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Functional human gastrointestinal organoids can be engineered from three primary germ layers derived separately from pluripotent stem cells.

ABSTRACT: Human organoid model systems lack important cell types that, in the embryo, are incorporated into organ tissues during development. We developed an organoid assembly approach starting with cells from the three primary germ layers-enteric neuroglial, mesenchymal, and epithelial precursors-that were derived separately from human pluripotent stem cells (PSCs). From these three cell types, we generated human antral and fundic gastric tissue containing differentiated glands surrounded by layers of smooth muscle containing functional enteric neurons that controlled contractions of the engineered antral tissue. Using this experimental system, we show that human enteric neural crest cells (ENCCs) promote mesenchyme development and glandular morphogenesis of antral stomach organoids. Moreover, ENCCs can act directly on the foregut to promote a posterior fate, resulting in organoids with a Brunner's gland phenotype. Thus, germ layer components that are derived separately from PSCs can be used for tissue engineering to generate complex human organoids.

SUBMITTER: Eicher AK

PROVIDER: S-EPMC8741755 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Functional human gastrointestinal organoids can be engineered from three primary germ layers derived separately from pluripotent stem cells.

Eicher Alexandra K AK Kechele Daniel O DO Sundaram Nambirajan N Berns H Matthew HM Poling Holly M HM Haines Lauren E LE Sanchez J Guillermo JG Kishimoto Keishi K Krishnamurthy Mansa M Han Lu L Zorn Aaron M AM Helmrath Michael A MA Wells James M JM

Cell stem cell 20211201 1

Human organoid model systems lack important cell types that, in the embryo, are incorporated into organ tissues during development. We developed an organoid assembly approach starting with cells from the three primary germ layers-enteric neuroglial, mesenchymal, and epithelial precursors-that were derived separately from human pluripotent stem cells (PSCs). From these three cell types, we generated human antral and fundic gastric tissue containing differentiated glands surrounded by layers of sm ...[more]

PMID: 34856121

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Project description:Maternal alcohol exposure during pregnancy can substantially impact the development of the fetus, causing a range of symptoms, known as fetal alcohol spectrum disorders (FASDs), such as cognitive dysfunction and psychiatric disorders, with the pathophysiology and mechanisms largely unknown. Recently developed human cerebral organoids from induced pluripotent stem cells are similar to fetal brains in the aspects of development and structure. These models allow more relevant in vitro systems to be developed for studying FASDs than animal models. Modeling binge drinking using human cerebral organoids, we sought to quantify the downstream toxic effects of alcohol (ethanol) on neural pathology phenotypes and signaling pathways within the organoids. The results revealed that alcohol exposure resulted in unhealthy organoids at cellular, subcellular, bioenergetic metabolism, and gene expression levels. Alcohol induced apoptosis on organoids. The apoptotic effects of alcohol on the organoids depended on the alcohol concentration and varied between cell types. Specifically, neurons were more vulnerable to alcohol-induced apoptosis than astrocytes. The alcohol-treated organoids exhibit ultrastructural changes such as disruption of mitochondria cristae, decreased intensity of mitochondrial matrix, and disorganized cytoskeleton. Alcohol exposure also resulted in mitochondrial dysfunction and metabolic stress in the organoids as evidenced by (1) decreased mitochondrial oxygen consumption rates being linked to basal respiration, ATP production, proton leak, maximal respiration and spare respiratory capacity, and (2) increase of non-mitochondrial respiration in alcohol-treated organoids compared with control groups. Furthermore, we found that alcohol treatment affected the expression of 199 genes out of 17,195 genes analyzed. Bioinformatic analyses showed the association of these dysregulated genes with 37 pathways related to clinically relevant pathologies such as psychiatric disorders, behavior, nervous system development and function, organismal injury and abnormalities, and cellular development. Notably, 187 of these genes are critically involved in neurodevelopment, and/or implicated in nervous system physiology and neurodegeneration. Furthermore, the identified genes are key regulators of multiple pathways linked in networks. This study extends for the first time animal models of binge drinking-related FASDs to a human model, allowing in-depth analyses of neurotoxicity at tissue, cellular, subcellular, metabolism, and gene levels. Hereby, we provide novel insights into alcohol-induced pathologic phenotypes, cell type-specific vulnerability, and affected signaling pathways and molecular networks, that can contribute to a better understanding of the developmental neurotoxic effects of binge drinking during pregnancy.

Dataset Information

Functional human gastrointestinal organoids can be engineered from three primary germ layers derived separately from pluripotent stem cells.

Publications

Functional human gastrointestinal organoids can be engineered from three primary germ layers derived separately from pluripotent stem cells.

Similar Datasets

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