamethasone variables, we used the Nanostring nSolver differential expression data model which includes a mixturenegative binomial modelwith optimization. We identified a time-associated "EMT-like" signature with differential expression seen in important actomyosin cytoskeleton, tight junction, integrin, and cell cycle pathway genes. Dexamethasone treatment resulted in a subtle yet significant counter-signal showing suppression of actomyosin genes and differential expression of various growth factor receptors. [ABSTRACT FROM AUTHOR]

Cytoplasmic dynein‐1 is a large minus‐end‐directed microtubule motor complex involved in membrane trafficking, organelle positioning, and microtubule organization. The roles of dynein light intermediate chains (DLICs; DLIC1 and DLIC2) within the complex are, however, still largely undefined. In this study, we investigated the possible roles of DLICs in epithelial homeostasis and colon cancer development. Mutant clonal analysis of Drosophila Dlic in the follicular epithelium of Drosophila ovary showed defects in nuclear positioning, epithelial integrity, and apical cell polarity. Consistently, knockdown of human DLIC1 and DLIC2 in colon carcinoma cells resulted in damaged epithelial organization, disturbed lumen formation, and impaired apical polarity establishment in three‐dimensional cell culture. Depletion of DLIC1 and DLIC2 led to reduced proliferation, enhanced apoptosis rates, disrupted mitotic spindle assembly, and induction of G2/M arrest in cell cycle progression. Moreover, reduced levels of DLIC1 in contrast to DLIC2 impaired the migratory ability. On the other hand, immunohistochemical examination of human colorectal tissue samples and further colorectal cancer dataset analysis showed a significant upregulation for DLIC1 in tumors, whereas DLIC2 expression was unchanged. In addition, the overexpression of DLIC1 caused increased proliferation, decreased apoptosis and enhanced migration, whereas DLIC2 overexpression did not result in any significant changes. Together, these results indicate that DLIC1 and DLIC2 contribute to the establishment and maintenance of epithelial homeostasis. Furthermore, these findings present the first evidence that DLIC1 and DLIC2 have distinct roles in colon cancer development and that DLIC1 may contribute to proliferative overgrowth and migratory characteristics. Cytoplasmic dynein 1 complexes contain either the dynein light intermediate chain (DLIC) 1 or 2 subunit, but not both of them, suggesting diverse dynein functions in respect to subunit heterogeneity. We investigated the possible roles of DLICs in epithelial homeostasis and colon cancer development. Increased levels of DLIC1, but not DLIC2, enhance proliferation, decrease apoptosis, and induce migration. Moreover, colon tumors show upregulation for DLIC1, but not for DLIC2. Diverse molecular interaction partners of DLIC1 and DLIC2 may define their discrete regulatory roles and different contributions to colon cancer development. [ABSTRACT FROM AUTHOR]

Epithelial homeostasis requires the precise balance of epithelial stem/progenitor proliferation and differentiation. While many signaling pathways that regulate epithelial stem cells have been identified, it is probable that other regulators remain unidentified. Here, we use gene-expression profiling by targeted DamID to identify the stem/progenitor-specific transcription and signaling factors in the Drosophila midgut. Many signaling pathway components, including ligands of most major pathways, exhibit stem/progenitor-specific expression and have regulatory regions bound by both intrinsic and extrinsic transcription factors. In addition to previously identified stem/progenitor-derived ligands, we show that both the insulin-like factor Ilp6 and TNF ligand eiger are specifically expressed in the stem/progenitors and regulate normal tissue homeostasis. We propose that intestinal stem cells not only integrate multiple signals but also contribute to and regulate the homeostatic signaling microenvironmental niche through the expression of autocrine and paracrine factors. [ABSTRACT FROM AUTHOR]

Summary: Innate lymphoid cells (ILC) are a recently identified group of tissue‐resident innate lymphocytes. Available data support the view that ILC or their progenitors are deposited and retained in tissues early during ontogeny. Thereby, ILC become an integral cellular component of tissues and organs. Here, we will review the intriguing relationships between ILC and basic developmental and homeostatic processes within tissues. Studying ILC has already led to the appreciation of the integral roles of immune cells in tissue homeostasis, morphogenesis, metabolism, regeneration, and growth. This area of immunology has not yet been studied in‐depth but is likely to reveal important networks contributing to disease tolerance and may be harnessed for future therapeutic approaches. [ABSTRACT FROM AUTHOR]

Polarized epithelia are a foundation of organ and appendage structures throughout Metazoa and serve as a physical barrier to preserve physiological functions. In proliferating epithelia, planar cell division occurs by orienting the mitotic spindle within the plane of the epithelium to ensure tissue organization. Conversely, loss of tissue architecture is a hallmark of carcinoma, and aberrant spindle orientation is hypothesized to contribute to tissue disorganization through dysplasia and cell dissemination. Recent in vivo studies have uncovered a role of planar spindle alignment in the robust maintenance of tissue architecture, which accompanies homeostatic mechanisms such as cell delamination and re-integration of misplaced cells following abnormal cell division. Furthermore, perpendicular spindle orientation shifts have been suggested as causes of cell fate change and epithelial plasticity manifested by epithelial-to-mesenchymal transition. This review describes the mechanism by which planar spindle orientation is tightly regulated and discusses the roles of mitotic spindle orientation in epithelial development and disease. [ABSTRACT FROM AUTHOR]

Intestinal infection by Cryptosporidium parvum causes significant alterations in the gene expression profile in host epithelial cells. Previous studies demonstrate that a panel of parasite RNA transcripts of low protein-coding potential are delivered into infected host cells and may modulate host gene transcription. Using in vitro models of human intestinal cryptosporidiosis, we report here that trans-suppression of the cadherin 3 ( CDH3 ) and lysyl oxidase like 4 ( LOXL4 ) genes in human intestinal epithelial cells following C. parvum infection involves host delivery of the Cdg7_FLc_1000 RNA, a C. parvum RNA that has been previously demonstrated to be delivered into the nuclei of infected host cells. Downregulation of CDH3 and LOXL4 genes was detected in host epithelial cells following C. parvum infection or in cells expressing the parasite Cdg7_FLc_1000 RNA. Knockdown of Cdg7_FLc_1000 attenuated the trans-suppression of CDH3 and LOXL4 genes in host cells induced by infection. Interestingly, Cdg7_FLc_1000 was detected to be recruited to the promoter regions of both CDH3 and LOXL4 gene loci in host cells following C. parvum infection. Host delivery of Cdg7_FLc_1000 promoted the PH domain zinc finger protein 1 (PRDM1)-mediated H3K9 methylation associated with trans-suppression in the CDH3 gene locus, but not the LOXL4 gene. Therefore, our data suggest that host delivery of Cdg7_FLc_1000 causes CDH3 trans-suppression in human intestinal epithelial cells following C. parvum infection through PRDM1-mediated H3K9 methylation in the CDH3 gene locus, whereas Cdg7_FLc_1000 induces trans-suppression of the host LOXL4 gene through H3K9/H3K27 methylation-independent mechanisms. [ABSTRACT FROM AUTHOR]

Intestinal infection by the zoonotic protozoan, Cryptosporidium parvum, causes significant alterations in the gene expression profile in host epithelial cells. The molecular mechanisms of how C. parvum may modulate host cell gene transcription and the pathological significance of such alterations are largely unclear. Previous studies demonstrate that a panel of parasite RNA transcripts are delivered into infected host cells and may modulate host gene transcription. Using in vitro models of intestinal cryptosporidiosis , in this study, we analyzed the impact of host delivery of C. parvum Cdg2_FLc_0220 RNA transcript on host gene expression profile. We found that alterations in host gene expression profile following C. parvum infection were partially associated with the nuclear delivery of Cdg2_FLc_0220. Specifically, we identified a total of 46 overlapping upregulated genes and 8 overlapping downregulated genes in infected cells and cells transfected with Full-Cdg2_FLc_0220. Trans-suppression of the DAZ interacting zinc finger protein 1 like ( DZIP1L ) gene, the top overlapping downregulated gene in host cells following C. parvum infection and cells transfected with Full-Cdg2_FLc_0220, was mediated by G9a, independent of PRDM1. Cdg2_FLc_0220-mediated trans-suppression of the DZIP1L gene was independent of H3K9 and H3K27 methylation. Data from this study provide additional evidence that delivery of C. parvum Cdg2_FLc_0220 RNA transcript in infected epithelial cells modulates the transcription of host genes, contributing to the alterations in the gene expression profile in host epithelial cells during C. parvum infection. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is characterized by a functional dysregulation of alternatively activated macrophage (AAM) and intestinal epithelial cells (IECs) homeostasis. Chromogranin-A (CHGA) secreted by neuroendocrine cells is implicated in intestinal inflammation and immune dysregulation. CHGA undergoes proteolytic processing to generate CHGA-derived peptides. Chromofungin (CHR: CHGA47–66) is a short CHGA-derived peptide encoded by CHGA Exon-IV and is involved in innate immune regulation, but the basis is poorly investigated. We investigated the expression of CHR in colonic tissue of patients with active UC and assessed the effects of the CHR in dextran sulfate sodium (DSS) colitis in mice and on macrophages and human colonic epithelial cells. We found that mRNA expression of CHR correlated positively with mRNA levels of AAM markers and gene expression of tight junction (TJ) proteins and negatively with mRNA levels of interleukin (IL)-8, IL-18, and collagen in patients with active UC. Moreover, AAM markers correlated positively with gene expression of TJ proteins and negatively with IL-8, IL-18, and collagen gene expression. Experimentally, intracolonic administration of CHR protected against DSS-induced colitis by priming macrophages into AAM, reducing colonic collagen deposition, and maintaining IECs homeostasis. This effect was associated with a significant increase of AAM markers, reduction of colonic IL-18 release and conservation of gene expression of TJ proteins. In vitro, CHR enhanced AAM polarization and increased the production of anti-inflammatory mediators. CHR-treated AAM conditioned medium increased Caco-2 cell migration, viability, proliferation, and mRNA levels of TJ proteins, and decreased oxidative stress-induced apoptosis and proinflammatory cytokines release. Direct CHR treatments had the same effect. In conclusion, CHR treatment reduces the severity of colitis and the inflammatory process via enhancing AAM functions and maintaining IECs homeostasis. CHR is involved in the pathogenesis of inflammation in experimental colitis. These findings provide insight into the mechanisms of colonic inflammation and could lead to new therapeutic strategies for UC.

Ulcerative colitis (UC) is characterized by a functional dysregulation of alternatively activated macrophage (AAM) and intestinal epithelial cells (IECs) homeostasis. Chromogranin-A (CHGA) secreted by neuroendocrine cells is implicated in intestinal inflammation and immune dysregulation. CHGA undergoes proteolytic processing to generate CHGA-derived peptides. Chromofungin (CHR: CHGA47-66) is a short CHGAderived peptide encoded by CHGA Exon-IV and is involved in innate immune regulation, but the basis is poorly investigated. We investigated the expression of CHR in colonic tissue of patients with active UC and assessed the effects of the CHR in dextran sulfate sodium (DSS) colitis in mice and on macrophages and human colonic epithelial cells. We found that mRNA expression of CHR correlated positively with mRNA levels of AAM markers and gene expression of tight junction (TJ) proteins and negatively with mRNA levels of interleukin (IL)-8, IL-18, and collagen in patients with active UC. Moreover, AAM markers correlated positively with gene expression of TJ proteins and negatively with IL-8, IL-18, and collagen gene expression. Experimentally, intracolonic administration of CHR protected against DSS-induced colitis by priming macrophages into AAM, reducing colonic collagen deposition, and maintaining IECs homeostasis. This effect was associated with a significant increase of AAM markers, reduction of colonic IL-18 release and conservation of gene expression of TJ proteins. In vitro, CHR enhanced AAM polarization and increased the production of anti-inflammatory mediators. CHR-treated AAM conditioned medium increased Caco-2 cell migration, viability, proliferation, and mRNA levels of TJ proteins, and decreased oxidative stress-induced apoptosis and proinflammatory cytokines release. Direct CHR treatments had the same effect. In conclusion, CHR treatment reduces the severity of colitis and the inflammatory process via enhancing AAM functions and maintaining IECs homeostasis. CHR is involved in the pathogenesis of inflammation in experimental colitis. These findings provide insight into the mechanisms of colonic inflammation and could lead to new therapeutic strategies for UC. [ABSTRACT FROM AUTHOR]

Background. Intestinal mucosal barrier dysfunction in liver cirrhosis and its implicated mechanisms is of great clinical importance because it is associated with the development of serious complications from diverse organs through promotion of systemic endotoxemia.Aim. The present study was designed to investigate whether enterocytes’ proliferation, apoptosis and intestinal oxidative stress are altered in the intestinal mucosa of patients with compensated and decompensated liver cirrhosis.Material and methods. Twelve healthy controls (group A) and twenty four cirrhotic patients at a compensated (n = 12, group B) or decompensated condition (n = 12, group C) were subjected to duodenal biopsy. In intestinal specimens mucosal apoptotic and mitotic activity and their ratio were recorded by means of morphological assessment and mucosal lipid hydroperoxides were measured. Plasma endotoxin concentration, an index of gut barrier function, was also determined.Results. Cirrhotic patients presented significantly higher serum endotoxin concentrations as compared to healthy controls (P < 0.001), whilst endotoxemia was higher in decompensated disease (P < 0.05 vs. compensated cirrhosis). Intestinal mucosal mitotic count was significantly lower in patients with compensated and decompensated cirrhosis compared to controls (P < 0.01, respectively), whilst a trend towards increased apoptosis was recorded. The mitotic/apoptotic ratio was significantly reduced in groups B (P < 0.05) and C (P < 0.01) as compared to controls. Intestinal lipid peroxidation was significantly increased in decompensated cirrhotics (P < 0.001 vs. groups A and B).Conclusions. The present study demonstrates for the first time that human liver cirrhosis is associated with decreased intestinal mucosal proliferation and proliferation/apoptosis ratio even at early stages of cirrhosis and increased intestinal oxidative stress in advanced liver disease.

Summary Prostate inflammation has been suggested as an etiology for benign prostatic hyperplasia (BPH). We show that decreased expression of the androgen receptor (AR) in luminal cells of human BPH specimens correlates with a higher degree of regional prostatic inflammation. However, the cause-and-effect relationship between the two events remains unclear. We investigated specifically whether attenuating AR activity in prostate luminal cells induces inflammation. Disrupting luminal cell AR signaling in mouse models promotes cytokine production cell-autonomously, impairs epithelial barrier function, and induces immune cell infiltration, which further augments local production of cytokines and chemokines including Il-1 and Ccl2 . This inflammatory microenvironment promotes AR-independent prostatic epithelial proliferation, which can be abolished by ablating IL-1 signaling or depleting its major cellular source, the macrophages. This study demonstrates that disrupting luminal AR signaling promotes prostate inflammation, which may serve as a mechanism for resistance to androgen-targeted therapy for prostate-related diseases. [ABSTRACT FROM AUTHOR]

Epithelial cell divisions are coordinated with cell loss to preserve epithelial integrity. However, how epithelia adapt their rate of cell division to changes in cell number, for instance during homeostatic turnover or wounding, is not well understood. Here, we show that epithelial cells sense local cell density through mechanosensitive E-cadherin adhesions to control G2/M cell-cycle progression. As local cell density increases, tensile forces on E-cadherin adhesions are reduced, which prompts the accumulation of the G2 checkpoint kinase Wee1 and downstream inhibitory phosphorylation of Cdk1. Consequently, dense epithelia contain a pool of cells that are temporarily halted in G2 phase. These cells are readily triggered to divide following epithelial wounding due to the consequent increase in intercellular forces and resulting degradation of Wee1. Our data collectively show that epithelial cell division is controlled by a mechanical G2 checkpoint, which is regulated by cell-density-dependent intercellular forces sensed and transduced by E-cadherin adhesions. [Display omitted] • E-cadherin adhesions mechanically sense cell density to control cell division rate • Reduced tension on E-cadherin at high cell density prompts accumulation of Wee1 • Wee1-mediated inhibition of Cdk1 prolongs G2 phase in dense epithelia • Increased tension triggers Wee1 degradation and mitotic entry of G2-halted cells Donker et al. show that epithelia adapt their rate of cell division to fluctuations in cell number by sensing corresponding changes in intercellular forces. These forces are transduced by E-cadherin adhesions to control cell-cycle progression through G2 phase via regulation of the kinase Wee1 and downstream inhibition of Cdk1. [ABSTRACT FROM AUTHOR]