Because it is very difficult to reverse salivary gland dysfunction due to radiation or Sjögren’s syndrome, several strategies have been proposed to mediate its effects. These include gene therapy, tissue engineering, and cell therapy, all of which are considered excellent models for regenerating complex tissues structures and restoring function. From a gene therapy approach, Baum et al. developed a novel way to use aquaporin-1 cDNA as a treatment strategy in current patients with radiation-induced salivary dysfunction [35, 36]. He devised a recombinant adenoviral vector to mediate the gene transfer and administered it to patients through a phase I/ II clinical trial. From a tissue-engineering standpoint, a three-dimensional (3D) culture system using hyaluronic acid (HA) hydrogels was created to artificially simulate the salivary gland. The seeded cells produced lobular-like acini that stained positive for alpha-amylase [37, 38]. Furthermore, poly-lactic-co-glycolic acid (PLGA) has been utilized as a scaffold to promote the self-organization of cells into a 3D construct [39–41]. Ogawa et al. has demonstrated the successful replacement of salivary gland function through the transplantation of a bioengineered salivary gland germ [42]. These innovative strategies demonstrate the potential of inducing salivary gland regeneration through tissue engineering techniques. The utilization of stem cell therapy, however, appears to hold the greatest promise. Stem cell therapy has already demonstrated successful gain of function in irradiated salivary glands. Stem cells, characterized by their ability to yield substantial cellular proliferation and the differentiation into various cell types, can be harvested from tissue-specific sources or non-tissue-specific sources. The latter represents a more useful way to collect the number of cells required to demonstrate an efficacious result. Lombaert et al. has shown that bone marrow-derived stem cells (BMSCs) ameliorate acinar cell loss and vascular damage [43]. Sumita et al. demonstrated that BMSCs, once transplanted into the mouse-tail vein, also led to the regain of function in irradiated salivary glands [44, 45]. Our research group reported previously that adipose tissue-derived stem cells (ADSCs) can ameliorate radiation-induced salivary dysfunction [46]. ADSCs represent an additional source of stem cells given the feasibility in collecting large amounts of these cells through the use of minimally invasive procedures compared to the harvesting of BMCs [47]. Use of ADSCs in our study led to an improvement in salivary flow rate compared to the sham group (Fig. 14.5). Furthermore, the proliferation of blood vessels (Figs. 14.6 and 14.7), paracrine effects (Fig. 14.8), and the differentiation of ADSCs into blood endothelial cells and ductal cells were observed (Fig. 14.9). Use of ADSCs appears to result in angiogenesis, improved production of mucin and amylase, decrease in number of atrophied acinar cells, reduction in fibrotic scarring, and improved blood flow. More recently, Lim et al. demonstrated the differentiation of infused ADSCs into salivary gland cells, highlighting the remarkable capability that stem cell research holds in treating radiation-induced salivary dysfunction [47].

The use of undifferentiated stem cells from the salivary gland itself has been shown to repair the function of salivary glands damaged by radiation [9, 48–52]. Radiation diminishes the capability of these stem cells to differentiate into the required cell lines, suggesting that the main reason for irreversible hyposalivation is inadequate production of acini cell precursors. Although tissue cultures are required to expand the number of undifferentiated stem cells sufficient to restore salivary function, they showcase a remarkable capability in regeneration with the provision that the required quantity of cells can be harvested. Thus, it is our hope that this innovative method constitutes the basis of treatment for patients presenting with xerostomia in the future.

Irreversible salivary gland hypofunction occurs from therapeutic radiation exposure to the head and neck area or Sjögren’s syndrome, both of which will lead to irreversible changes in salivary gland acinar cells.