Rapamycin mitigates Valproic Acid-induced teratogenicity in human and animal models by suppressing AP-1-mediated senescence
Pietrogrande, G.; Shaker, M.; Stednitz, S.; Soheilmoghaddam, F.; Aguado, J.; Morrison, S.; Zambrano, S.; Tabassum, T.; Javed, I.; Cooper-White, J. J.; Davis, T.; Scott, E.; O'Brien, T.; Wolvetang, E. J.
Show abstract
Valproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear. Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube. We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs at the expense of neural lineages. We next show that the clinically-approved drug, Rapamycin, inhibits AP1-mediated senescence and restores aberrant NCC differentiation trajectory in human organoids exposed to VPA. Notably, in vivo validation in developing zebrafish highlighted the therapeutic promise of this approach. Collectively our data identifies a novel mechanism for VPA-associated neurodevelopmental teratogenicity and a potential pharmacological preventative strategy. The results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery and safety testing.
Matching journals
The top 10 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Prosaposin maintains adult neural stem cells in a state associated with deep quiescence 96%
- Canonical Wnt pathway controls mESCs self-renewal through inhibition of spontaneous differentiation via β-catenin/TCF/LEF functions 96%
- Single cell transcriptomics reveals correct developmental dynamics and high-quality midbrain cell types by improved hESC differentiation. 94%
Similar papers in this journal
- Impaired p53-mediated DNA damage response contributes to microcephaly in Nijmegen Breakage Syndrome patient-derived cerebral organoids 97%
- Cockayne syndrome patient iPSC-derived brain organoids and neurospheres show early transcriptional dysregulation of biological processes associated with brain development and metabolism. 94%
- A shared pathogenic mechanism for valproic acid and SHROOM3 knockout in a brain organoid model of neural tube defects 94%
Similar papers in this journal
Similar papers in this journal
- The efficient induction of human retinal ganglion-like cells provides a platform for studying optic neuropathies 95%
- The rates of adult neurogenesis and oligodendrogenesis are linked to cell cycle regulation through p27-dependent gene repression of SOX2 94%
- A sub-set of guanine- and cytosine-rich genes are actively transcribed at the nuclear Lamin B1 region 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.