THE ORIGINS AND PROGRESSION OF PYLORIC METAPLASIA FOLLOWING GASTRIC MUCOSAL INJURY

The human gastric mucosa contends with insults throughout the course of its normal functions. Superficial injuries are rapidly resolved by the normal cellular lineages within the glandular epithelium. Deeper injuries often cause loss of acid-secreting cells, necessitating extensively coordinated repair mechanisms that significantly alter the cellular content of the gastric glands, culminating in pyloric metaplasia. Pyloric metaplasia is defined by the hyperplastic expansion of foveolar and mucous neck cell lineages as well as spasmolytic polypeptide-expressing metaplasia (SPEM) cells transdifferentiated from zymogenic chief cells. SPEM cells resemble mucus-secreting deep antral gland cells and possess proliferative qualities meant to aid in wound healing. Chief cell transdifferentiation into SPEM cells is regulated by an orderly process in which differentiated zymogenic cells re-enter the cell cycle after downregulating mature transcriptional programs. The resolution of injury is followed by the restitution of normal cell lineages. However, metaplasia can persist when there is continuing inflammation and/or severe chronic injury. The aberrant persistence of proliferative SPEM cells can drive glandular intestinalization. The resulting intestinal metaplasia glands, particularly those with mixed gastric and intestinal lineages, are at increased risk for progression to dysplasia and ultimately gastric cancer. Understanding the dynamics of metaplastic cell lineage progression and uncovering lineage transition markers is critical to identifying targets suitable for therapeutic intervention. Here, we discuss the current knowledge, controversies and remaining questions pertaining to the establishment and progression of metaplasia in response to deep gastric mucosal injury.