Ionizing Radiation Alters Human Embryonic Stem Cell Properties and Differentiation Capacity by Diminishing the Expression of Activin Receptors

Abstract

Exposure of the embryo to ionizing radiation (IR) is detrimental as it can cause genotoxic stress leading to immediate and latent consequences such as functional defects, malformations, or cancer. Human embryonic stem (hES) cells can mimic the preimplantation embryo and help to assess the biological effects of IR during early development. In this study, we describe the alterations H9 hES cells exhibit after X-ray irradiation in respect to cell cycle progression, apoptosis, genomic stability, stem cell signaling, and their capacity to differentiate into definitive endoderm. Early postirradiation, hES cells responded with an arrest in G2/M phase, elevated apoptosis, and increased chromosomal aberrations. Significant downregulation of stem cell signaling markers of the TGF beta-, Wnt-, and Hedgehog pathways was observed. Most prominent were alterations in the expression of activin receptors. However, hES cells responded differently depending on the culture conditions chosen for maintenance. Enzymatically passaged cells were less sensitive to IR than mechanically passaged ones showing fewer apoptotic cells and fewer changes in the stem cell signaling 24 h after irradiation, but displayed higher levels of chromosomal aberrations. Even though many of the observed changes were transient, surviving hES cells, which were differentiated 4 days postirradiation, showed a lower efficiency to form definitive endoderm than their mock-irradiated counterparts. This was demonstrated by lower expression levels of SOX17 and microRNA miR-375. In conclusion, hES cells are a suitable tool for the IR risk assessment during early human development. However, careful choice of the culture methods and a vigorous monitoring of the stem cell quality are mandatory for the use of these cells. Exposure to IR influences the stem cell properties of hES cells even when immediate radiation effects are overcome. This warrants consideration in the risk assessment of radiation effects during the earliest stages of human development.

Carbon Ion Radiobiology

“…Taken together, transcriptomics seems to be able to help the selection of patients that will benefit from C-ion therapy, going beyond dosimetric analyses and models of normal tissue complication probabilities [ 199 ]. In addition to animal models, human organoids can also represent a useful tool to select differential panels of genes associated to exposure to X-rays and C-ions [ 200 , 201 ].…”

Radiation Response of Murine Embryonic Stem Cells

“…Their ability to differentiate in three germ layers makes them an ideal developmental model system to explore potential developmental toxicity mechanisms of (simulated) microgravity and radiation. The main advantage of using murine CGR8 embryonic stem cells (mESCs) is the avoidance of ethical concerns related to human ESCs (hESCs), which have been suggested for risk assessment of ionizing radiation exposure during early human development [ 16 ]. The effects of simulated and real microgravity on mESC differentiation [ 17 , 18 , 19 ] and on human cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) [ 20 ] at the transcriptomics level were reported earlier.…”

Integrins Were Involved in Soybean Agglutinin Induced Cell Apoptosis in IPEC-J2

“…Caspase-3 is involved in many apoptotic pathways, such as mitochondrial, death receptor pathways and endoplasmic reticulum stress pathway. Recently, Luft, et al [ 19 ] and Nagayama and Tatsuno [ 20 ] judged apoptosis as by determination of the fraction of cells positive for active caspase-3. Bcl-2 is a proto-oncogene, which can inhibit apoptosis, mainly because Bcl-2 regulates a variety of cell proliferation- and apoptosis-related protein activity [ 21 , 22 ].…”