Stomach Organ and Cell Lineage Differentiation: from Embryogenesis to Adult Homeostasis

Abstract

Gastric diseases cause considerable worldwide burden. However, the stomach is still poorly understood in terms of the molecular-cellular processes that govern its development and homeostasis. In particular, the complex relationship between the differentiated cell types located within the stomach and the stem and progenitor cells that give rise to them is significantly understudied relative to other organs. In this review, we will highlight the current state of the literature relating to specification of gastric cell lineages from embryogenesis to adulthood. Special emphasis is placed on substantial gaps in knowledge about stomach specification that we think should be tackled to advance the field. For example, it has long been assumed that adult gastric units have a granule-free stem cell that gives rise to all differentiated lineages. Here we will point out that there are also other models that fit all extant data, such as long-lived lineage-committed progenitors that might serve as a source of new cells during homeostasis.

Figure 1

Architecture of the adult stomach and the organization of corpus and antral units. (A) The adult human stomach is composed entirely of glandular epithelium (blue, red), whereas (B) the adult rodent stomach contains a squamous-epithelium–lined forestomach (green), in addition to a glandular stomach. (C) Adult corpus units contain pit/foveolar cells (purple), isthmal stem cells (white), parietal cells (blue), mucous neck cells (green), endocrine cells (light blue), and chief cells (red). Cells transitioning from neck to chief cells are indicated in yellow. (D) Antral units primarily contain pit/fovelar cells (light purple), proliferative isthmal stem cells (white), basal gland cells (light green) similar to mucous neck cells with a hint of chief cell differentiation, and endocrine cells (grey). Note that up to half of human antral gastric units also contain parietal cells (not shown).

Figure 2

Transcription factor domains in the development of the gastric region. Representation of the mouse developing posterior foregut at (A) approximately E10 and at (B) approximately E13. (A and B) Color codes correspond to specific transcription factor signatures in panel C. The future forestomach and esophagus (green) expresses Sox2, but not other glandular markers such as Gata4 and Pdx1. The future corpus (blue) expresses Sox2 and Gata4, but not the more posterior regional markers such as Pdx1. The future antrum (red) expresses Sox2, Gata4, and Pdx1, but not the intestinal marker Cdx2. The future anterior small intestine expresses Cdx2, Gata4, and Pdx1, but not the anterior endodermal marker Sox2. The anterior boundary of Gata4 (blue/green border) is expressed in the glandular stomach but not the forestomach (green). (D) Speculative model of glandular stomach specification during development. Based on developmental studies, early foregut progenitors express the important transcription factors of the FoxA family, Sox17, and Gata4/6. Around this time, an appropriate balance of WNT, FGF, and RA signaling is needed to specify the region of the gut that gives rise to gastric progenitors. These pathways actively posteriorize the endoderm—too little or too much signaling could drive the endoderm to a more anterior or posterior fate, respectively. Future gastric progenitors need to acquire Sox2 expression and not the intestine determinant Cdx2, which is expressed in more posterior endoderm. Once organ budding begins, local mesenchymal signals are crucial to enforce glandular identity and repress adjacent nonglandular stomach organ fates such as the esophagus/forestomach and intestine. Potentially, these signals act through driving expression of potential gastric specification transcription factors such as Gata4 and Hnf1β.

Figure 3

Putative lineage tree of the adult corpus stem cell. Based on the labeling and ultrastructural studies of Karam and Leblond, the isthmus contains a granule-free stem cell that enters the cell cycle to give rise to progenitors that migrate up and down the corpus unit. Cells that migrate up the unit adopt a prepit phenotype (light purple) and eventually turn into mature pit cells (purple). Cells that migrate down the unit appear to adopt a preneck (light green), preparietal (light blue), or pre-endocrine/endocrine phenotype (grey). Neck cells (green) appear to undergo a further transition at the bottom of the unit and eventually become transitional cells with both neck and chief cell characteristics, and finally fully mature chief cells. It is clear that the granule-free cell is long-lived and self-renewing, but each of the progenitors committed to more specific lineage(s) also might be long-lived and self-renewing as well.

Figure 4

Potential behavior of the adult stem cell and lineage-committed progenitors in the adult corpus. (A) If the prediction by Karam and Leblond that there is a single adult stem cell in the corpus holds true, then labeling that cell eventually will result in the long-term maintenance of label as well as labeling of all corpus cell types. (B) It remains possible that the corpus contains long-lived lineage–restricted progenitors as well. Such cells would have early characteristics of pit cells or neck cells, they would be self-renewing and long-lived but give rise only to differentiated pit or neck/chief cells, respectively. Labeled-nucleotide pulse-chase experiments performed by Karam and Leblond to understand how stem cells behave in the stomach would not be able to distinguish between the 2 possibilities (ie, a long-lived multipotent stem cell vs long-lived committed progenitors). Lineage tracing experiments with an appropriate promoter (eg, similar to Lgr5 in the intestine) should be able to distinguish how stem cell hierarchies are arranged. Examples of different lineage tracing patterns with hypothetical, appropriate promoters are shown. If a promoter that is pit-cell lineage-specific could be induced and traced, then the Karam and Leblond model (all cells rapidly arise from a long-lived, self-renewing, multipotent stem cell) would result in temporary labeling of the pit lineage with eventual loss of the label because the stem cell would not be labeled, and pit cell progenitors are not long-lived. However, if long-lived lineage-restricted progenitors exist (contrary to Karam and Leblond), then labeling the prepit cell will result in maintenance of the label throughout the pit cell lineage because the prepit cells will self-renew and not die, and they will continue to label all their progeny. Similar predictions would hold to other cell lineages in the corpus.