Abstract
ObjectivesCell-based therapy has been reported to repair or restore damaged salivary gland (SG) tissue after irradiation. This study was aimed at determining whether systemic administration of human adipose-derived mesenchymal stem cells (hAdMSCs) can ameliorate radiation-induced SG damage.MethodshAdMSCs (1×106) were administered through a tail vein of C3H mice immediately after local irradiation, and then this infusion was repeated once a week for 3 consecutive weeks. At 12 weeks after irradiation, functional evaluations were conducted by measuring salivary flow rates (SFRs) and salivation lag times, and histopathologic and immunofluorescence histochemistry studies were performed to assay microstructural changes, apoptosis, and proliferation indices. The engraftment and in vivo differentiation of infused hAdMSCs were also investigated, and the transdifferentiation of hAdMSCs into amylase-producing SG epithelial cells (SGCs) was observed in vitro using a co-culture system.ResultsThe systemic administration of hAdMSCs exhibited improved SFRs at 12 weeks after irradiation. hAdMSC-transplanted SGs showed fewer damaged and atrophied acinar cells and higher mucin and amylase production levels than untreated irradiated SGs. Immunofluorescence TUNEL assays revealed fewer apoptotic cells in the hAdMSC group than in the untreated group. Infused hAdMSCs were detected in transplanted SGs at 4 weeks after irradiation and some cells were found to have differentiated into SGCs. In vitro, a low number of co-cultured hAdMSCs (13%–18%) were observed to transdifferentiate into SGCs.ConclusionThe findings of this study indicate that hAdMSCs have the potential to protect against irradiation-induced cell loss and to transdifferentiate into SGCs, and suggest that hAdMSC administration should be viewed as a candidate therapy for the treatment of radiation-induced SG damage.
Highlights
Salivary hypofunction with its subjective symptom of dry mouth is the most significant long-term complication of radiotherapy for the treatment of head and neck cancers
Characteristics of human adipose-derived mesenchymal stem cells (hAdMSCs) The mesenchymal stem cells used in this study were highly purified with the CD73- and CD90-positive, and CD31, CD34and CD-45-negative immunophenotype
Some human Alu-positive cells expressed a-amylase, the acinar cell marker. These results suggest that systemically administered hAdMSCs are able to transdifferentiate into SG epithelial cells (SGCs)
Summary
Salivary hypofunction with its subjective symptom of dry mouth (xerostomia) is the most significant long-term complication of radiotherapy for the treatment of head and neck cancers. A systematic review by Jensen et al revealed that the prevalence of xerostomia ranges from 74 to 85% after all radiation therapies for head and neck cancer, and that salivary secretion and xerostomia showed incomplete improvements, even after parotid-sparing intensity-modulated radiation therapy. No satisfactory therapy has been devised to treat salivary hypofunction, and current treatment strategies are confined to the minimization of SG radiation damage by parotid-sparing radiation delivery or conservative care based on the use of salivary substitutes and sialogogues. Adipose tissues contain higher densities of MSCs than bone marrow. [13] For these reasons, AdMSC based treatments for a variety of diseases have been investigated for use in the tissue engineering and regenerative medicine fields
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