Writer｜Rachel Du
Layout Designer｜Cecilia Qin
Molecular Mechanism of Gastric Progenitor Cell Differentiation That Can Lead to Various Gastric Diseases
Defective gastric progenitor cell differentiation is associated with several gastric diseases such as atrophic gastritis, intestinal chemosis and gastric cancer. The gastric body is the major part of the mouse and human glandular stomach and contains functional epithelial cells that secrete mural cell acids, main cell proteases, and pit and neck cell mucus. These cells are continuously replenished by stem/progenitor cell populations in the gastric unit, thus defects in differentiation of gastric epithelial cells are associated with gastric diseases. For example, chronic H. pylori infection can lead to pseudopyloric chemosis, in which proliferating progenitor and premature cells express increased neck and principal cell markers, while the number of mural cells is reduced.
Through ultrastructural evidence, we know that in healthy gastric body tissues, highly proliferating isthmus progenitor cells in the upper middle part of the gastric unit differentiate into a variety of epithelial cell lineages, including concave, cervical, mural, and endocrine cells. In the past, the progenitor cells were thought to differentiate from the neck cells, but recent studies have shown that the progenitor cells possesses a stem cell-like self-renewal capacity for maintaining their own numbers. Currently, researchers do not have a clear understanding of the mechanism by which the close coordination between progenitor cell self-renewal and differentiation to maintain tissue integrity. To investigate this process, scientists used Quartz-Seq2, a single-cell RNA sequencing technology, to analyze the gene expression dynamics of progenitor cell differentiation into depressed cell, neck cell and wall cell lineages in healthy adult mouse somatic tissues.
The results showed that the EGFR-ERK signaling pathway plays an important role in promoting the differentiation of depressed cells, while NF-κB signaling maintains the undifferentiated state of gastric progenitor cells. Furthermore, inhibition of EGFR in vivo by pharmacology revealed a decrease in the number of recessed cells. This finding was surprising because in previous studies, EGFR signaling was considered to be one of the major predisposing factors for the development of gastric cancer. However, the researchers' findings suggest that in normal gastric homeostasis, EGFR signaling acts as a promotee of differentiation rather than cell mitosis.
Gastric gland cell differentiation and signaling studies: The researchers performed a detailed single-cell analysis of the differentiation process of gastric gland cells and explored the regulatory mechanisms involving signaling pathways.
EGFR signaling: EGFR is a receptor tyrosine kinase that is associated with overexpression of these receptors in gastric cancer by HER2 (Erbb2) and EGFR. However, this study found that in healthy gastric glands, EGFR signaling acts as a promoter of differentiation rather than cell division.
TGFα-EGFR-ERK signaling: TGFα promotes sunken cell differentiation but inhibits sunken cell proliferation via the EGFR-ERK signaling pathway in healthy gastric glands at steady state.
TNFSF12-NF-κB signaling: TNFSF12-NF-κB signaling plays a role in isthmic progenitor cell maintenance, maintaining these cells in an undifferentiated state.
Limitations of the study are that while computer analysis inferred signaling networks, the study has not validated signaling pathways involved in neck and wall cell differentiation. And, some cellular markers were not detected in their gastric-like organs. Overall, this study broadens the understanding of gastric progenitor cell differentiation in the academic community. activation of EGFR-ERK signaling plays an active role in the differentiation of gastric progenitor cells and contributes to the formation of recessed cells. This finding contributes to further understanding of the mechanisms underlying gastric diseases and provides new ideas for the development of therapeutic approaches for related diseases. However, further studies are still needed to reveal the complete mechanism of gastric progenitor cell differentiation and its relationship with the disease.
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