Regional Differences Following Partial Salivary Gland Resection

Abstract

Regenerative medicine aims to repair, replace, or restore function to tissues damaged by aging, disease, or injury. Partial organ resection is not only a common clinical approach in cancer therapy, it is also an experimental injury model used to examine mechanisms of regeneration and repair in organs. We performed a partial resection, or partial sialodenectomy, in the murine submandibular salivary gland (SMG) to establish a model for investigation of repair mechanisms in salivary glands (SGs). After partial sialoadenectomy we performed whole gland measurements over a period of 56 days and found that the gland reached its maximum size 14 days after injury. We used microarray analysis and immunohistochemistry to examine mRNA and protein changes in glands over time. Microarray analysis identified dynamic changes in the transcriptome three days after injury that were largely resolved by day 14. At the 3 day time point, we detected gene signatures for cell cycle regulation, inflammatory/repair response, and extracellular matrix remodeling in the partially resected glands.Using quantitative immunohistochemistry, we identified a transient proliferative response throughout the gland, in which both secretory epithelial and stromal cells expressed Ki67 that was detectable at day 3 and largely resolved by day 14. IHC also revealed that while most of the gland underwent a wound healing response that resolved by day 14, a small region of the gland showed an aberrant sustained fibrotic response characterized by increased levels of ECM deposition and sustained Ki67 levels in stromal cells. The partial submandibular salivary gland resection model provides an opportunity to examine a normal healing response and an aberrant fibrotic response within the same gland to uncover mechanisms that prevent wound healing and regeneration in mammals. Understanding regional differences in the wound healing responses may ultimately impact regenerative therapies for patients.

Regulation of Myoepithelial Differentiation in 3-Dimensional Culture

“…In many cases, irreversible damage is concentrated in the saliva-producing acinar cells and myoepithelial cells of the submandibular salivary gland (Grundmann et al, 2009; Hakim et al, 2002; Vissink et al, 2010). Thus, much current research employing murine models is aimed at understanding mechanisms to regenerate salivary gland tissue, including the replacement of acinar and myoepithelial cells following damage induced by radiation, obstruction or resection (May et al, 2018; Ninche et al, 2020; OKeefe et al, 2020; Weng et al, 2018).…”