NGFR/Ngfr-marked basal duct progenitors drive ductal--acinar regeneration in injured salivary glands

Abstract

Severe salivary gland injury can cause chronic xerostomia and persistent secretory dysfunction, yet the epithelial populations that support repair remain poorly defined. Here, we identify NGFR/Ngfr as a conserved surface marker for isolating organoid-forming epithelial stem/progenitor cells from human and mouse salivary glands and show that mouse Ngfr-lineage cells contribute to ductal-acinar regeneration after injury. Single-cell transcriptomic analysis of human salivary gland tissue identified a restricted NGFR-expressing basal duct epithelial subpopulation with progenitor-like features and early positions along inferred epithelial differentiation trajectories. Functionally, NGFR-expressing cells showed enhanced primary and secondary organoid-forming capacity, and NGFR-enriched human organoids engrafted after transplantation into injured salivary glands of immunodeficient mice. In mouse salivary glands, isolated Ngfr-expressing cells showed enriched organoid-forming activity, and Ngfr expression localized to injury-associated ductal regions after duct ligation and local inflammatory injury. Ngfr-CreERT2 lineage tracing further showed that Ngfr-lineage cells contribute to ductal and acinar compartments during post-injury regeneration. Together, these findings establish NGFR/Ngfr as a conserved surface marker for prospectively isolating basal duct epithelial stem/progenitor populations with organoid-forming activity and injury-responsive ductal-acinar regenerative potential.