The parietal, chief, pit, and neck cells make up the gastric corpus, which is a major component of the glandular stomach. Each of these specialised epithelial cells plays a crucial part in digestion, and they are constantly replenished by new ones created by stem cell differentiation.
Gastric disorders such as intestinal metaplasia and gastric cancer are caused by flaws in this process. The basic mechanisms responsible for stem cell renewal and differentiation, and consequently the maintenance of stomach homeostasis, remain unknown.
Aiming to bridge this gap, a group of researchers led by Hitomi Takada and Akira Kurisaki of the Nara Institute of Science and Technology (NAIST), Japan has recently proposed two signalling pathways that play a role in the regulation of stem cell differentiation. Their findings have been published in Nature Communications.
"The signalling pathways that induce the differentiation of stem cells into a particular gastric cell type are yet to be confirmed. To address this gap, we employed Quartz-Seq2--the most precise single-cell RNA sequencing technology developed by RIKEN--along with in vitro gastric assays using cells isolated from gastric glands, and in vivo experiments using mouse models," says Takada, lead author of the study.
The team's combinatorial approach allowed them to profile the gene expression dynamics of stem cell differentiation into pit, neck, and parietal cell lineages, and identify the signalling pathways that regulated pit cell differentiation.
Using pseudo-time-dependent gene analysis (which provides information on gene expression as the cells pass through various stages during differentiation) along with the in vitro and in vivo assays, the team identified that the transforming growth factor alpha-epidermal growth factor receptor-extracellular signal-regulated kinase (TGFa-EGFR-ERK) signalling pathway was responsible for stem cells' differentiation into mucus-secreting pit cells.
The team also noted that fewer pit cells were produced when EGFR was pharmacologically inhibited, suggesting that this pathway is needed for gastric stem cell differentiation toward pit cells in mice.
Further, the team also identified the tumour necrosis factor ligand superfamily member 12-nuclear factor kappa light chain enhancer of activated B cell (TNFSF12-NF-kB) signalling pathway and noted that it helped maintain gastric epithelial cells in an undifferentiated state.
Setting some context to their findings, "We knew that EGFR signalling is intricately involved in gastric cancers and several EGF receptors are overexpressed in various cancers. However, it was a pleasant surprise to find through our single-cell analysis that EGFR signalling has a differentiation-promoting role rather than a mitogenic role in healthy gastric homeostasis," explains Kurisaki, senior author of the study.
This study is the first step towards understanding the mechanisms which are involved in maintaining cellular homeostasis in a healthy stomach.
So, where does the group go from here? They are buoyed by the prospects moving forward. "We've shown that TGFa-EGFR-ERK and TNFSF12-NF-kB form a fine-tuned regulatory framework for healthy stomach epithelial homeostasis. This has laid the foundation to investigate the mechanisms of other gastrointestinal diseases," concludes Takada. (ANI)
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