Intestinal Enteroendocrine Cells: Present and Future Druggable Targets

Atanga, Roger; Singh, Varsha; In, Julie

doi:10.3390/ijms24108836

Cited by 11 publications

(3 citation statements)

References 142 publications

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“…EECs comprise approximately 1% of the intestinal epithelium and secrete hormones and peptides to recruit immune cells [34]. Distinctive staining of CHGA was observed for HROC43, HROC60, HROC159 T2 M4, and HROC239 T0 M1.…”

Section: Discussionmentioning

confidence: 97%

Novel In Vitro Models for Cell Differentiation and Drug Transport Studies of the Human Intestine

Przybylla,

Krohn,

Sellin

et al. 2023

Cells

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The most common in vitro model for absorption, distribution, metabolism, and excretion (ADME) purposes is currently the Caco-2 cell line. However, clear differences in gene and protein expression towards the small intestine and an, at best, fair prediction accuracy of intestinal drug absorption restrict the usefulness of a model for intestinal epithelial cells. To overcome these limitations, we evaluated a panel of low-passaged patient-derived colorectal cancer cell lines of the HROC collection concerning similarities to small intestinal epithelial cells and their potential to predict intestinal drug absorption. After initial screening of a larger panel, ten cell lines with confluent outgrowth and long-lasting barrier-forming potential were further characterized in close detail. Tight junctional complexes and microvilli structures were detected in all lines, anda higher degree of differentiation was observed in 5/10 cell lines. All lines expressed multiple transporter molecules, with the expression levels in three lines being close to those of small intestinal epithelial cells. Compared with the Caco-2 model, three HROC lines demonstrated both higher similarity to jejunal epithelial tissue cells and higher regulatory potential of relevant drug transporters. In summary, these lines would be better-suited human small intestinal epithelium models for basic and translational research, especially for ADME studies.

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Section: Discussionmentioning

confidence: 97%

Novel In Vitro Models for Cell Differentiation and Drug Transport Studies of the Human Intestine

Przybylla,

Krohn,

Sellin

et al. 2023

Cells

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“…Peripheral 5-HT can circulate systemically via platelets and acted as a mitogen in injured organs. 79 , 80 In a murine model of liver injury, 5-HT promoted liver regeneration after partial hepatectomy, while mice lacking TPH1 could not fully regenerate their liver. 81 These findings suggested that EECs can undergo adaptive reprogramming during injury and provided insights for potential new regenerative therapeutics in the gut.…”

Section: Discussionmentioning

confidence: 99%

Single Cell Analysis of Human Colonoids Exposed to Uranium-Bearing Dust

Atanga,

Appell,

Thompson

et al. 2024

Environ Health Perspect

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Background: Uranium exposure remains an important environmental legacy and physiological health concern, with hundreds of abandoned uranium mines located in the Southwestern United States largely impacting underserved indigenous communities. The negative effects of heavy metals on barrier permeability and inhibition of intestinal epithelial healing have been described; however, transcriptomic changes within the intestinal epithelial cells and impacts on lineage differentiation are largely unknown. Objectives: Herein, we sought to determine the molecular and cellular changes that occur in the colon in response to uranium bearing dust (UBD) exposure. Methods: Human colonoids from three biologically distinct donors were acutely exposed to UBD then digested for single cell RNA sequencing to define the molecular changes that occur to specific identities of colonic epithelial cells. Validation in colonoids was assessed using morphological and imaging techniques. Results: Human colonoids acutely exposed to UBD exhibited disrupted proliferation and hyperplastic differentiation of the secretory lineage cell, enteroendocrine cells (EEC). Single-cell RNA sequencing also showed more EEC subtypes present in UBD-exposed colonoids. Discussion: These findings highlight the significance of crypt-based proliferative cells and secretory cell differentiation using human colonoids to model major colonic responses to uranium-bearing particulate dust exposure. https://doi.org/10.1289/EHP13855

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“…In contrast, the closed type EECs are located basolaterally without direct contact with the lumen (Gribble & Reimann, 2016). Both types of EECs synthesize and store peptides or hormones in secretory granules and release them by exocytosis at the basolateral membrane upon mechanical, chemical or neural stimulation (Atanga et al, 2023). As open-type cells, L cells received both chemical and mechanical signals from the luminal contents, and neural signals from the nerves (Furness et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Mechano-regulation of GLP-1 production by Piezo1 in intestinal L cells

Huang,

Mo,

Yang

et al. 2024

Preprint

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Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone secreted by intestinal L cells and vital for postprandial glycemic control. As open-type enteroendocrine cells, whether L cells can sense mechanical stimuli caused by chyme and thus regulate GLP-1 synthesis and secretion is unexplored. Our study showed expression of Piezo1 in intestinal L cells. Its level varied in different energy status and correlates with blood glucose and GLP-1 levels. Mice with L cell-specific loss of Piezo1 (IntL-Piezo1-/-) exhibited impaired glucose tolerance, increased body weight, reduced GLP-1 production and decreased CaMKKβ/CaMKIV-mTORC1 signaling pathway under normal chow diet or high fed diet. Activation of the intestinal Piezo1 by its agonist Yoda1 or intestinal bead implantation increased the synthesis and secretion of GLP-1, thus alleviated glucose intolerance in diet-induced-diabetic mice. Overexpression of Piezo1, Yoda1 treatment or stretching stimulated GLP-1 production and CaMKKβ/CaMKIV-mTORC1 signaling pathway, which could be abolished by knockdown or blockage of Piezo1 in primary cultured mouse L cells and STC-1 cells. These findings suggest a previously undiscovered mechano-regulation of GLP-1 production in L cells, which may shed new light on the treatments of diabetes.

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Intestinal Enteroendocrine Cells: Present and Future Druggable Targets

Cited by 11 publications

References 142 publications

Novel In Vitro Models for Cell Differentiation and Drug Transport Studies of the Human Intestine

Novel In Vitro Models for Cell Differentiation and Drug Transport Studies of the Human Intestine

Single Cell Analysis of Human Colonoids Exposed to Uranium-Bearing Dust

Mechano-regulation of GLP-1 production by Piezo1 in intestinal L cells

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