Spatiotemporal Transcriptomic Dissection Uncovers Age-Dependent Deceleration of Esophageal Cell Differentiation

Area of Science:

• Gastroenterology
• Stem Cell Biology
• Aging Research

Background:

• Tissue homeostasis relies on precise stem and progenitor cell regulation, which declines with age.
• Age-related changes in esophageal epithelial cell lineages are not well understood.
• Understanding these dynamics is crucial for addressing age-related esophageal dysfunction.

Purpose of the Study:

• To investigate the age-related dynamics of human esophageal epithelial cell lineages.
• To identify how stem cell populations and signaling pathways change with aging.
• To determine the primary drivers of age-related decline in esophageal homeostasis.

Main Methods:

• Single-cell transcriptomics analysis of human esophageal epithelia across different age groups.
• Identification and characterization of quiescent (qeSCs) and proliferative (peSCs) esophageal stem cells.
• Analysis of cell lineage trajectories, cell plasticity, cell-cell interactions, and signaling pathway activity (WNT, NOTCH, Interleukin-1).

Main Results:

• Two stem cell populations, qeSCs and peSCs, were identified.
• Younger tissues showed higher WNT10A expression in qeSCs and stronger peSC connectivity to differentiated cells, indicating efficient turnover.
• NOTCH signaling was more active in stem cells in younger tissues, shifting to differentiated cells in older tissues. Interleukin-1 pathway activity decreased with age.

Conclusions:

• Age-related decline in esophageal homeostasis is mainly due to impaired differentiation dynamics.
• Stem cell self-renewal capacity appears less affected by aging than differentiation processes.
• These findings provide insights into age-associated esophageal changes and potential therapeutic targets.