Mesenchymal stem cell-derived HGF attenuates radiation-induced senescence in salivary glands via compensatory proliferation

A Soto-Gamez; M van Es; E Hageman; S A Serna-Salas; H Moshage; M Demaria; S Pringle; R P Coppes

doi:10.1016/j.radonc.2023.109984

Mesenchymal stem cell-derived HGF attenuates radiation-induced senescence in salivary glands via compensatory proliferation

Radiother Oncol. 2024 Jan:190:109984. doi: 10.1016/j.radonc.2023.109984. Epub 2023 Nov 4.

Authors

A Soto-Gamez¹, M van Es¹, E Hageman¹, S A Serna-Salas², H Moshage², M Demaria³, S Pringle⁴, R P Coppes⁵

Affiliations

¹ Dept. of Biomedical Sciences of Cells & Systems, University of Groningen (RUG) and University Medical Center Groningen (UMCG), Groningen, the Netherlands; Dept. of Radiation Oncology, University of Groningen (RUG) and University Medical Center Groningen (UMCG), Groningen, the Netherlands.
² Dept of Gastroenterology and Hepatology, University of Groningen (RUG) and University Medical Center Groningen (UMCG), Groningen, the Netherlands.
³ European Research Institute for the Biology of Ageing, University of Groningen (RUG) and University Medical Center Groningen (UMCG), Groningen, the Netherlands.
⁴ Dept. of Rheumatology and Clinical Immunology, University of Groningen (RUG) and University Medical Center Groningen (UMCG), Groningen, the Netherlands.
⁵ Dept. of Biomedical Sciences of Cells & Systems, University of Groningen (RUG) and University Medical Center Groningen (UMCG), Groningen, the Netherlands; Dept. of Radiation Oncology, University of Groningen (RUG) and University Medical Center Groningen (UMCG), Groningen, the Netherlands. Electronic address: r.p.coppes@umcg.nl.

PMID: 37926332
DOI: 10.1016/j.radonc.2023.109984

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.

Keywords: Hepatocyte Growth Factor; Mesenchymal Stem Cell; Organoids; Radiation-induced hyposalivation; Xerostomia.

MeSH terms

Cell Proliferation
Cellular Senescence / radiation effects
Hepatocyte Growth Factor* / pharmacology
Humans
Mesenchymal Stem Cells*
Proteomics
Salivary Glands

Substances

Hepatocyte Growth Factor
HGF protein, human