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Cell Stem Cell Aug 2022Lgr5 intestinal stem cells (ISCs) depend on niche factors for their proper function. However, the source of these ISC niche factors and how they support ISCs in vivo...
Lgr5 intestinal stem cells (ISCs) depend on niche factors for their proper function. However, the source of these ISC niche factors and how they support ISCs in vivo remain controversial. Here, we report that ISCs depend on lymphatic endothelial cells (LECs) and RSPO3GREM1 fibroblasts (RGFs). In the intestine and colon, LECs are surrounded by RGFs and are located near ISCs at the crypt base. Both LECs and RGFs provide the critical ISC niche factor RSPO3 to support ISCs, where RSPO3 loss in both cell types drastically compromises ISC numbers, villi length, and repair after injury. In response to injury, LEC and RGF numbers expand and produce greater amounts of RSPO3 and other growth/angiocrine factors to foster intestinal repair. We propose that LECs represent a novel niche component for ISCs, which together with RGFs serve as the major in vivo RSPO3 source for ISCs in homeostasis and injury-mediated regeneration.
Topics: Endothelial Cells; Fibroblasts; Homeostasis; Intestinal Mucosa; Intestines; Stem Cells
PubMed: 35931033
DOI: 10.1016/j.stem.2022.06.013 -
Nutrients Feb 2020This review aims to discuss the role of nutrition and feeding practices in necrotizing enterocolitis (NEC), NEC prevention, and its complications, including surgical... (Review)
Review
This review aims to discuss the role of nutrition and feeding practices in necrotizing enterocolitis (NEC), NEC prevention, and its complications, including surgical treatment. A thorough PubMed search was performed with a focus on meta-analyses and randomized controlled trials when available. There are several variables in nutrition and the feeding of preterm infants with the intention of preventing necrotizing enterocolitis (NEC). Starting feeds later rather than earlier, advancing feeds slowly and continuous feeds have not been shown to prevent NEC and breast milk remains the only effective prevention strategy. The lack of medical treatment options for NEC often leads to disease progression requiring surgical resection. Following resection, intestinal adaptation occurs, during which villi lengthen and crypts deepen to increase the functional capacity of remaining bowel. The effect of macronutrients on intestinal adaptation has been extensively studied in animal models. Clinically, the length and portion of intestine that is resected may lead to patients requiring parenteral nutrition, which is also reviewed here. There remain significant gaps in knowledge surrounding many of the nutritional aspects of NEC and more research is needed to determine optimal feeding approaches to prevent NEC, particularly in infants younger than 28 weeks and <1000 grams. Additional research is also needed to identify biomarkers reflecting intestinal recovery following NEC diagnosis individualize when feedings should be safely resumed for each patient.
Topics: Animals; Enterocolitis, Necrotizing; Humans; Infant; Infant Formula; Infant Nutritional Physiological Phenomena; Infant, Newborn; Infant, Premature; Intestines; Milk; Milk, Human; Parenteral Nutrition
PubMed: 32085587
DOI: 10.3390/nu12020520 -
Nature May 2019Intestinal organoids are complex three-dimensional structures that mimic the cell-type composition and tissue organization of the intestine by recapitulating the...
Intestinal organoids are complex three-dimensional structures that mimic the cell-type composition and tissue organization of the intestine by recapitulating the self-organizing ability of cell populations derived from a single intestinal stem cell. Crucial in this process is a first symmetry-breaking event, in which only a fraction of identical cells in a symmetrical sphere differentiate into Paneth cells, which generate the stem-cell niche and lead to asymmetric structures such as the crypts and villi. Here we combine single-cell quantitative genomic and imaging approaches to characterize the development of intestinal organoids from single cells. We show that their development follows a regeneration process that is driven by transient activation of the transcriptional regulator YAP1. Cell-to-cell variability in YAP1, emerging in symmetrical spheres, initiates Notch and DLL1 activation, and drives the symmetry-breaking event and formation of the first Paneth cell. Our findings reveal how single cells exposed to a uniform growth-promoting environment have the intrinsic ability to generate emergent, self-organized behaviour that results in the formation of complex multicellular asymmetric structures.
Topics: Adaptor Proteins, Signal Transducing; Animals; Calcium-Binding Proteins; Cell Cycle Proteins; Intercellular Signaling Peptides and Proteins; Intestines; Mice; Organoids; Paneth Cells; Phosphoproteins; Receptors, G-Protein-Coupled; Single-Cell Analysis; YAP-Signaling Proteins
PubMed: 31019299
DOI: 10.1038/s41586-019-1146-y -
Biophysical Journal Feb 2021In the intestinal epithelium, proliferated epithelial cells ascend the crypts and villi and shed at the villus tips into the gut lumen. In this study, we theoretically...
In the intestinal epithelium, proliferated epithelial cells ascend the crypts and villi and shed at the villus tips into the gut lumen. In this study, we theoretically investigate the roles of the villi on cell turnover. We present a stochastic model that focuses on the duration over which cells migrate the shortest paths between the crypt orifices and the villus tips, where shedding cells are randomly chosen from among those older than the shortest-path cell migration times. By extending the length of the shortest path to delay cell shedding, the finger-like shape of the villus would tightly regulate shedding-cell ages compared with flat surfaces and shorter projections; the villus allows epithelial cells to shed at around the same age, which limits them from shedding early or staying in the epithelium for long periods. Computational simulations of cell dynamics agreed well with the predictions. We also examine various mechanical conditions of cells and confirm that coordinated collective cell migration supports the predictions. These results suggest the important roles of the villi in homeostatic maintenance of the small intestine, and we discuss the applicability of our approach to other tissues with collective cell movement.
Topics: Epithelial Cells; Epithelium; Intestinal Mucosa; Intestine, Small; Intestines
PubMed: 33453270
DOI: 10.1016/j.bpj.2021.01.003 -
Molecular Medicine Reports Mar 2020A high‑fat diet (HFD) or obesity‑promoting diet is closely associated with metabolic diseases and intestinal tumors, particularly in middle‑aged individuals...
A high‑fat diet (HFD) or obesity‑promoting diet is closely associated with metabolic diseases and intestinal tumors, particularly in middle‑aged individuals (typically 45‑64 years old). The intestinal epithelium constitutes a barrier that separates the host from the food and microbiota in the gut, and thus, a dysfunctional epithelium is associated with a number of diseases. However, the changes caused to the function of intestinal epithelium in response to an HFD have not been well‑studied to date. In the present study, middle‑aged female mice (12 months old) fed an HFD for a period of 14 weeks were used to determine the effects of HFD on the intestine. Characteristics including the body weight, fat deposition, glucose metabolism, inflammatory state and intestinal morphology were assessed, while the intestinal stem cell (ISC) counts and the ability of isolated intestinal crypts to form organoid bodies in 3D culture were examined. Intestinal epithelial barrier function, including secretory defense, tight junctions and cell apoptosis, were also studied. Morphologically, the HFD resulted in a mild reduction in the length of villi of the small intestine, the colon length and the depth of colon crypts. In addition, the ISC counts were increased in the small intestine and colon in HFD‑fed mice. The ability of crypts to grow into organoids (mini‑guts) was also increased in crypts obtained from mice fed an HFD, while HFD compromised the epithelial barrier function of the colon. These results demonstrated how an HFD affects the intestinal epithelium and highlighted the need to carefully consider dietary patterns.
Topics: Animals; Apoptosis; Cardiovascular Diseases; Colonic Neoplasms; Diet, High-Fat; Disease Models, Animal; Female; Gastrointestinal Microbiome; Homeostasis; Humans; Intestinal Mucosa; Intestines; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; Stem Cells; Tight Junctions
PubMed: 32016468
DOI: 10.3892/mmr.2020.10932 -
Cellular and Molecular Gastroenterology... 2023The development of the mammalian intestine, from its earliest origins as a morphologically uniform sheet of endoderm cells during gastrulation into the complex organ... (Review)
Review
The development of the mammalian intestine, from its earliest origins as a morphologically uniform sheet of endoderm cells during gastrulation into the complex organ system that is essential for the life of the organism, is a truly fascinating process. During midgestation development, reciprocal interactions between endoderm-derived epithelium and mesoderm-derived mesenchyme enable villification, or the conversion of a radially symmetric pseudostratified epithelium into the functional subdivision of crypts and villi. Once a mature crypt-villus axis is established, proliferation and differentiation of new epithelial cells continue throughout life. Spatially localized signals including the wingless and Int-1, fibroblast growth factor, and Hippo systems, among others, ensure that new cells are being born continuously in the crypt. As cells exit the crypt compartment, a gradient of bone morphogenetic protein signaling limits proliferation to allow for the specification of multiple mature cell types. The first major differentiation decision is dependent on Notch signaling, which specifies epithelial cells into absorptive and secretory lineages. The secretory lineage is subdivided further into Paneth, goblet, tuft, and enteroendocrine cells via a complex network of transcription factors. Although some of the signaling molecules are produced by epithelial cells, critical components are derived from specialized crypt-adjacent mesenchymal cells termed telocytes, which are marked by Forkhead box l1, GLI Family Zinc Finger 1, and platelet-derived growth factor receptor α. The crucial nature of these processes is evidenced by the multitude of intestinal disorders such as colorectal cancer, short-bowel syndrome, and inflammatory bowel disease, which all reflect perturbations of the development and/or differentiation of the intestine.
Topics: Animals; Cell Differentiation; Intestines; Intestinal Mucosa; Enteroendocrine Cells; Epithelial Cells; Mammals
PubMed: 37507088
DOI: 10.1016/j.jcmgh.2023.07.011 -
Annual Review of Physiology 2016The intestine is supported by a complex vascular system that undergoes dynamic and transient daily shifts in blood perfusion, depending on the metabolic state. Moreover,... (Review)
Review
The intestine is supported by a complex vascular system that undergoes dynamic and transient daily shifts in blood perfusion, depending on the metabolic state. Moreover, the intestinal villi have a steep oxygen gradient from the hypoxic epithelium adjacent to the anoxic lumen to the relative higher tissue oxygenation at the base of villi. Due to the daily changes in tissue oxygen levels in the intestine, the hypoxic transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α are essential in maintaining intestinal homeostasis. HIF-2α is essential in maintaining proper micronutrient balance, the inflammatory response, and the regenerative and proliferative capacity of the intestine following an acute injury. However, chronic activation of HIF-2α leads to enhanced proinflammatory response, intestinal injury, and colorectal cancer. In this review, we detail the major mechanisms by which HIF-2α contributes to health and disease of the intestine and the therapeutic implications of targeting HIF-2α in intestinal diseases.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Homeostasis; Humans; Intestinal Diseases; Intestinal Mucosa; Intestines; Oxygen
PubMed: 26667076
DOI: 10.1146/annurev-physiol-021115-105202 -
Development (Cambridge, England) Jul 2016The vertebrate small intestine requires an enormous surface area to effectively absorb nutrients from food. Morphological adaptations required to establish this... (Review)
Review
The vertebrate small intestine requires an enormous surface area to effectively absorb nutrients from food. Morphological adaptations required to establish this extensive surface include generation of an extremely long tube and convolution of the absorptive surface of the tube into villi and microvilli. In this Review, we discuss recent findings regarding the morphogenetic and molecular processes required for intestinal tube elongation and surface convolution, examine shared and unique aspects of these processes in different species, relate these processes to known human maladies that compromise absorptive function and highlight important questions for future research.
Topics: Animals; Humans; Intestinal Absorption; Intestines; Microvilli; Models, Biological; Morphogenesis; Signal Transduction
PubMed: 27381224
DOI: 10.1242/dev.135400 -
Physiology & Behavior Sep 2014Obese and lean individuals respond differently to nutrients with changes in digestion, absorption and hormone release. This may be a result of differences in intestinal... (Review)
Review
Obese and lean individuals respond differently to nutrients with changes in digestion, absorption and hormone release. This may be a result of differences in intestinal epithelial morphology and function driven by the hyperphagia or the type of diet associated with obesity. It is well known that the maintenance and growth of the intestine is driven by the amount of luminal nutrients, with high nutrient content resulting in increases in cell number, villi length and crypt depth. In addition, the type of nutrient appears to contribute to alterations in the morphology and function of the epithelial cells. This intestinal adaptation may be what is driving the differences in nutrient processing in lean versus obese individuals. This review describes how nutrients may be able to induce changes in intestinal epithelial cell proliferation, differentiation and function and the link between intestinal adaptation and obesity.
Topics: Acclimatization; Animals; Cell Proliferation; Epithelial Cells; Food; Humans; Intestinal Mucosa; Intestines; Obesity
PubMed: 24704111
DOI: 10.1016/j.physbeh.2014.03.026 -
Journal of Veterinary Diagnostic... May 2022Healthy horses and other animals have large numbers of resident leukocytes in the intestinal wall, but there is scant information regarding which and how many leukocytes...
Healthy horses and other animals have large numbers of resident leukocytes in the intestinal wall, but there is scant information regarding which and how many leukocytes are normally present in the equine intestinal wall. Our aim was to provide a reference range of leukocytes in the intestinal mucosal and submucosal propria of normal horses. We included in our study intestinal tissues from 22 Thoroughbred racehorses with no clinical intestinal disease, which had been euthanized because of catastrophic musculoskeletal injuries. Neutrophils, lymphocytes, eosinophils, macrophages, and plasma cells were counted in 5 random 17,600-µm areas of villus lamina propria of the duodenum, jejunum, and ileum, and deep lamina propria of the duodenum, jejunum, ileum, right ventral colon, left ventral colon, left dorsal colon, right dorsal colon, and small colon. Other features investigated in the same intestinal segments included villus height and width (small intestine), presence of ciliated protozoa, Paneth cells number, subcryptal leukocyte layers (number of leukocyte layers between the bottom of the crypts and the muscularis mucosae), and submucosal leukocytes. Lymphocytes were the most numerous cells in all segments analyzed, followed by plasma cells, eosinophils, macrophages, and neutrophils. Eosinophil numbers were significantly higher in both lamina propria and submucosa of the large intestine than in the small intestine. The duodenum had shorter and thinner villi than either jejunum or ileum. The data provided from our study will be useful for diagnosticians examining inflammatory processes in the intestinal tract of horses.
Topics: Animals; Colon; Horse Diseases; Horses; Intestinal Diseases; Intestinal Mucosa; Jejunum; Leukocyte Count
PubMed: 34293980
DOI: 10.1177/10406387211031944