ABSTRACT
BACKGROUND & AIM: Irradiation of the salivary glands during head and neck cancer treatment induces cellular senescence in response to DNA damage and contributes to radiation-induced hyposalivation by affecting the salivary gland stem/progenitor cell (SGSC) niche. Cellular senescence, such as that induced by radiation, is a state of cell-cycle arrest, accompanied by an altered pro-inflammatory secretome known as the senescence-associated secretory phenotype (SASP) with potential detrimental effects on the surrounding microenvironment. We hypothesized that the pro-regenerative properties of mesenchymal stem cells (MSCs) may attenuate cellular senescence post-irradiation. Therefore, here we evaluated the effects of adipose-derived MSCs (ADSCs) on the radiation-induced response of salivary gland organoids (SGOs). METHODS: Proteomic analyses to identify soluble mediators released by ADSCs co-cultured with SGOS revealed secretion of hepatocyte growth factor (HGF) in ADSCs, suggesting a possible role in the stem cell crosstalk. Next, the effect of recombinant HGF in the culture media of ex vivo grown salivary gland cells was tested in 2D monolayers and 3D organoid models. RESULTS: Treatment with HGF robustly increased salivary gland cell proliferation. Importantly, HGF supplementation post-irradiation enhanced proliferation at lower doses of radiation (0, 3, 7 Gy), but not at higher doses (10, 14 Gy) where most cells stained positive for senescence-associated beta-galactosidase. Furthermore, HGF had no effect on the senescence-associated secretory phenotype (SASP) of irradiated SGOs, suggesting there may be compensatory proliferation by cell-division competent cells instead of a reversal of cellular senescence after irradiation. CONCLUSION: ADSCs may positively influence radiation recovery through HGF secretion and can promote the ex vivo expansion of salivary gland stem/progenitor cells to enhance the effects of co-transplanted SGSC.
Subject(s)
Hepatocyte Growth Factor , Mesenchymal Stem Cells , Humans , Hepatocyte Growth Factor/pharmacology , Proteomics , Salivary Glands , Cellular Senescence/radiation effects , Cell ProliferationABSTRACT
Two congenital anterior horn cell diseases may be responsible for neonatal muscular atrophy. The acute Werdnig-Hoffmann disease (SMA-I) has a progressive course, the anterior horn cell degeneration (AHCD) is non progressive in the postnatal period. In case of Werdnig-Hoffmann disease symptoms of hypotonia and muscle weakness may be present at birth, but become progressive during the first months of live. The full clinical picture of AHCD is present at birth. In the latter clinical symptoms of fetal hypokinesia may be noticed during intrauterine life. Histopathological muscle investigation reveals a more or less characteristic neurogenic pattern in Werdnig-Hoffmann disease, in AHCD neurogenic and myopathic changes are variable. Two examples of these diseases will be discussed.