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

Abstract

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.

Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation

“…The fundamental cellular and molecular mechanisms underlying the loss of salivary gland function are not clearly understood (4). Evidence derived largely from animal models supports the notion that radiation-induced salivary hypofunction is a multifactorial process initiated by DNA damage to various tissue components within the gland, including the parenchymal acinar cells, endothelium, stem/progenitor cells and also parasympathetic innervation (10)(11)(12)(13)(14)(15)(16). Apoptosis, occurring within the first few days following irradiation, has also been proposed as a fundamental mechanism underlying loss of both acinar cells and glandular innervation (15,17,18).…”

Therapeutic mechanisms of granulocyte-colony stimulating factor in methotrexate-induced parotid lesion in adult rats and possible role of telocytes: A histological study

“…Another explanation of such vacuolations might be mitochondrial swelling [37] identified in both acini and ducts. Further clarification could come from altered secretory materials detailed in another study [32] where there were electron-lucent granules and significantly decreased PAS density in acinar and ductal cells.…”

“…Stem cells could support the injured tissues via anti-inflammatory, immunosuppressive, anti-apoptotic and antioxidant effects in addition to consumption of pro-apoptotic and inflammatory molecules [61] . They could also reinforce tissue stem cells to proliferate and replace the damaged cells [37] . These BMHSCs reparative effects might occur through paracrine secretion of trophic factors as cytokines, chemokines and growth factors [59] .…”

Rescue Effects and Underlying Mechanisms of IntraglandShhGene Delivery on Irradiation-Induced Hyposalivation

“…8,17,29 However, after IR KGF treatment did not significantly rescue IR-induced hyposalivation, whereas mobilizing bone marrow-derived cells including endothelial progenitors ameliorated vascular damage and facilitated functional restoration of salivary glands. 30,31 Hh signaling promotes homeostatic angiogenesis during tissue repair and/or regeneration via multiple pathways. In the adult heart and skeletal muscle, ischemic episodes lead to an upregulation of Shh expression by perivascular and fibroblast-like stromal cells, and paracrine effects of Shh on stromal fibroblasts induce the secretion of proangiogenic factors VEGFs and Angiopoietin-1/2 in a Gli-dependent transcriptional manner, which in turn act on endothelial cells to promote angiogenesis.…”