Abstract
Reliable data on the effects of chronic prenatal exposure to low dose (LD) of ionizing radiation in humans are missing. There are concerns about adverse long-term effects that may persist throughout postnatal life of the offspring. Due to their slow cell cycle kinetics and life-long residence time in the organism, mesenchymal stem cells (MSCs) are more susceptible to low level genotoxic stress caused by extrinsic multiple LD events. The aim of this study was to investigate the effect of chronic, prenatal LD gamma irradiation to the biology of MSCs later in life. C3H mice were exposed in utero to chronic prenatal irradiation of 10 mGy/day over a period of 3 weeks. Two years later, MSCs were isolated from the bone marrow and analyzed in vitro for their radiosensitivity, for cellular senescence and for DNA double-strand break recognition after a second acute gamma-irradiation. In addition to these cellular assays, changes in protein expression were measured using HPLC–MS/MS and dysregulated molecular signaling pathways identified using bioinformatics. We observed radiation-induced proteomic changes in MSCs from the offspring of in utero irradiated mice (leading to ~ 9.4% of all detected proteins being either up- or downregulated) as compared to non-irradiated controls. The proteomic changes map to regulation pathways involved in the extracellular matrix, the response to oxidative stress, and the Wnt signaling pathway. In addition, chronic prenatal LD irradiation lead to an increased rate of in vitro radiation-induced senescence later in life and to an increased number of residual DNA double-strand breaks after 4 Gy irradiation, indicating a remarkable interaction of in vivo radiation in combination with a second acute dose of in vitro radiation. This study provides the first insight into a molecular mechanism of persistent MSC damage response by ionizing radiation exposure during prenatal time and will help to predict therapeutic safety and efficacy with respect to a clinical application of stem cells.
Highlights
Mesenchymal stem cells (MSCs) are adult stem cells in vertebrates which serve as a source for the regeneration of various tissue types throughout the lifetime of an1 3 Vol.:(0123456789)Radiation and Environmental Biophysics (2021) 60:397–410 organism
Unsupervised clustering of dysregulated proteins in one dimension and sample ID in the second dimension shows a consistent separation between MSCs from control mice and from mice which received an in utero low dose (LD) gamma irradiation (Fig. S1)
We have shown that chronic low dose exposures to IR in the uterus, comparable to those received by repeated CT scans, had an effect on the proteome of murine mesenchymal stem cells two years later
Summary
Mesenchymal stem cells (MSCs) are adult stem cells in vertebrates which serve as a source for the regeneration of various tissue types throughout the lifetime of an1 3 Vol.:(0123456789)Radiation and Environmental Biophysics (2021) 60:397–410 organism. Functional impairment of MSCs associated with cellular ageing and senescence has been linked with degenerative diseases, but MSCs are prone to malignant transformation (Ganguly et al 2017), with the potential consequence of sarcoma development (Lin et al 2009; Shimizu et al 2010). Due to their slow cell cycle kinetics and their long residence time in the organism (Nombela-Arrieta et al 2011), MSCs can be affected by a chronic LDR or multiple protracted radiation exposures to a higher degree than cells with a rapid turnover. When DNA damage becomes too extensive due to reduced repair capacity, the cells accumulate irreversible damage, causing either senescence or apoptosis (Alessio et al 2015; Watters 1999), or they may suffer from mutations and undergo malignant transformation (Rando 2006)
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