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Organoids and Engineered Organ Systems - 2018
Epithelial Traffic Control: IL22 Gives TA Cells the Green Light
The intestinal epithelial barrier is instrumental in the physical separation of gut microbiota from underlying innate and adaptive immune cells and stromal cells.1 This “barrier” is anything but static, however, with intestinal stem cells (ISCs) tightly controlling regeneration of the epithelial lining along the crypt–villus axis in a coordinated balance between ISC self-renewal and differentiation into transit-amplifying (TA) cells.2 Although numerous, well-defined growth factor pathways are known to regulate ISC and TA cell expansion dynamics in the steady state, far less is understood about how specific cytokines expressed during tissue injury and inflammation influence this intricate process.An Organoid-Based Preclinical Model of Human Gastric Cancer
Our goal was to develop an initial study for the proof of concept whereby gastric cancer organoids are used as an approach to predict the tumor response in individual patients.Interleukin 22 Expands Transit-Amplifying Cells While Depleting Lgr5+ Stem Cells via Inhibition of Wnt and Notch Signaling
Epithelial regeneration is essential for homeostasis and repair of the mucosal barrier. In the context of infectious and immune-mediated intestinal disease, interleukin (IL) 22 is thought to augment these processes. We sought to define the mechanisms by which IL22 promotes mucosal healing.Three-Dimensional Organoids Reveal Therapy Resistance of Esophageal and Oropharyngeal Squamous Cell Carcinoma Cells
Oropharyngeal and esophageal squamous cell carcinomas, especially the latter, are a lethal disease, featuring intratumoral cancer cell heterogeneity and therapy resistance. To facilitate cancer therapy in personalized medicine, three-dimensional (3D) organoids may be useful for functional characterization of cancer cells ex vivo. We investigated the feasibility and the utility of patient-derived 3D organoids of esophageal and oropharyngeal squamous cell carcinomas.Advancing Regulatory Science Through Innovation: In Vitro Microphysiological Systems
The challenge of modern product development and globalization underscores the critical importance of ensuring that regulatory science keeps pace with advances in basic and applied science and technology. In 2011, the US Food and Drug Administration (FDA) launched its Advancing Regulatory Science Initiative to accelerate scientific innovation and improve regulatory decision-making practices, with the goal of providing safe and effective products. The FDA identified several priority areas in which the Agency believed that new or enhanced engagement was essential in fulfilling its public health and regulatory mission.IL22 Inhibits Epithelial Stem Cell Expansion in an Ileal Organoid Model
Crohn’s disease is an inflammatory bowel disease that affects the ileum and is associated with increased cytokines. Although interleukin (IL)6, IL17, IL21, and IL22 are increased in Crohn’s disease and are associated with disrupted epithelial regeneration, little is known about their effects on the intestinal stem cells (ISCs) that mediate tissue repair. We hypothesized that ILs may target ISCs and reduce ISC-driven epithelial renewal.Microfluidic Organ-on-a-Chip Models of Human Intestine
Microfluidic organ-on-a-chip models of human intestine have been developed and used to study intestinal physiology and pathophysiology. In this article, we review this field and describe how microfluidic Intestine Chips offer new capabilities not possible with conventional culture systems or organoid cultures, including the ability to analyze contributions of individual cellular, chemical, and physical control parameters one-at-a-time; to coculture human intestinal cells with commensal microbiome for extended times; and to create human-relevant disease models.Interleukin-17A Promotes Parietal Cell Atrophy by Inducing Apoptosis
Atrophic gastritis caused by chronic inflammation in the gastric mucosa leads to the loss of gastric glandular cells, including acid-secreting parietal cells. Parietal cell atrophy in a setting of chronic inflammation induces spasmolytic polypeptide expressing metaplasia, a critical step in gastric carcinogenesis. However, the mechanisms by which inflammation causes parietal cell atrophy and spasmolytic polypeptide expressing metaplasia are not well defined. We investigated the role of interleukin-17A (IL-17A) in causing parietal cell atrophy.The Esophageal Organoid System Reveals Functional Interplay Between Notch and Cytokines in Reactive Epithelial Changes
Aberrations in the esophageal proliferation-differentiation gradient are histologic hallmarks in eosinophilic esophagitis (EoE) and gastroesophageal reflux disease. A reliable protocol to grow 3-dimensional (3D) esophageal organoids is needed to study esophageal epithelial homeostasis under physiological and pathologic conditions.Translating Developmental Principles to Generate Human Gastric Organoids
Gastric diseases, including peptic ulcer disease and gastric cancer, are highly prevalent in human beings. Despite this, the cellular biology of the stomach remains poorly understood relative to other gastrointestinal organs such as the liver, intestine, and colon. In particular, little is known about the molecular basis of stomach development and the differentiation of gastric lineages. Although animal models are useful for studying gastric development, function, and disease, there are major structural and physiological differences in human stomachs that render these models insufficient.Bioengineered Systems and Designer Matrices That Recapitulate the Intestinal Stem Cell Niche
The relationship between intestinal stem cells (ISCs) and the surrounding niche environment is complex and dynamic. Key factors localized at the base of the crypt are necessary to promote ISC self-renewal and proliferation, to ultimately provide a constant stream of differentiated cells to maintain the epithelial barrier. These factors diminish as epithelial cells divide, migrate away from the crypt base, differentiate into the postmitotic lineages, and end their life span in approximately 7 days when they are sloughed into the intestinal lumen.Esophageal 3D Culture Systems as Modeling Tools in Esophageal Epithelial Pathobiology and Personalized Medicine
The stratified squamous epithelium of the esophagus shows a proliferative basal layer of keratinocytes that undergo terminal differentiation in overlying suprabasal layers. Esophageal pathologies, including eosinophilic esophagitis, gastroesophageal reflux disease, Barrett's esophagus, squamous cell carcinoma, and adenocarcinoma, cause perturbations in the esophageal epithelial proliferation-differentiation gradient. Three-dimensional (3D) culture platforms mimicking in vivo esophageal epithelial tissue architecture ex vivo have emerged as powerful experimental tools for the investigation of esophageal biology in the context of homeostasis and pathology.Human Fetal-Derived Enterospheres Provide Insights on Intestinal Development and a Novel Model to Study Necrotizing Enterocolitis (NEC)
Untreated necrotizing enterocolitis (NEC) can lead to massive inflammation resulting in intestinal necrosis with a high mortality rate in preterm infants. Limited access to human samples and relevant experimental models have hampered progress in NEC pathogenesis. Earlier evidence has suggested that bacterial colonization of an immature and developing intestine can lead to an abnormally high inflammatory response to bacterial bioproducts. The aim of our study was to use human fetal organoids to gain insights into NEC pathogenesis.Move Over Caco-2 Cells: Human-Induced Organoids Meet Gut-on-a-Chip
The intestinal epithelium serves as both a crucial barrier and a critical site of interaction between the body and the environment. As such, it comprises a large surface area, and is implicated in a wide range of diseases including inflammatory bowel disease, celiac disease, infectious diarrheas, and intestinal cancers. Architecturally, the small intestine is notable for its proliferative crypts, where stem and transit-amplifying progenitor cells reside, and villi, which consist of multiple differentiated cell types from the absorptive and secretory lineages, including enterocytes, goblet cells, Paneth cells, tuft cells, M cells, and enteroendocrine cells.Parietal Cell Death by Cytokines
Parietal cell atrophy in the human stomach occurs along a continuum of gastric inflammation, atrophy, and then metaplasia, a preneoplastic lesion. In mice, and to a lesser extent in human beings, the best-characterized type of metaplasia is spasmolytic polypeptide-expressing metaplasia. Inflammation in the stomach generally arises in response to autoimmune gastritis or an infection from Helicobacter pylori. Although relatively rare, autoimmune gastritis is known to occur in response to autoantibodies to parietal cell proteins, specifically the α and β subunits of the proton pump H+, K+-adenosine triphosphatase.Molecular Basis and Differentiation-Associated Alterations of Anion Secretion in Human Duodenal Enteroid Monolayers
Human enteroids present a novel tool to study human intestinal ion transport physiology and pathophysiology. The present study describes the contributions of Cl- and HCO3- secretion to total cyclic adenosine monophosphate (cAMP)-stimulated electrogenic anion secretion in human duodenal enteroid monolayers and the relevant changes after differentiation.Human Fetal Enterospheres: New Tools for the Study of Necrotizing Enterocolitis
Necrotizing enterocolitis (NEC) is a serious and often life-threatening disorder that affects the gastrointestinal tract of premature infants. The disease develops in seemingly stable infants, who, after receiving formula feeds, suddenly develop abdominal distention and feeding intolerance, which often progresses to systemic sepsis and death. At laparotomy, which is required in approximately half of all babies with NEC, patchy regions of intestinal necrosis are encountered, necessitating intestinal resection in an attempt to save the infant’s life.Monoclonal Antibodies Reveal Dynamic Plasticity Between Lgr5- and Bmi1-Expressing Intestinal Cell Populations
Continual renewal of the intestinal epithelium is dependent on active- and slow-cycling stem cells that are confined to the crypt base. Tight regulation of these stem cell populations maintains homeostasis by balancing proliferation and differentiation to support critical intestinal functions. The hierarchical relation of discrete stem cell populations in homeostasis or during regenerative epithelial repair remains controversial. Although recent studies have supported a model for the active-cycling leucine-rich repeat-containing G-protein–coupled receptor 5 (Lgr5)+ intestinal stem cell ( ISC ) functioning upstream of the slow-cycling B lymphoma Mo-MLV insertion region 1 homolog (Bmi1)-expressing cell, other studies have reported the opposite relation.Mapping the Duodenal Crypt-Villus Transport Axis
The epithelial cells that line the intestines have a physiological imperative to absorb nutrients while forming a semipermeable barrier that prevents the incursion of undesirable luminal solutes.1 They also both absorb and secrete electrolytes to drive the accompanying passive transfer of water, thereby maintaining appropriate levels of luminal fluidity to support the processes of digestion and absorption. It has been estimated that the gut is presented with 8–9 L of fluid per day, with only the minority coming from oral intake of food and beverages—the remainder derives from the various intestinal secretions that mediate digestive and other functions.Integration of Sensors in Gastrointestinal Organoid Culture for Biological Analysis
The gastrointestinal (GI) tract regulates physiologic responses in complex ways beyond facilitating nutrient entry into the circulatory system. Because of the anatomic location of the GI tract, studying in vivo physiology of the human gut, including host cell interaction with the microbiota, is limited. GI organoids derived from human stem cells are gaining interest as they recapitulate in vivo cellular phenotypes and functions. An underdeveloped capability that would further enhance the utility of these miniature models of the GI tract is to use sensors to quantitatively characterize the organoid systems with high spatiotemporal resolution.Decrypting the Crypt: Novel Monoclonal Antibodies to Identify Intestinal Stem Cell Populations
Despite extensive efforts to fully characterize and identify the stem cell pools at the base of the small intestinal crypts, there remains controversy over the precise identity of these cells. The active crypt base columnar cell, labeled by leucine-rich G-protein–coupled receptor 5 (Lgr5), is the workhorse of epithelial renewal, but other cell populations are able to contribute to this renewal, particularly after intestinal damage. The accurate labeling of these additional stem cell populations is plagued by the small numbers of these cells and the plasticity of the cell itself.A Method for Cryogenic Preservation of Human Biopsy Specimens and Subsequent Organoid Culture
Human tissue–derived gastrointestinal (GI) organoids have revolutionized the study of human biology,1–3 and are powerful tools for studying human physiology and disease; however, generation of organoids is limited by access to human tissue and a short window of viability for human samples, putting a hard limit on the time and place in which a patient sample can be used for research.4 These restraints mean that a laboratory must be relatively geographically close to the source of collection to use the sample within the window of viability.A High-Throughput Organoid Microinjection Platform to Study Gastrointestinal Microbiota and Luminal Physiology
The human gut microbiota is becoming increasingly recognized as a key factor in homeostasis and disease. The lack of physiologically relevant in vitro models to investigate host–microbe interactions is considered a substantial bottleneck for microbiota research. Organoids represent an attractive model system because they are derived from primary tissues and embody key properties of the native gut lumen; however, access to the organoid lumen for experimental perturbation is challenging. Here, we report the development and validation of a high-throughput organoid microinjection system for cargo delivery to the organoid lumen and high-content sampling.The Next MacGyver: A Platform to Study Intestinal Organoids Using High-Throughput Computer-Driven Microinjection
The complex microbial community that lives in the colon plays an important role in diverse biological pathways and is linked to many diseases including inflammatory bowel disease, obesity, and cancer. Defining how microbial interactions influence host cellular molecular pathways is crucial for exploring the potential therapeutic benefits of manipulating microbial communities to treat intestinal disorders. In 2009, pioneering work in the gastrointestinal field led to the development of intestinal organoid cultures, either derived from pluripotent embryonic or reprogrammed somatic stem cells,1 or from adult stem cells derived directly from intestinal tissue or biopsy specimens.Enhanced Utilization of Induced Pluripotent Stem Cell–Derived Human Intestinal Organoids Using Microengineered Chips
Human intestinal organoids derived from induced pluripotent stem cells have tremendous potential to elucidate the intestinal epithelium’s role in health and disease, but it is difficult to directly assay these complex structures. This study sought to make this technology more amenable for study by obtaining epithelial cells from induced pluripotent stem cell–derived human intestinal organoids and incorporating them into small microengineered Chips. We then investigated if these cells within the Chip were polarized, had the 4 major intestinal epithelial subtypes, and were biologically responsive to exogenous stimuli.
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