Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA.
Toxicol Sci. 2017 May 1;157(1):172-182. doi: 10.1093/toxsci/kfx026.
The number of mesenchymal stem cell (MSC) therapeutic modalities has grown in recent years. Adipose-derived mesenchymal stem/stromal cells (ASCs) can be isolated and expanded relatively easily as compared with their bone-marrow counterparts, making them a particularly promising source of MSCs. And although the biological mechanisms surrounding ASCs are actively being investigated, little is known about the effects that in vivo environmental exposures might have on their ability to properly differentiate. Therefore, we hypothesized that ASCs isolated from mice exposed to inorganic arsenic (iAs) would have an altered response towards adipogenic, osteogenic, and/or chondrogenic differentiation. To test this hypothesis, C57BL/6J male mice were provided drinking water containing 0, 300, or 1000 ppb iAs. ASCs were then isolated and differentiated, which was assessed by immunocytochemistry and real-time quantitative PCR (RT-qPCR). Our results showed that total urinary arsenic equilibrated within 1 week of exposure to iAs and was maintained throughout the study. ASCs isolated from each exposure group maintained differentiation capabilities for each lineage. The magnitude of differentiation-specific gene expression, however, appeared to be concentration dependent. For osteogenesis and chondrogenesis, differentiation-specific gene expression decreased, whereas adipogenesis showed a biphasic response with an initial decrease followed by an increase in adipogenic-related gene expression following iAs exposure. These results suggest that the level in which differentiation-specific genes are induced within these stromal cells might be sensitive to environmental contaminants. These findings highlight the need to take into account potential environmental exposures prior to selecting stromal cell donors, so ASCs can achieve optimal efficiency in regenerative therapy applications.
近年来，间充质干细胞（MSC）治疗方法的数量不断增加。与骨髓来源的间充质干细胞相比，脂肪来源的间充质干细胞/基质细胞（ASCs）可以相对容易地分离和扩增，使其成为 MSC 的特别有前途的来源。尽管围绕 ASCs 的生物学机制正在积极研究，但对于体内环境暴露对其适当分化能力的影响知之甚少。因此，我们假设从暴露于无机砷（iAs）的小鼠中分离的 ASCs 对脂肪形成、成骨和/或软骨形成的分化反应会发生改变。为了验证这一假设，我们给 C57BL/6J 雄性小鼠提供含有 0、300 或 1000 ppb iAs 的饮用水。然后分离和分化 ASCs，通过免疫细胞化学和实时定量 PCR（RT-qPCR）进行评估。我们的结果表明，总尿砷在接触 iAs 后 1 周内达到平衡，并在整个研究过程中保持稳定。从每个暴露组分离的 ASCs 保持了每个谱系的分化能力。然而，分化特异性基因表达的幅度似乎与浓度有关。对于成骨和软骨形成，分化特异性基因表达减少，而脂肪形成则表现出双相反应，即 iAs 暴露后，脂肪形成相关基因的表达先减少后增加。这些结果表明，这些基质细胞中诱导分化特异性基因的水平可能对环境污染物敏感。这些发现强调了在选择基质细胞供体之前需要考虑潜在的环境暴露，以便 ASCs 在再生治疗应用中达到最佳效率。
