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Comparative Study
. 2015 Mar;56(2):269-77.
doi: 10.1093/jrr/rru098. Epub 2014 Nov 24.

Radiation response of mesenchymal stem cells derived from bone marrow and human pluripotent stem cells

Mohammad S Islam  1 , Melissa E Stemig  1 , Yutaka Takahashi  2 , Susanta K Hui  3
Affiliations
Comparative Study

Radiation response of mesenchymal stem cells derived from bone marrow and human pluripotent stem cells

Mohammad S Islam et al. J Radiat Res. 2015 Mar.

Abstract

Mesenchymal stem cells (MSCs) isolated from human pluripotent stem cells are comparable with bone marrow-derived MSCs in their function and immunophenotype. The purpose of this exploratory study was comparative evaluation of the radiation responses of mesenchymal stem cells derived from bone marrow- (BMMSCs) and from human embryonic stem cells (hESMSCs). BMMSCs and hESMSCs were irradiated at 0 Gy (control) to 16 Gy using a linear accelerator commonly used for cancer treatment. Cells were harvested immediately after irradiation, and at 1 and 5 days after irradiation. Cell cycle analysis, colony forming ability (CFU-F), differentiation ability, and expression of osteogenic-specific runt-related transcription factor 2 (RUNX2), adipogenic peroxisome proliferator-activated receptor gamma (PPARγ), oxidative stress-specific dismutase-1 (SOD1) and Glutathione peroxidase (GPX1) were analyzed. Irradiation arrested cell cycle progression in BMMSCs and hESMSCs. Colony formation ability of irradiated MSCs decreased in a dose-dependent manner. Irradiated hESMSCs showed higher adipogenic differentiation compared with BMMSCs, together with an increase in the adipogenic PPARγ expression. PPARγ expression was upregulated as early as 4 h after irradiation, along with the expression of SOD1. More than 70% downregulation was found in Wnt3A, Wnt4, Wnt 7A, Wnt10A and Wnt11 in BMMSCs, but not in hESMSCs. hESMSCs are highly proliferative but radiosensitive compared with BMMSCs. Increased PPARγ expression relative to RUNX2 and downregulation of Wnt ligands in irradiated MSCs suggest Wnt mediated the fate determination of irradiated MSCs.

Keywords: adipogenesis; human pluripotent stem cell; mesenchymal stem cell; osteogenesis; radiation effect.

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Figures

Fig. 1.
Fig. 1.
Cell cycle distributions in (a) BMMSCs (n = 6–7), and (b) hESMSCs (n = 4–5) 1 day after irradiation or without irradiation. (c) The difference in cell cycle distribution between BMMSCs and hESMSCs. The majority of BMMSCs were in G1 phase, whereas the majority of hESMSCs were in G2/M phase. Percentage of cells in those phases increased in a dose-dependent manner. Statistically significant differences were observed between BMMSCs and hESMSCs. Bars represent mean and standard error: *P < 0.05; **P < 0.01.
Fig. 2.
Fig. 2.
Colony-forming ability of MSCs after irradiation. (a) Microscopic pictures of cells after Giemsa staining. (b) Quantitative data of colony-forming ability (n = 4–6). Colonies formed by MSCs was counted at 14 days after radiation. An aggregate of at least 30 cells was considered a colony. The number of colonies decreased in a dose-dependent manner. hESMSCs formed significantly higher numbers of colonies compared with BMMSCs at 0 Gy. Bars represent mean and standard error: *P < 0.05 vs 0 Gy; **P < 0.01 vs 0 Gy, #P < 0.01 vs hESMSCs.
Fig. 3.
Fig. 3.
Effect of irradiation on osteogenic and adipogenic differentiation in MSCs. (a) Osteogenic differentiation in BMMSCs and hESMSCs with von Kossa staining. (b) Adipogenic differentiation in BMMSCs and hESMSCs with Oil Red O staining. Osteogenic differentiation was reduced by irradiation in both MSCs. Adipogenic differentiation was increased in hESMSCs, while BMMSCs showed no change.
Fig. 4.
Fig. 4.
Effect of irradiation on the gene expression levels of (a) PPARγ/RUNX2 ratio (n = 4–6), (b) SOD1 (n = 2–4), and (c) GPX1 (n = 3) in BMMSCs and hESMSCs 1 day or 5 days after irradiation. The ratio of PPARγ to RUNX2 expression temporarily increased in hESMSCs 1 day after irradiation. SOD1 expression was higher in the irradiated MSCs one day after radiation compared with non-irradiated MSCs. hESMSCs had higher expression of SOD1 for all doses at this time-point compared with BMMSCs. GPX1 expression did not increase much compared with 0 Gy in BMMSCs, but temporal increase was observed in hESMSCs. Each bar represents mean and standard error. No statistically significant differences were found between doses and days after irradiation.
Fig. 5.
Fig. 5.
Gene expression changes in the Wnt pathway in BMMSCs and hESMSCs after irradiation of 2 Gy. (a) A heatmap of fold up- or downregulation in irradiated BMMSCs compared with the non-irradiated cells, (b) A similar heatmap for hESMSCs. (c) Genes in the plate. (d) Genes downregulated more than 70%. SOX 17 was the only gene downregulated in both BMMSCs and hESMSCs.
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