Cytokine Treatment Improves Parenchymal and Vascular Damage of Salivary Glands after Irradiation

Purpose: During radiotherapy for head and neck cancer, co-irradiation (IR) of salivary glands results in acute and often lifelong hyposalivation. Recently, we showed that bone marrow-derived cells (BMC) can partially facilitate postradiation regeneration of the mouse submandibular gland. In this study, we investigate whether optimized mobilization of BMCs can further facilitate regeneration of radiation-damaged salivary glands. Experimental Design: Salivary glands of mice reconstituted with eGFP(+) bone marrow cells were irradiated with a single dose of 15 Gy. One month later, BMCs were mobilized using granulocyte colony-stimulating factor (G-CSF) or the combination of FMS-like tyrosine kinase-3 ligand, stem cell factor, and G-CSF (termed F/S/G) as mobilizing agents. Salivary gland function and morphology were evaluated at 90 days post-IR by measuring the saliva flow rate, the number of acinar cells, and the functionality of the vasculature. Results: Compared with G-CSF alone, the combined F/S/G treatment mobilized a 10-fold higher number and different types of BMCs to the bloodstream and increased the number of eGFP(+) cells in the irradiated submandibular gland from 49% to 65%. Both treatments reduced radiation-induced hyposalivation from almost nothing in the untreated group to similar to 20% of normal amount. Surprisingly, however, F/S/G treatment resulted in significant less damage to submandibular blood vessels and induced BMC-derived neovascularization. Conclusions: Post-IR F/S/G treatment facilitates regeneration of the submandibular gland and ameliorates vascular damage. The latter is partly due to BMCs differentiating in vascular cells but is likely to also result from direct stimulation of existing blood vessel cells.