An engineered Sox17 induces somatic to neural stem cell fate transitions independently from pluripotency reprogramming

Advanced strategies to interconvert cell types provide promising avenues to model cellular pathologies and to develop therapies for neurological disorders. Yet, methods to directly transdifferentiate somatic cells into multipotent induced neural stem cells (iNSCs) are slow and inefficient, and it is unclear whether cells pass through a pluripotent state with full epigenetic reset. We report iNSC reprogramming from embryonic and aged mouse fibroblasts as well as from human blood using an engineered Sox17 (eSox17(FNV)). eSox17(FNV) efficiently drives iNSC reprogramming while Sox2 or Sox17 fail. eSox17(FNV) acquires the capacity to bind different protein partners on regulatory DNA to scan the genome more efficiently and has a more potent transactivation domain than Sox2. Lineage tracing and time-resolved transcriptomics show that emerging iNSCs do not transit through a pluripotent state. Our work distinguishes lineage from pluripotency reprogramming with the potential to generate more authentic cell models for aging-associated neurodegenerative diseases.

Automated summary

Advanced strategies to convert cell types provide potential avenues for modeling cellular pathologies and developing therapies for neurological disorders. However, direct transdifferentiation of somatic cells into multipotent induced neural stem cells (iNSCs) is slow and inefficient, and it is unclear if cells go through a pluripotent state with full epigenetic reset. Our study reports the successful reprogramming of iNSCs from embryonic and aged mouse fibroblasts, as well as human blood, using an engineered version of Sox17 (eSox17(FNV)). This method efficiently drives iNSC reprogramming and shows promise in generating more authentic cell models for aging-associated neurodegenerative diseases.