Abstract
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.
Highlights
The current evaluation methods for a drug’s safety largely rely on non-human animal-based platforms
Standard toxic compound was chosen from the list of top-ranked compounds according to common hazardous material classification of five authorities, including the International Agency for Research on Cancer (IARC), Association Advancing Occupational and Environmental Health (ACGIH), National Toxicology Program (NTP), US Environmental Protection Agency (US EPA), and European Chemicals Agency (ECHA)
A transwell migration assay demonstrated the inhibitory effect of toxic materials on the migration ability of stem cells in vitro (Fig. 1c)
Summary
The current evaluation methods for a drug’s safety largely rely on non-human animal-based platforms. Even advanced animal-based platforms do not appropriately mimic extremely complex human physiology[1]. While human tumor-derived or engineered cell-based systems have some advantages for evaluation, they have genomic abnormalities and do not reflect. Early changes in the gene-expression profile mediated by exposure to toxic materials are more likely to indicate the initiation of toxic processes than are late-stage events, providing more sensitive and accurate markers of early toxic events[6]. Toxic materials may cause serious decline in stem cell function and loss of stemness[7]. Early-response genes involved in stem cell properties, such as self-renewal and differentiation capabilities, can be used as specific markers to predict toxicity.
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