Epithelial Cell Lineage and Signaling in Murine Salivary Glands

Abstract

Maintaining salivary gland function is critical for oral health. Loss of saliva is a common side effect of therapeutic irradiation for head and neck cancer or autoimmune diseases such as Sjögren’s syndrome. There is no curative treatment, and current strategies proposed for functional regeneration include gene therapy to reengineer surviving salivary gland tissue, cell-based transplant therapy, use of bioengineered glands, and development of drugs/biologics to stimulate in vivo regeneration or increase secretion. Understanding the genetic and cellular mechanisms required for development and homeostasis of adult glands is essential to the success of these proposed treatments. Recent advances in genetic lineage tracing provide insight into epithelial lineage relationships during murine salivary gland development. During early fetal gland development, epithelial cells expressing keratin 14 (K14) Sox2, Sox9, Sox10, and Trp63 give rise to all adult epithelium, but as development proceeds, lineage restriction occurs, resulting in separate lineages of myoepithelial, ductal, and acinar cells in postnatal glands. Several niche signals have been identified that regulate epithelial development and lineage restriction. Fibroblast growth factor signaling is essential for gland development, and other important factors that influence epithelial patterning and maturation include the Wnt, Hedgehog, retinoic acid, and Hippo signaling pathways. In addition, other cell types in the local microenvironment, such as endothelial and neuronal cells, can influence epithelial development. Emerging evidence also suggests that specific epithelial cells will respond to different types of salivary gland damage, depending on the cause and severity of damage and the resulting damaged microenvironment. Understanding how regeneration occurs and which cell types are affected, as well as which signaling factors drive cell lineage decisions, provides specific targets to manipulate cell fate and improve regeneration. Taken together, these recent advances in understanding cell lineages and the signaling factors that drive cell fate changes provide a guide to develop novel regenerative treatments.

Development of a functional salivary gland tissue chip with potential for high-content drug screening

“…In addition, several supportive cell and tissue types are disrupted during dissociation and may be required to enhance longitudinal SGm function. These tissues include vasculature, nerves, and mesenchyme, which are intrinsic to salivary gland development, homeostasis, and regeneration 13 – 15 , 112 . For example, primary embryonic mesenchyme supported salivary organoid formation with robust AQP5 expression in co-culture with E16 salivary epithelium 113 , 114 .…”

Generation of a Single-Cell RNAseq Atlas of Murine Salivary Gland Development

“…Krt5 + cells have also been reported to generate acinar cells upon severe injury ( Weng, et al., 2018 ), and lineage tracing studies have shown that Krt5+ BD cells act as progenitors for GCTs and SD cells ( Aure, et al., 2019 ). Little is understood about the factors driving BD cell differentiation and maturation, as well as those involved in their plasticity to regenerate acinar cells.…”

Transcriptomic and Single-Cell Analysis of the Murine Parotid Gland

“…This, we suspect, is largely due to the relative ease with which SMGs can be dissected, unlike PGs, which are considerably smaller in mice and tucked away in a rather inaccessible site. However, given the importance of the PG in normal development and the disease context, it is imperative that any studies on the SG also take into account unique and common molecular attributes of all glandular subtypes, especially the PG (Aure et al 2019). Here we have extended our prior genomic studies on the SG and focused on the PG, with a goal to better identify the genes that are expressed during various stages of gland maturation and, importantly, enriched in the PG.…”