Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.
Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea.
Cell Death Dis. 2018 Jun 20;9(7):724. doi: 10.1038/s41419-018-0748-x.
The toxicological evaluation of potential drug candidates is very important in the preclinical phase of drug development. Toxic materials may cause serious decline in stem cell function and loss of stemness. Indeed, we found that toxic exposure more profoundly suppressed the growth of stem cells than terminally differentiated fibroblasts. Importantly, toxic exposure suppressed stem cell migration and multi-lineage differentiation potential in vitro and in vivo. Moreover, early-response genes involved in stem cell properties such as self-renewal and differentiation capabilities can be used as specific markers to predict toxicity. In the present study, we also identified a labile toxic response gene, SERPINB2, which is significantly increased in response to various toxic agents in human stem cells in vitro and in vivo. Consistently, self-renewal, migration, and multi-lineage differentiation potential were markedly decreased following SERPINB2 overexpression. To the best of our knowledge, this is the first study to focus on the functions of SERPINB2 on the regenerative potential of stem cells in response to various existing chemicals, and the findings will facilitate the development of promising toxicity test platforms for newly developed chemicals.
在药物开发的临床前阶段，对潜在药物候选物的毒理学评价非常重要。有毒物质可能会导致干细胞功能严重下降和干细胞特性丧失。事实上，我们发现有毒物质暴露比终末分化的成纤维细胞更能显著抑制干细胞的生长。重要的是，有毒物质暴露抑制了体外和体内干细胞的迁移和多能分化潜能。此外，涉及干细胞特性（如自我更新和分化能力）的早期反应基因可用作特定标记物来预测毒性。在本研究中，我们还鉴定了一个不稳定的毒性反应基因 SERPINB2，其在体外和体内对各种毒性物质的人干细胞中显著增加。一致地，SERPINB2 过表达后，自我更新、迁移和多能分化潜能明显降低。据我们所知，这是第一项专注于 SERPINB2 在响应各种现有化学物质的干细胞再生潜力方面的功能的研究，研究结果将有助于为新开发的化学物质开发有前途的毒性测试平台。
