ABSTRACT
Osteogenesis imperfecta (OI) is a disorder of low bone mass and increased fracture risk due to a range of genetic variants that prominently include mutations in genes encoding type I collagen. While it is well known that OI reflects defects in the activity of bone-forming osteoblasts, it is currently unclear whether OI also reflects defects in the many other cell types comprising bone, including defects in skeletal vascular endothelium or the skeletal stem cell populations that give rise to osteoblasts and whether correcting these broader defects could have therapeutic utility. Here, we find that numbers of skeletal stem cells (SSCs) and skeletal arterial endothelial cells (AECs) are augmented in Col1a2oim/oim mice, a well-studied animal model of moderate to severe OI, suggesting that disruption of a vascular SSC niche is a feature of OI pathogenesis. Moreover, crossing Col1a2oim/oim mice to mice lacking a negative regulator of skeletal angiogenesis and bone formation, Schnurri 3 (SHN3), not only corrected the SSC and AEC phenotypes but moreover robustly corrected the bone mass and spontaneous fracture phenotypes. As this finding suggested a strong therapeutic utility of SHN3 inhibition for the treatment of OI, a bone-targeting AAV was used to mediate Shn3 knockdown, rescuing the Col1a2oim/oim phenotype and providing therapeutic proof-of-concept for targeting SHN3 for the treatment of OI. Overall, this work both provides proof-of-concept for inhibition of the SHN3 pathway and more broadly addressing defects in the stem/osteoprogenitor niche as is a strategy to treat OI.
Subject(s)
Disease Models, Animal , Osteogenesis Imperfecta , Stem Cell Niche , Animals , Osteogenesis Imperfecta/pathology , Osteogenesis Imperfecta/genetics , Mice , Bone and Bones/pathology , Bone and Bones/drug effects , Stem Cells/metabolism , Stem Cells/pathology , Collagen Type I/metabolism , Collagen Type I/genetics , Osteogenesis/drug effects , Mice, Inbred C57BLABSTRACT
In intestinal resection animal models of short bowel syndrome (SBS), the remaining epithelium mounts a robust adaptive response characterized by early stem cell expansion and increased crypt depth, villus height and nutrient absorption. In humans the adaptive response is critical for resumption of oral nutrition, yet it may be variable, and underlying mechanisms are much less well understood. Current knowledge relating to the role of stem and mesenchymal niche cells in the adaptive response in animal models and in human SBS are addressed in this review.
Subject(s)
Intestinal Mucosa , Short Bowel Syndrome , Stem Cell Niche , Short Bowel Syndrome/physiopathology , Short Bowel Syndrome/pathology , Humans , Stem Cell Niche/physiology , Animals , Intestinal Mucosa/pathology , Disease Models, Animal , Stem Cells/pathologyABSTRACT
Fibroblasts are present throughout the body and function to maintain tissue homeostasis. Recent studies have identified diverse fibroblast subsets in healthy and injured tissues1,2, but the origins and functional roles of injury-induced fibroblast lineages remain unclear. Here we show that lung-specialized alveolar fibroblasts take on multiple molecular states with distinct roles in facilitating responses to fibrotic lung injury. We generate a genetic tool that uniquely targets alveolar fibroblasts to demonstrate their role in providing niches for alveolar stem cells in homeostasis and show that loss of this niche leads to exaggerated responses to acute lung injury. Lineage tracing identifies alveolar fibroblasts as the dominant origin for multiple emergent fibroblast subsets sequentially driven by inflammatory and pro-fibrotic signals after injury. We identify similar, but not completely identical, fibroblast lineages in human pulmonary fibrosis. TGFß negatively regulates an inflammatory fibroblast subset that emerges early after injury and stimulates the differentiation into fibrotic fibroblasts to elicit intra-alveolar fibrosis. Blocking the induction of fibrotic fibroblasts in the alveolar fibroblast lineage abrogates fibrosis but exacerbates lung inflammation. These results demonstrate the multifaceted roles of the alveolar fibroblast lineage in maintaining normal alveolar homeostasis and orchestrating sequential responses to lung injury.
Subject(s)
Acute Lung Injury , Cell Lineage , Fibroblasts , Pneumonia , Pulmonary Alveoli , Pulmonary Fibrosis , Animals , Female , Humans , Male , Mice , Acute Lung Injury/pathology , Acute Lung Injury/metabolism , Cell Differentiation , Fibroblasts/pathology , Fibroblasts/metabolism , Homeostasis , Pneumonia/pathology , Pneumonia/metabolism , Pulmonary Alveoli/pathology , Pulmonary Alveoli/cytology , Pulmonary Alveoli/metabolism , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/metabolism , Stem Cell Niche , Stem Cells/metabolism , Stem Cells/cytology , Stem Cells/pathology , Transforming Growth Factor beta/metabolismABSTRACT
Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes, in addition to the bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in interferon-induced transmembrane protein 5 (IFITM5). Here, we generated a conditional Rosa26-knockin mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in patients with OI type V. Surprisingly, expression of mutant Ifitm5 in mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with an increase in the skeletal progenitor cell population within the periosteum. Lineage tracing showed that chondrogenic cells expressing the mutant Ifitm5 had decreased differentiation into osteoblastic cells in diaphyseal bone. Moreover, mutant IFITM5 disrupted early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. These data identify the contribution of a signaling defect altering osteo-chondroprogenitor differentiation as a driver in the pathogenesis of OI type V.
Subject(s)
Cell Differentiation , MAP Kinase Signaling System , Osteoblasts , Osteogenesis Imperfecta , SOX9 Transcription Factor , Animals , Female , Male , Mice , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice, Transgenic , Mutation , Osteoblasts/metabolism , Osteoblasts/pathology , Osteogenesis/genetics , Osteogenesis Imperfecta/genetics , Osteogenesis Imperfecta/pathology , Osteogenesis Imperfecta/metabolism , SOX9 Transcription Factor/genetics , SOX9 Transcription Factor/metabolism , Stem Cells/metabolism , Stem Cells/pathology , Extracellular Signal-Regulated MAP KinasesABSTRACT
According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, has been shown to suppress intestinal stemness. Here, we used Paneth cells as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation in mice. Upon inflammation, Paneth cell-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in patients with inflammatory bowel disease, but also of a larger fraction of human sporadic colon cancers. The latter is possibly because of the inflammatory consequences of western-style dietary habits, a major colon cancer risk factor. Machine learning methods designed to predict the cell-of-origin of cancer from patient-derived tumor samples confirmed that, in a substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineages and not in stem cells.
Subject(s)
Carcinogenesis , Cell Lineage , Colonic Neoplasms , Inflammation , Paneth Cells , Animals , Mice , Cell Lineage/genetics , Paneth Cells/pathology , Humans , Inflammation/genetics , Inflammation/pathology , Carcinogenesis/genetics , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Mutation , Stem Cells/pathology , Cell Differentiation/genetics , Cell Transformation, Neoplastic/genetics , Adenomatous Polyposis Coli Protein/genetics , Mice, Inbred C57BL , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/pathologyABSTRACT
Congenital diaphragmatic hernia (CDH) is a birth defect characterized by incomplete closure of the diaphragm, herniation of abdominal organs into the chest, and compression of the lungs and the heart. Besides complications related to pulmonary hypoplasia, 1 in 4 survivors develop neurodevelopmental impairment, whose etiology remains unclear. Using a fetal rat model of CDH, we demonstrated that the compression exerted by herniated organs on the mediastinal structures results in decreased brain perfusion on ultrafast ultrasound, cerebral hypoxia with compensatory angiogenesis, mature neuron and oligodendrocyte loss, and activated microglia. In CDH fetuses, apoptosis was prominent in the subventricular and subgranular zones, areas that are key for neurogenesis. We validated these findings in the autopsy samples of four human fetuses with CDH compared to age- and sex-matched controls. This study reveals the molecular mechanisms and cellular changes that occur in the brain of fetuses with CDH and creates opportunities for therapeutic targets.
Subject(s)
Brain , Hernias, Diaphragmatic, Congenital , Neurons , Oligodendroglia , Animals , Hernias, Diaphragmatic, Congenital/pathology , Hernias, Diaphragmatic, Congenital/diagnostic imaging , Neurons/pathology , Neurons/metabolism , Oligodendroglia/pathology , Oligodendroglia/metabolism , Rats , Humans , Brain/pathology , Brain/diagnostic imaging , Brain/embryology , Female , Stem Cells/pathology , Fetus/pathology , Disease Models, Animal , Pregnancy , MaleABSTRACT
Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are primary cicatricial alopecia that cause a major impact on quality of life due to irreversible hair loss and symptoms as itching, burning and pain. They are characterized by permanent loss of hair follicle stem cells (HFSCs) by pathomechanisms still poorly understood, resulting in poor efficacy of currently available treatments. Caveolae are flask-shaped lipid rafts invaginated within the plasma membrane of multiple cell types. Although their role in the HF physiology and pathophysiology is relatively unknown, we have previously demonstrated that the primary structural component of caveolae (caveolin-1 or Cav1) is upregulated in FFA. Thus, we propose to investigate the expression and localization of caveolae-associated structural proteins (Cav1, Cav2, and Cavin-1) and HFSCs (identified by K15) in both LPP and FFA. We analyzed 4 patients with LPP biopsied in affected and non-affected (NA) scalp, 4 patients with FFA biopsied in affected scalp and 4 healthy controls. Affected scalp of LPP and FFA demonstrated increased levels of Cav1 and Cavin-1 compared with HC and LPP-NA. Moreover, Cav1, Cav2 and Cavin1 all exhibit high colocalization with K15 and their expression appears to be negatively correlated, supporting the hypothesis that these proteins are important players in LPP/FFA and may serve as therapeutic targets in future treatments.
Subject(s)
Alopecia , Caveolae , Caveolin 1 , Hair Follicle , Lichen Planus , Up-Regulation , Humans , Alopecia/pathology , Alopecia/metabolism , Hair Follicle/pathology , Hair Follicle/metabolism , Lichen Planus/metabolism , Lichen Planus/pathology , Middle Aged , Female , Caveolin 1/metabolism , Male , Caveolae/metabolism , Scalp/pathology , Adult , Keratin-15/metabolism , Aged , Biopsy , Fibrosis , Stem Cells/metabolism , Stem Cells/pathology , RNA-Binding Proteins/metabolismABSTRACT
BACKGROUND: We examined associations of CD44, CD24 and ALDH1A1 breast stem cell markers with mammographic breast density (MBD), a well-established breast cancer (BCa) risk factor. METHODS: We included 218 cancer-free women with biopsy-confirmed benign breast disease within the Nurses' Health Study (NHS) and NHSII. The data on BCa risk factors were obtained from biennial questionnaires. Immunohistochemistry (IHC) was done on tissue microarrays. For each core, the IHC expression was assessed using a semi-automated platform and expressed as percent of positively stained cells for each marker out of the total cell count. MBD was assessed with computer-assisted techniques. Generalised linear regression was used to examine the associations of each marker with square root-transformed percent density (PD), absolute dense and non-dense areas (NDA), adjusted for BCa risk factors. RESULTS: Stromal CD44 and ALDH1A1 expression was positively associated with PD (≥ 10% vs. <10% ß = 0.56, 95% confidence interval [CI] [0.06; 1.07] and ß = 0.81 [0.27; 1.34], respectively) and inversely associated with NDA (ß per 10% increase = -0.17 [-0.34; -0.01] and ß for ≥10% vs. <10% = -1.17 [-2.07; -0.28], respectively). Epithelial CD24 expression was inversely associated with PD (ß per 10% increase = -0.14 [-0.28; -0.01]. Stromal and epithelial CD24 expression was positively associated with NDA (ß per 10% increase = 0.35 [0.2 × 10-2; 0.70] and ß per 10% increase = 0.34 [0.11; 0.57], respectively). CONCLUSION: Expression of stem cell markers is associated with MBD.
Subject(s)
Aldehyde Dehydrogenase 1 Family , Breast Density , CD24 Antigen , Hyaluronan Receptors , Retinal Dehydrogenase , Humans , Female , CD24 Antigen/metabolism , Hyaluronan Receptors/metabolism , Hyaluronan Receptors/analysis , Aldehyde Dehydrogenase 1 Family/metabolism , Retinal Dehydrogenase/metabolism , Middle Aged , Adult , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/diagnostic imaging , Biopsy , Breast/pathology , Breast/diagnostic imaging , Breast/metabolism , Mammography/methods , Stem Cells/metabolism , Stem Cells/pathology , Biomarkers, Tumor/metabolism , Aldehyde Dehydrogenase/metabolismABSTRACT
The equilibrium between the hypertrophic growth of existing adipocytes and adipogenesis is vital in managing metabolic stability in white adipocytes when faced with overnutrition. Adipogenesis has been established as a key player in combating metabolic irregularities caused by various factors. However, the benefits of increasing adipogenesis-mediated white adipose tissue (WAT) expansion for metabolic health regulation remain uncertain. Our findings reveal an increase in Impdh2 expression during the adipogenesis phase, both in vivo and in vitro. Xmp enhances adipogenic potential by fostering mitotic clonal expansion (MCE). The conditional knockout of Impdh2 in adipocyte progenitor cells(APCs) in adult and aged mice effectively curbs white adipose tissue expansion, ameliorates glucose tolerance, and augments energy expenditure under high-fat diet (HFD). However, no significant difference is observed under normal chow diet (NCD). Concurrently, the knockout of Impdh2 in APCs significantly reduces the count of new adipocytes induced by HFD, without affecting adipocyte size. Mechanistically, Impdh2 regulates the proliferation of APCs during the MCE phase via Xmp. Exogenous Xmp can significantly offset the reduction in adipogenic abilities of APCs due to Impdh2 deficiency. In summary, we discovered that adipogenesis-mediated WAT expansion, induced by overnutrition, also contributes to metabolic abnormalities. Moreover, the pivotal role of Impdh2 in regulating adipogenesis in APCs offers a novel therapeutic approach to combat obesity.
Subject(s)
Adipocytes , Adipogenesis , Adipose Tissue, White , Diet, High-Fat , IMP Dehydrogenase , Overnutrition , Animals , Male , Mice , Adipocytes/metabolism , Adipogenesis/genetics , Adipose Tissue, White/metabolism , Cell Proliferation , Energy Metabolism/genetics , Gene Deletion , Mice, Inbred C57BL , Mice, Knockout , Overnutrition/metabolism , Overnutrition/genetics , Stem Cells/metabolism , Stem Cells/cytology , Stem Cells/pathology , IMP Dehydrogenase/genetics , IMP Dehydrogenase/metabolismABSTRACT
The early mechanisms of spontaneous tumor initiation that precede malignancy are largely unknown. We show that reduced aPKC levels correlate with stem cell loss and the induction of revival and metaplastic programs in serrated- and conventional-initiated premalignant lesions, which is perpetuated in colorectal cancers (CRCs). Acute inactivation of PKCλ/ι in vivo and in mouse organoids is sufficient to stimulate JNK in non-transformed intestinal epithelial cells (IECs), which promotes cell death and the rapid loss of the intestinal stem cells (ISCs), including those that are LGR5+. This is followed by the accumulation of revival stem cells (RSCs) at the bottom of the crypt and fetal-metaplastic cells (FMCs) at the top, creating two spatiotemporally distinct cell populations that depend on JNK-induced AP-1 and YAP. These cell lineage changes are maintained during cancer initiation and progression and determine the aggressive phenotype of human CRC, irrespective of their serrated or conventional origin.
Subject(s)
Colorectal Neoplasms , Epithelial Cells , Metaplasia , Protein Kinase C , Animals , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/genetics , Protein Kinase C/metabolism , Protein Kinase C/genetics , Metaplasia/pathology , Metaplasia/metabolism , Mice , Humans , Epithelial Cells/metabolism , Epithelial Cells/pathology , Stem Cells/metabolism , Stem Cells/pathology , Transcription Factor AP-1/metabolism , Transcription Factor AP-1/genetics , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , YAP-Signaling Proteins/metabolism , Cell Transformation, Neoplastic/pathology , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/deficiency , Organoids/metabolism , Organoids/pathology , Cell Lineage , Isoenzymes/metabolism , Isoenzymes/genetics , Isoenzymes/deficiency , Neoplastic Stem Cells/pathology , Neoplastic Stem Cells/metabolismABSTRACT
Limbal stem cell deficiency (LSCD) is a clinically challenging eye disease caused by damage to limbal stem cells (LSCs). Currently, the international consensus classifies LSCD into three clinical stages based on the disease severity. However, no existing animal models attempt to replicate the varying degrees of LSCD observed in clinical cases. The present study demonstrates an easy-to-create, reproducible, and reliable mouse model of graded LSCD. To achieve mild, moderate, or severe LSCD, filter paper rings with a variety of central angles (90°, 180°, or 270°) are utilized to deliver alkali burns to different sizes of the limbal area (1, 2, or 3 quarters). The animal model has successfully resulted in the development of clinical signs and pathological manifestations in escalating severity that are similarly observed in the three clinical stages of LSCD. Our study thus provides new insights into distinct pathological features underlying different grades of LSCD and serves as a new tool for further exploring the disease mechanisms and developing new effective therapeutics for repairing damaged LSCs.
Subject(s)
Burns, Chemical , Corneal Diseases , Disease Models, Animal , Eye Burns , Limbus Corneae , Stem Cells , Animals , Limbus Corneae/pathology , Mice , Stem Cells/pathology , Corneal Diseases/pathology , Burns, Chemical/pathology , Eye Burns/chemically induced , Eye Burns/pathology , Mice, Inbred C57BL , Female , Limbal Stem Cell DeficiencyABSTRACT
Alcohol-associated liver disease (ALD) is a prevalent liver disease, yet research is hampered by the lack of suitable and reliable human ALD models. Herein, we generated human adipose stromal/stem cell (hASC)-derived hepatocellular organoids (hAHOs) and hASC-derived liver organoids (hALOs) in a three-dimensional system using hASC-derived hepatocyte-like cells and endodermal progenitor cells, respectively. The hAHOs were composed of major hepatocytes and cholangiocytes. The hALOs contained hepatocytes and nonparenchymal cells and possessed a more mature liver function than hAHOs. Upon ethanol treatment, both steatosis and inflammation were present in hAHOs and hALOs. The incubation of hALOs with ethanol resulted in increases in the levels of oxidative stress, the endoplasmic reticulum protein thioredoxin domain-containing protein 5 (TXNDC5), the alcohol-metabolizing enzymes ADH1B and ALDH1B1, and extracellular matrix accumulation, similar to those of liver tissues from patients with ALD. These results present a useful approach for understanding the pathogenesis of ALD in humans, thus facilitating the discovery of effective treatments.
Subject(s)
Adipose Tissue , Ethanol , Hepatocytes , Liver Diseases, Alcoholic , Organoids , Humans , Organoids/pathology , Organoids/drug effects , Ethanol/pharmacology , Ethanol/adverse effects , Liver Diseases, Alcoholic/pathology , Liver Diseases, Alcoholic/metabolism , Hepatocytes/drug effects , Hepatocytes/pathology , Hepatocytes/metabolism , Adipose Tissue/pathology , Adipose Tissue/cytology , Alcohol Dehydrogenase/metabolism , Oxidative Stress/drug effects , Liver/pathology , Liver/drug effects , Liver/metabolism , Stem Cells/drug effects , Stem Cells/metabolism , Stem Cells/pathology , Models, Biological , Aldehyde Dehydrogenase 1 Family/metabolism , Aldehyde Dehydrogenase 1 Family/genetics , Stromal Cells/pathology , Stromal Cells/drug effects , Stromal Cells/metabolism , Thioredoxins/metabolismABSTRACT
Idiopathic pulmonary fibrosis (IPF) is an aging-associated interstitial lung disease resulting from repeated epithelial injury and inadequate epithelial repair. Alveolar type II cells (AEC2s) are progenitor cells that maintain epithelial homeostasis and repair the lung after injury. In the current study, we assessed lipid metabolism in AEC2s from human lungs of patients with IPF and healthy donors, as well as AEC2s from bleomycin-injured young and old mice. Through single-cell RNA sequencing, we observed that lipid metabolism-related genes were downregulated in IPF AEC2s and bleomycin-injured mouse AEC2s. Aging aggravated this decrease and hindered recovery of lipid metabolism gene expression in AEC2s after bleomycin injury. Pathway analyses revealed downregulation of genes related to lipid biosynthesis and fatty acid ß-oxidation in AEC2s from IPF lungs and bleomycin-injured, old mouse lungs compared with the respective controls. We confirmed decreased cellular lipid content in AEC2s from IPF lungs and bleomycin-injured, old mouse lungs using immunofluorescence staining and flow cytometry. Futhermore, we show that lipid metabolism was associated with AEC2 progenitor function. Lipid supplementation and PPARγ (peroxisome proliferator activated receptor γ) activation promoted progenitor renewal capacity of both human and mouse AEC2s in three-dimensional organoid cultures. Lipid supplementation also increased AEC2 proliferation and expression of SFTPC in AEC2s. In summary, we identified a lipid metabolism deficiency in AEC2s from lungs of patients with IPF and bleomycin-injured old mice. Restoration of lipid metabolism homeostasis in AEC2s might promote AEC2 progenitor function and offer new opportunities for therapeutic approaches to IPF.
Subject(s)
Aging , Alveolar Epithelial Cells , Bleomycin , Idiopathic Pulmonary Fibrosis , Lipid Metabolism , Stem Cells , Idiopathic Pulmonary Fibrosis/metabolism , Idiopathic Pulmonary Fibrosis/pathology , Animals , Humans , Mice , Stem Cells/metabolism , Stem Cells/pathology , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , Aging/metabolism , Aging/pathology , PPAR gamma/metabolism , Male , Mice, Inbred C57BL , FemaleABSTRACT
BACKGROUND: According to the stem cell hypothesis, breast carcinogenesis may be related to the breast stem cell pool size. However, little is known about associations of breast cancer risk factors, such as anthropometric measures, with the expression of stem cell markers in noncancerous breast tissue. METHODS: The analysis included 414 women with biopsy-confirmed benign breast disease in the Nurses' Health Study and Nurses' Health Study II. Birthweight, weight at age 18, current weight, and current height were reported via self-administered questionnaires. IHC staining of stem cell markers (CD44, CD24, and aldehyde dehydrogenase family 1 member A1) in histopathologically normal epithelial and stromal breast tissue was quantified using an automated computational image analysis system. Linear regression was used to examine the associations of early-life and adult anthropometric measures with log-transformed stem cell marker expression, adjusting for potential confounders. RESULTS: Birthweight [≥10.0 vs. <5.5 lbs: ß (95% confidence interval) = 4.29 (1.02, 7.56); P trend = 0.001 in the stroma] and adult height [≥67.0 vs. <63.0 inch: 0.86 (0.14, 1.58); P trend = 0.02 in the epithelium and stroma combined] were positively associated with CD44 expression. Childhood body fatness was inversely associated (P trend = 0.03) whereas adult height was positively associated with CD24 expression in combined stroma and epithelium (P trend = 0.03). CONCLUSIONS: Our data suggest that anthropometric measures, such as birthweight, adult height, and childhood body fatness, may be associated with the stem cell expression among women with benign breast disease. IMPACT: Anthropometric measures, such as birthweight, height, and childhood body fatness, may have long-term impacts on stem cell population in the breast.
Subject(s)
Aldehyde Dehydrogenase 1 Family , CD24 Antigen , Hyaluronan Receptors , Retinal Dehydrogenase , Humans , Female , Adult , CD24 Antigen/metabolism , Aldehyde Dehydrogenase 1 Family/metabolism , Hyaluronan Receptors/metabolism , Retinal Dehydrogenase/metabolism , Middle Aged , Biopsy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Breast/pathology , Anthropometry/methods , Stem Cells/metabolism , Stem Cells/pathology , Aldehyde Dehydrogenase/metabolismABSTRACT
Telomere dynamics are linked to aging hallmarks, and age-associated telomere loss fuels the development of epithelial cancers. In Apc-mutant mice, the onset of DNA damage associated with telomere dysfunction has been shown to accelerate adenoma initiation via unknown mechanisms. Here, we observed that Apc-mutant mice engineered to experience telomere dysfunction show accelerated adenoma formation resulting from augmented cell competition and clonal expansion. Mechanistically, telomere dysfunction induces the repression of EZH2, resulting in the derepression of Wnt antagonists, which causes the differentiation of adjacent stem cells and a relative growth advantage to Apc-deficient telomere dysfunctional cells. Correspondingly, in this mouse model, GSK3ß inhibition countered the actions of Wnt antagonists on intestinal stem cells, resulting in impaired adenoma formation of telomere dysfunctional Apc-mutant cells. Thus, telomere dysfunction contributes to cancer initiation through altered stem cell dynamics, identifying an interception strategy for human APC-mutant cancers with shortened telomeres.
Subject(s)
Adenomatous Polyposis Coli Protein , Stem Cells , Telomere , Animals , Mice , Telomere/metabolism , Adenomatous Polyposis Coli Protein/genetics , Adenomatous Polyposis Coli Protein/metabolism , Stem Cells/metabolism , Stem Cells/pathology , Enhancer of Zeste Homolog 2 Protein/metabolism , Enhancer of Zeste Homolog 2 Protein/genetics , Adenoma/pathology , Adenoma/genetics , Adenoma/metabolism , Intestines/pathology , Cell Differentiation , Humans , Glycogen Synthase Kinase 3 beta/metabolism , Glycogen Synthase Kinase 3 beta/genetics , DNA Damage , Mice, Inbred C57BL , Wnt Signaling PathwayABSTRACT
Intestinal stem cells (ISCs) sustain epithelial renewal by dynamically altering behaviors of proliferation and differentiation in response to various nutrition and stress inputs. However, how ISCs integrate bioactive substance morin cues to protect against heat-stable enterotoxin b (STb) produced by Escherichia coli remains an uncertain question with implications for treating bacterial diarrhea. Our recent work showed that oral mulberry leaf-derived morin improved the growth performance in STb-challenged mice. Furthermore, morin supplementation reinstated the impaired small-intestinal epithelial structure and barrier function by stimulating ISC proliferation and differentiation as well as supporting intestinal organoid expansion ex vivo. Importantly, the Wnt/ß-catenin pathway, an ISC fate commitment signal, was reactivated by morin to restore the jejunal crypt-villus architecture in response to STb stimulation. Mechanically, the extracellular morin-initiated ß-catenin axis is dependent or partially dependent on the Wnt membrane receptor Frizzled7 (FZD7). Our data reveal an unexpected role of leaf-derived morin, which represents molecular signaling targeting the FZD7 platform instrumental for controlling ISC regeneration upon STb injury.
Subject(s)
Antioxidants , Bacterial Toxins , Enterotoxins , Escherichia coli Infections , Escherichia coli Proteins , Jejunum , Morus , Plant Extracts , Mice , Morus/chemistry , Plant Leaves/chemistry , Wnt Signaling Pathway , Stem Cells/drug effects , Stem Cells/microbiology , Stem Cells/pathology , Escherichia coli Proteins/metabolism , In Vitro Techniques , Plant Extracts/pharmacology , Jejunum/drug effects , Jejunum/metabolism , Jejunum/microbiology , Jejunum/pathology , Regeneration , Bacterial Toxins/isolation & purification , Enterotoxins/isolation & purification , Escherichia coli Infections/drug therapy , Antioxidants/pharmacologyABSTRACT
Background: 5-fluorouracil (5-FU) is an antimetabolic agent used for treating slowly growing solid tumors like breast and ovarian carcinoma. Thymoquinone (TQ) is the main biologically active constituent of Nigella sativa, it has been found to demonstrate anticancerous effects in several preclinical studies, and this is because TQ possesses multitarget nature. Stem cells-derived exosomes are in the spotlight of research and are promising tissue regenerative and anticancer cell-derived nanovesicles. Aim: Herein, we studied the antineoplastic effects of Exosomes derived from mammary stem cells (MaSCs-Exo) on breast cancer cells, alone or combined with TQ when compared to a breast cancer chemotherapeutic agent; 5-FU. Methods: Our approach included performing viability test and measuring the expression of pro-apoptotic gene (Bax), anti-apoptotic gene (BCL-2) and angiogenic gene (VEGF) on Human MCF-7 cells (breast adenocarcinoma cells), the MCF-7 cells were cultured and incubated with medium containing 5-FU (25 µg/ml), TQ (200 µg/ml), MaSCs-Exo (100 µg protein equivalent), a combination of TQ (200 µg/ml) and MaSCs-Exo (100 µg). Results: Our obtained results show that TQ and MaSCs-Exo each can effectively inhibit breast cancer cell line (MCF-7) proliferation and growth. Also, the results show that the combination of TQ and MaSCs-Exo had higher cytotoxic effects on MCF-7 breast cancer cells than TQ or 5-FU, alone. Conclusion: The present study shows a promising anticancer potential of exosomes isolated from mammary stem cells; this effect was potentiated by adding TQ with MaSCs-derived exosomes.
Subject(s)
Antineoplastic Agents , Benzoquinones , Breast Neoplasms , Exosomes , Humans , Animals , Female , Breast Neoplasms/veterinary , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Apoptosis , Exosomes/metabolism , Exosomes/pathology , Cell Line, Tumor , Stem Cells/metabolism , Stem Cells/pathologyABSTRACT
We identified a progenitor cell population highly enriched in samples from invasive and chemo-resistant carcinomas, characterized by a well-defined multigene signature including APOD, DCN, and LUM. This cell population has previously been labeled as consisting of inflammatory cancer-associated fibroblasts (iCAFs). The same signature characterizes naturally occurring fibro-adipogenic progenitors (FAPs) as well as stromal cells abundant in normal adipose tissue. Our analysis of human gene expression databases provides evidence that adipose stromal cells (ASCs) are recruited by tumors and undergo differentiation into CAFs during cancer progression to invasive and chemotherapy-resistant stages.
Subject(s)
Adipogenesis , Humans , Animals , Carcinoma/pathology , Carcinoma/genetics , Carcinoma/metabolism , Stem Cells/pathology , Stem Cells/metabolism , Stem Cells/cytology , Cancer-Associated Fibroblasts/pathology , Cancer-Associated Fibroblasts/metabolism , Adipose Tissue/cytology , Adipose Tissue/pathology , Neoplasms/pathology , Neoplasms/geneticsABSTRACT
CONTEXT: The recent WHO 2022 Classification of pituitary tumours identified a novel group of 'plurihormonal tumours without distinct lineage differentiation (WDLD)'. By definition, these express multiple combinations of lineage commitment transcription factors, in a monomorphous population of cells. OBJECTIVES: To determine the expression of stem cell markers (SOX2, Nestin, CD133) within tumours WDLD, immature PIT-1 lineage and acidophil stem cell tumours, compared with committed cell lineage tumours. METHODS: Retrospective evaluation of surgically resected pituitary tumours from St Vincent's Hospital, Sydney. Patients were selected to cover a range of tumour types, based on transcription factor and hormone immunohistochemistry. Clinical data was collected from patient files. Radiology reports were reviewed for size and invasion. Samples were analysed by immunohistochemistry and RT-qPCR for SF-1, PIT-1, T-PIT, SOX2, Nestin and CD133. Stem cell markers were compared between tumours WDLD and those with classically "mature" types. RESULTS: On immunohistochemistry, SOX2 was positive in a higher proportion of tumours WDLD compared with those meeting WHO lineage criteria, 7/10 v 10/42 (70 v 23.4%, p = 0.005). CD133 was positive in 2/10 tumours WDLD but 0/41 meeting lineage criteria, P = 0.003. On RT-qPCR, there was no significant difference in relative expression of stem cell markers (SOX2, CD133, Nestin) between tumours with and WDLD. CONCLUSIONS: Our study is the first to biologically characterise pituitary tumours WDLD. We demonstrate that these tumours exhibit a higher expression of the stem cell marker SOX2 compared with other lineage-differentiated tumours, suggesting possible involvement of stem cells in their development.