2. Academic Validation
  3. An engineered Sox17 induces somatic to neural stem cell fate transitions independently from pluripotency reprogramming

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

  • Sci Adv. 2023 Aug 25;9(34):eadh2501. doi: 10.1126/sciadv.adh2501.
Mingxi Weng 1 2,  Haoqing Hu 1,  Matthew S Graus 3 4,  Daisylyn Senna Tan 1,  Ya Gao 1,  Shimiao Ren 1,  Derek Hoi Hang Ho 1 2,  Jakob Langer 1,  Markus Holzner 1,  Yuhua Huang 1,  Guang Sheng Ling 1,  Cora Sau Wan Lai 1 5,  Mathias Francois 3 4 6,  Ralf Jauch 1 2
Affiliations

Affiliations

  • 1 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 2 Center for Translational Stem Cell Biology, Hong Kong SAR, China.
  • 3 The David Richmond Laboratory for Cardiovascular Development: Gene Regulation and Editing Program, The Centenary Institute, Camperdown, NSW 2006, Australia.
  • 4 Genome Imaging Centre, The Centenary Institute, Camperdown, NSW 2006, Australia.
  • 5 State Key Laboratory of Cognitive and Brain Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 6 The University of Sydney, School of Medical Sciences, Camperdown, NSW 2006, Australia.
PMID: 37611093 DOI: 10.1126/sciadv.adh2501
Abstract

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 (eSox17FNV). eSox17FNV efficiently drives iNSC reprogramming while Sox2 or Sox17 fail. eSox17FNV 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.

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