Regulatory Mechanisms Driving Salivary Gland Organogenesis

Abstract

Salivary glands develop as highly branched structures designed to produce and secrete saliva. Advances in mouse genetics, stem cell biology and regenerative medicine are having a tremendous impact on our understanding of salivary gland organogenesis. Understanding how SMG initiation, branching morphogenesis and cell differentiation occur, as well as defining the progenitor/stem cells and cell and tissue interactions that drive SMG development will help guide regenerative approaches for patients suffering from loss of salivary gland function. This review focuses on recent literature from the past 5 years investigating the regulatory mechanisms driving submandibular gland (SMG) organogenesis.

RETRACTED: Btbd7 is essential for region-specific epithelial cell dynamics and branching morphogenesis in vivo

“…This complex, highly dynamic process remodels a simple epithelial bud into a highly arborized branched organ structure that maximizes epithelial surface area for secretion or absorption. Although many studies have highlighted requirements for numerous signaling molecules and transcription factors during branching morphogenesis (Costantini and Kopan, 2010;Harunaga et al, 2011;Hauser and Hoffman, 2015;Hennighausen and Robinson, 2005;Iber and Menshykau, 2013;Kwon and Larsen, 2015;Shih et al, 2013;Varner and Nelson, 2014), it is not fully understood at the cell and tissue level how such diverse regulatory pathways orchestrate the extensive physical remodeling that shapes branched epithelial tissues. Recent advances in microscopy have established that specific dynamic cell behaviors, such as changes in cell motility, cell-cell adhesion and cell-extracellular matrix interactions, are key functional mediators of this tissue reorganization (Daley and Yamada, 2013;Friedl and Gilmour, 2009;Harunaga et al, 2011;Huebner and Ewald, 2014;Kim and Nelson, 2012;Nelson and Larsen, 2015;Varner and Nelson, 2014).…”

Generation of functional salivary gland tissue from human submandibular gland stem/progenitor cells

“…During natural submandibular gland development, after the invagination of the oral epithelium into mesenchyme at E11, the mesenchyme begins to condense and an early initial epithelial bud generates at E12. A branching structure is then formed, and terminal differentiation and functional maturation ensue [32]. Fetal development of epithelial stem/progenitor cells requires bidirectional signaling networks, including both secreted factors and physical interactions, with mesenchyme [32,33].…”

“…A branching structure is then formed, and terminal differentiation and functional maturation ensue [32]. Fetal development of epithelial stem/progenitor cells requires bidirectional signaling networks, including both secreted factors and physical interactions, with mesenchyme [32,33]. E12.5 mouse SMG mesenchyme was introduced to induce the transplanted hSMGepiS/PC-derived spheres under the renal capsules of nude mice.…”

Extracellular matrix dynamics in cell migration, invasion and tissue morphogenesis

“…A particularly complex series of cell‐matrix interactions occurs during embryonic development of multiple organs in the highly dynamic process termed branching morphogenesis . This process converts a simple single epithelial bud to highly branched structures that greatly enhance epithelial surface area to provide sufficient exchange of gases in lungs, produce copious saliva by salivary glands and excrete litres of urine by kidneys.…”

“…For example, transcriptomic approaches will be valuable, including single‐cell sequencing to characterize the diverse cells of different early embryonic organs and their capacity to secrete specific matrix proteins as they self‐organize during development into complex, functionally distinct tissues and organs. MicroRNAs have also emerged as important regulators during branching morphogenesis, but also in cancer initiation/progression; some miRNAs may be implicated in both processes. Their roles in extracellular matrix remodelling during branching morphogenesis and cancer progression are poorly understood.…”