Salivary gland development: a template for regeneration

Abstract

The mammalian salivary gland develops as a highly branched structure designed to produce and secrete saliva. This review will focus on research on mouse submandibular gland development and the translation of this basic research toward therapy for patients suffering from salivary hypofunction. Here we review the most recent literature that has enabled a better understanding of the mechanisms of salivary gland development. Additionally, we discuss approaches proposed to restore salivary function using gene and cell-based therapy. Increasing our understanding of the developmental mechanisms involved during development is critical to design effective therapies for regeneration and repair of damaged glands.

Keywords: Branching morphogenesis; Parasympathetic innervation; Progenitor cells; Regeneration; Salivary gland development; Stem cells; Submandibular gland.

Figure 1

Reciprocal interactions among the epithelium (Ecadherin staining, red), nerves (Tubb3 staining green), blood vessels (Pecam staining green) and basement membrane (Perlecan staining green) regulate branching morphogenesis during submandibular (SMG) and sublingual gland (SLG) development. The brightfield image shows and E13 SMG and SLG cultured overnight, the mesenchyme (Mes) and parasympathetic ganglia (PSG) are also visible. The fluorescent images are projections of multiple confocal sections, Scale bar 100μM.

Figure 2

Proliferation of the progenitor cells occurs in the epithelial endbuds and increases the size of the glands. Cell proliferation in BrdU (red) labeling of an E13 SMG or SMG epithelial explants grown in the presence of FGFs. The epithelia are cultured in an extracellular matrix that contains heparan sulfate, which restricts FGF10 diffusion through the matrix. FGF10 treatment results in cell proliferation only at the tips of the endbuds, whereas FGF7 diffuses through the matrix and induces proliferation throughout the explant. The fluorescent images are projections of multiple confocal sections. The epithelium in the E13 SMG is stained with Ecadherin (green) and the nuclei in all images with DAPI (blue). Scale bar; 100μM.

Figure 3

K14-lineage tracing in the post-natal day 1 SMG. By crossing K14Cre to Rosa^mTmG mice, K14+ cells and their progeny are visualized with membrane-bound GFP (mGFP, green). Cell types that are not derived from the K14-lineage express Tomato (mTm, blue). Single confocal sections (2 μm) show K14+ cells (green) are progenitors of both epithelial acinar (a) and ductal (d) compartments of the SMG. Sections were also stained with an antibody to K5 (red), which shows the K5 cells are in the K14 lineage. Staining with an antibody to K14 (red) shows the endogenous K14+ cells. Refer to reference [57] for more detailed information.