Single-Cell Studies of Intestinal Stem Cell Heterogeneity During Homeostasis and Regeneration

Norkin, Maxim; Capdevila, Claudia; Calderon, Ruben I.; Su, Tianhong; Trifas, Maria; Ordóñez‐Morán, Paloma; Yan, Kelley S.

doi:10.1007/978-1-0716-0747-3_9

Cited by 5 publications

(5 citation statements)

References 55 publications

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“…The intestinal epithelium is particularly well-suited for scRNA-seq studies because it is a dynamic, selfrenewing tissue whose vast cellular diversity and lineage relationships remain poorly understood (Figures 1 and 3) (91,92). Grün et al devised an algorithm to identify rare cell types on scRNA-seq data acquired from intestinal organoids cultured ex vivo (33).…”

Section: Single-cell Transcriptomic Methods For Lineage Reconstruction In the Intestinal Epitheliummentioning

confidence: 99%

Cellular origins and lineage relationships of the intestinal epithelium

Capdevila

Trifas

Miller

et al. 2021

American Journal of Physiology-Gastrointestinal and Liver Physi

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Knowledge of the development and hierarchical organization of tissues is key to understanding how they are perturbed in injury and disease, as well as how they may be therapeutically manipulated to restore homeostasis. The rapidly regenerating intestinal epithelium harbors diverse cell types and their lineage relationships have been studied using numerous approaches, from classical label-retaining and genetic lineage tracing methods to novel transcriptome-based annotations. Here, we describe the developmental trajectories that dictate differentiation and lineage specification in the intestinal epithelium. We focus on the most recent single-cell RNA-sequencing (scRNA-seq)-based strategies for understanding intestinal epithelial cell lineage relationships, underscoring how they have refined our view of the development of this tissue and highlighting their advantages and limitations. We emphasize how these technologies have been applied to understand the dynamics of intestinal epithelial cells in homeostatic and injury-induced regeneration models.

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Section: Single-cell Transcriptomic Methods For Lineage Reconstruction In the Intestinal Epitheliummentioning

confidence: 99%

Cellular origins and lineage relationships of the intestinal epithelium

Capdevila

Trifas

Miller

et al. 2021

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Advances in single-cell analysis technology will make it possible to identify more specific subsets of gastric stem cells. Indeed, increasingly many results support the presence of cellular heterogeneity in the stem cell population [84][85][86]. In light of previous studies, we assume that some subsets derived from chief cells or isthmus cells could generate all lineages of the gastric corpus, including gastric-secreting parietal cells and endocrine cells.…”

mentioning

confidence: 60%

Gastric stem cell research and gastric organoids

Jeong

Nam

2022

Organoid

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The stomach is a complex organ lined with ordered epithelium consisting of different adult stem cell (ASC) pools. In the previous decade, research into gastric epithelial stem cells has been performed using lineage tracing methods, and several putative ASC markers in the gastric gland have been identified, although their roles in homeostasis maintenance and the origin of cancer remain to be clarified. With advances in gastric stem cell research, 3-dimensional (3D) organoid culture has been developed on the basis of in-depth insights into the control of stem cell self-renewal, proliferation, and differentiation. Since the initial report that single intestinal stem cells have the ability to generate long-lived 3D structures that exhibit budding forms and self-renewal, tissue-specific adaptations of this method have been established in various organs, such as the small intestine, colon, liver, and stomach. In the murine stomach, putative ASCs isolated from the corpus and antrum generate gastric organoids that can simulate organ-specific cells to some extent. In addition, a few trials have been conducted to generate long-lived 3D organoids using human-derived ASCs and pluripotent stem cells. We hope that this review will provide comprehensive knowledge on gastric stem cell research and gastric organoids.

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“…In contrast, we observed a strong increase in the expression of mRNAs characteristic of goblet cells, such as chloride channel accessory 1 (Clca1), Muc2 and Tff3 (43). In addition, the expression of genes encoding enterocyte markers such as Alpi, Fabp1 and Sis was increased (35,36) (Supplementary Fig. S4C).…”

Section: Control Of Secretory Cell Type Switching Between Paneth and ...mentioning

confidence: 99%

“…2A). Three clusters, 12, 8 and 13, represented the pathway to absorptive enterocytes [intestinal alkaline phosphatase (Alpi)-, sucraseisomaltase (Sis)-and fatty acid binding protein 1 (Fabp1)-positive] (35,36). The cells in cluster 9 were Olfm4-and Lgr4-positive and produced genes related to Paneth and goblet cells.…”

Section: Intestinal Epithelial Cell Dynamics and Microbiota Compositi...mentioning

confidence: 99%

The fate of secretory cells during intestinal homeostasis, regeneration, and tumor formation is regulated by Tcf4

Janeckova,

Stastna,

Hrckulak

et al. 2024

Preprint

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The single-layer epithelium of the gastrointestinal tract is a dynamically renewing tissue that ensures nutrient absorption, secretory and barrier functions and is involved in immune responses. The basis for this homeostatic renewal is the Wnt signaling pathway. Blocking this pathway can lead to epithelial damage, while its abnormal activation can result in the development of intestinal tumors. In this study, we investigated the dynamics of intestinal epithelial cells and tumorigenesis using a conditional mouse model. Using single-cell and bulk RNA sequencing and histological analysis, we elucidated the cellular responses following the loss of specific cell types. We focused on the fate of cells in the lower parts of the intestinal crypts and the development of colon adenomas. By partially inactivating the transcription factor Tcf4, a key effector of the Wnt signaling pathway, we analyzed the regeneration of isolated hyperproliferative foci (crypts). Our results suggest that the damaged epithelium is not restored by a specific regeneration program associated with oncofetal gene production, but rather by a standard homeostatic renewal pathway. Moreover, disruption of Tcf4 in secretory progenitors resulted in a significant shift in the cell lineage from Paneth cells to goblet cells, characterized by morphological changes and loss of Paneth cell-specific genes. We also found that hyperactivation of the Wnt signaling pathway in colonic adenomas correlated with the upregulation of genes typical of Paneth cells in the intestine, followed by the emergence of secretory tumor cells producing the Wnt3 ligand. The absence of Tcf4 led to a phenotypic shift of the tumor cells towards goblet cells. Our study presents a new model of epithelial regeneration based on the genetically driven partial elimination of intestinal crypts. We highlight the critical role of Tcf4 in the control of cell lineage decisions in the intestinal epithelium and colon tumors.

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Single-Cell Studies of Intestinal Stem Cell Heterogeneity During Homeostasis and Regeneration

Cited by 5 publications

References 55 publications

Cellular origins and lineage relationships of the intestinal epithelium

Cellular origins and lineage relationships of the intestinal epithelium

Gastric stem cell research and gastric organoids

The fate of secretory cells during intestinal homeostasis, regeneration, and tumor formation is regulated by Tcf4

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