Salivary Gland Homeostasis Is Maintained through Acinar Cell Self-Duplication

Abstract

Summary Current dogma suggests that salivary gland homeostasis is stem cell-dependent. However, the extent of stem cell contribution to salivary gland maintenance has not been determined. We have investigated acinar cell replacement during homeostasis, growth and regeneration, using an inducible CreERT2 expressed under the control of the Mist1 gene locus. Genetic labeling, followed by a chase period, showed that acinar cell replacement is not driven by the differentiation of unlabeled stem cells. Analysis using R26Brainbow2.1 reporter revealed continued proliferation and clonal expansion of terminally differentiated acinar cells in all major salivary glands. Induced injury also demonstrated the regenerative potential of pre-labeled acinar cells. Our results support a revised model for salivary gland homeostasis based predominantly on self-duplication of acinar cells, rather than on differentiation of stem cells. The proliferative capacity of differentiated acinar cells may prove critical in the implementation of cell-based strategies to restore the salivary glands.

Rescue Effects and Underlying Mechanisms of IntraglandShhGene Delivery on Irradiation-Induced Hyposalivation

“…27 Similar mechanisms have been reported for the growth and maintenance of other glands in the digestive tract including liver and pancreas. [37][38][39] Our data from the lineage-tracing assay of cells expressing Bmi1, a putative marker of salivary gland stem/progenitor cells and a direct target of Hh/Gli signaling, are consistent with the acinar cell self-duplication model, and suggest that transient activation of Hh/Gli signaling rescues IR-induced hyposalivation mainly in a non-cell-autonomous manner.…”

“…These data indicated that after obstruction-induced regeneration Bmi1 + cells gave rise to regenerated ductal structures but did not significantly contribute to acinar structures, which is consistent with the finding that duplication of surviving acinar cells contributes to salivary gland regeneration. 27 Ninety days after IR and after CreER activation, the b-Gal + progeny of Bmi1 + cells were rarely found in SMGs, and transient Hh activation by Ad-Shh instillation did not significantly increase the number of b-Gal + progeny of Bmi1 + cells as indicated by both X-Gal staining and b-Gal IF (Fig. 5B).…”

Defining epithelial cell dynamics and lineage relationships in the developing lacrimal gland

“…+ + cells have been reported to populate the acini of the salivary gland by self-duplication, progenitor characteristics of these cells were not determined (Aure et al, 2015). Thus, whether these SOX10…”

Expression of a Neural Stem/Progenitor Cell Marker Nestin in Salivary Glands

“…20,21 Recently, there are reports of the main source of regenerated acinar cells after duct ligation is self-duplication of residual acinar cell, 22 and normal salivary gland homeostasis results mainly from selfduplication of acinar cells. 23 Our results suggested that the origin of acinar cells that regenerate after tissue injury may not be limited to duct cells.…”