The integrated developmental stress response (ISR-DASR) shift reveals a functional transition from cellular to stem cell organismal adaptation.

Stress responses are essential for cellular survival and organismal, developmental progression. In somatic cells and embryonic stem cells (ESC), there exists the sequential transcriptional programs of the integrated stress response (ISR) and senescence-associated secretory phenotype (SASP), which enable stepwise adaptation to adverse conditions. We recently identified a distinct developmentally associated stress response (DASR) in mouse ESC that hypothetically emerges only after successful completion of cellular adaptation (ISR), reflecting a shift toward organismal-level adaptation. In explanation, a cellular response is a cell autonomous cell survival response, and it enables a stem cell response leading to organismal development and survival. Here, we test whether placental trophoblast stem cells (TSC), also undergo this ISR-DASR transition. Using transcriptomic profiling of mouse TSC exposed to strong, hyperosmotic stress (at 400mM sorbitol), we find that early responses (0.5-2 h) are dominated by biosynthetic and metabolic gene functions characteristic of cellular adaptation, whereas later responses (6-24 h) are enriched for developmental and differentiation pathways, consistent with DASR activation. These findings suggest that the ISR-DASR transition is a general feature of the response of stressed, developmental stem cells. They also highlight potential biomarkers for improving in vitro fertilization, understanding miscarriage, and advancing regenerative medicine.