Rescue of Salivary Gland Function after Stem Cell Transplantation in Irradiated Glands

Abstract

Head and neck cancer is the fifth most common malignancy and accounts for 3% of all new cancer cases each year. Despite relatively high survival rates, the quality of life of these patients is severely compromised because of radiation-induced impairment of salivary gland function and consequential xerostomia (dry mouth syndrome). In this study, a clinically applicable method for the restoration of radiation-impaired salivary gland function using salivary gland stem cell transplantation was developed. Salivary gland cells were isolated from murine submandibular glands and cultured in vitro as salispheres, which contained cells expressing the stem cell markers Sca-1, c-Kit and Musashi-1. In vitro, the cells differentiated into salivary gland duct cells and mucin and amylase producing acinar cells. Stem cell enrichment was performed by flow cytrometric selection using c-Kit as a marker. In vitro, the cells differentiated into amylase producing acinar cells. In vivo, intra-glandular transplantation of a small number of c-Kit+ cells resulted in long-term restoration of salivary gland morphology and function. Moreover, donor-derived stem cells could be isolated from primary recipients, cultured as secondary spheres and after re-transplantation ameliorate radiation damage. Our approach is the first proof for the potential use of stem cell transplantation to functionally rescue salivary gland deficiency.

Development of Poly(Ethylene Glycol) Hydrogels for Salivary Gland Tissue Engineering Applications

“…The SMG cell population is heterogeneous and consists of terminally differentiated cells, many of which undergo apoptosis after isolation. 8,10 However, the process of apoptosis takes *3 h, 78 which is in stark contrast to the *60-80% of SMG cell death observed after only minutes of exposure to chain-addition polymerizations (Fig. 1B).…”

“…After 2-3 days of suspension culture, dissociated SMG cells form microsphere cell clusters ( > 50 mm in diameter) that include both duct and acinar cells. 8,10 The viability of microspheres encapsulated within thiol-ene polymerized PEG hydrogels was analyzed using LIVE/DEAD imaging at days 0, 4, 7, and 14 after encapsulation (Fig. 5A-F) and by measuring whole hydrogel cellular ATP levels (Fig.…”

“…[4][5][6] No salivary gland stem cell has been definitively identified as contributing to gland regeneration; however, several duct cell subtypes have been characterized as progenitor cells. [7][8][9][10][11][12] Furthermore, although the direct injection of progenitor cell populations, namely c-Kit + salivary progenitor cells 10,13 or mesenchymal stem cells (MSCs), 14 into irradiated submandibular glands (SMGs) showed some functional improvement, restoration of saliva secretion was incomplete, and highly variable. 13 To reproducibly promote regeneration and functional recovery of irradiated salivary glands, biomaterial-based approaches for cell transplantation have been explored.…”

Rescue of radiation-induced cognitive impairment through cranial transplantation of human embryonic stem cells

“…Many of these approaches have been used successfully in animal models to ameliorate degenerative conditions such as Alzheimer's (31, 32), Parkinson's (33,34), and Huntington's (35) disease, as well as other disorders such as epilepsy (36)(37)(38), excitotoxic brain damage (39), and traumatic brain injury (40). While a recent laboratory study has demonstrated the efficacy of transplanting salivary stem cells to alleviate radiation-induced xerostomia (41), with the exception of the bone marrow, the application of stem cell therapies to reduce radiation-induced normal tissue damage is still in its infancy. Ultimately, the success (or failure) of such approaches will depend on the functional engraftment of transplanted cells into the irradiated tissue bed.…”

Salivary Gland Branching Morphogenesis — Recent Progress and Future Opportunities

“…If stem cells can be isolated from salivary glands of patients, for example prior to administration of radiation therapy to treat head and neck carcinoma, it may be possible to transplant these cells back into patients to restore salivary gland function. The feasibility of this approach has already been demonstrated in a mouse model system (Lombaert et al , 2008). Ongoing investigations to identify reliable markers for salivary gland stem/progenitor cells and to use growth factors to guide cell fate decisions for effective differentiation should accelerate research in this promising area (Lombaert and Hoffman, 2010).…”