Application of regenerative medicine to salivary gland hypofunction

Abstract

Dry mouth results from hypofunction of the salivary glands due to Sjögren's syndrome (SS), various medications, and radiation therapy for head and neck cancer. In severe cases of salivary gland hypofunction, sialagogues are not always effective due to the loss of salivary parenchyma. Therefore, regenerative medicine using stem cell therapy is a promising treatment for severe cases. Stem cells are classified into three groups: tissue stem cells, embryonic stem cells, and induced pluripotent stem cells. Tissue stem cells, such as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and salivary stem/progenitor cells, could rescue irradiation-induced salivary gland hypofunction. Both HSCs and MSCs can rescue salivary gland hypofunction through soluble factors in a paracrine manner, while salivary stem/progenitor cells can reconstitute the damaged salivary glands. In fact, we clarified that CD133-positive cells in mouse submandibular glands showed stem cell features, which reconstituted the damaged salivary glands. Furthermore, we focused on the challenge of producing functional salivary glands that are three-dimensionally induced from mouse ES cells.

Keywords: Cell therapy; Organoid; Regenerative medicine; Salivary gland hypofunction; Stem cells.

Fig. 1

Lip biopsy specimen of minor salivary glands in SS patient. Lymphocyte infiltration surrounds intralobular ducts and diffusely spreads to whole salivary glands. Scale bar: 100 μm.

Fig. 2

Salisphere formation in vitro. Salivary galnd cells were cultured in DMEM/F12 medium containing 20 ng/ml of EGF, 20 ng/ml of FGF2, N2, 10 mg/ml of insulin for 14 days. Salisphere was formed. Scale bar: 50 μm.

Fig. 3

Submandibular gland development. The development of one of the major salivary glands, the submandibular gland (SMG), in mice begins with epithelial thickening of oral mucosa at E11.5, and then, the epithelial invaginates into the underlying mesenchyme. The epithelium branching starts at E13.5. The ducts develop lumen at E15.5 and the canalicular stage from about E15.5. Terminal buds are formed at E17.5.

Fig. 4

Generation of the salivary gland organoid in 3D ESC cultures. Bright-field view of the aggregate showing the epithelial branching structure that resembled to salivary gland primordium (arrow head). Scale bar: 300 μm.