This study investigates the effects of space flight on human neural stem cells (NSCs) and their response to Earth's gravity upon readmission. The researchers found that while most NSCs survived and self-renewed after space flight, some exhibited enhanced stress responses and autophagy-like behavior (ALB). The secretome from space-flown NSCs was shown to induce a four-fold increase in ALB in naïve NSCs, with the protein SPARC being the most abundant and responsible for endoplasmic reticulum (ER) stress. This study provides new insights into the response of neural cells to microgravity and highlights the potential of SPARC as a biomarker for microgravity-induced ALB. The findings have implications for understanding intracranial hypertension and other health anomalies observed in astronauts, suggesting potential countermeasures to mitigate these issues.This study investigates the effects of space flight on human neural stem cells (NSCs) and their response to Earth's gravity upon readmission. The researchers found that while most NSCs survived and self-renewed after space flight, some exhibited enhanced stress responses and autophagy-like behavior (ALB). The secretome from space-flown NSCs was shown to induce a four-fold increase in ALB in naïve NSCs, with the protein SPARC being the most abundant and responsible for endoplasmic reticulum (ER) stress. This study provides new insights into the response of neural cells to microgravity and highlights the potential of SPARC as a biomarker for microgravity-induced ALB. The findings have implications for understanding intracranial hypertension and other health anomalies observed in astronauts, suggesting potential countermeasures to mitigate these issues.