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Τετάρτη 22 Νοεμβρίου 2017

Injury Induces Endogenous Reprogramming and Dedifferentiation of Neuronal Progenitors to Multipotency

Publication date: Available online 22 November 2017
Source:Cell Stem Cell
Author(s): Brian Lin, Julie H. Coleman, Jesse N. Peterson, Matthew J. Zunitch, Woochan Jang, Daniel B. Herrick, James E. Schwob
Adult neurogenesis in the olfactory epithelium is often depicted as a unidirectional pathway during homeostasis and repair. We challenge the unidirectionality of this model by showing that epithelial injury unlocks the potential for Ascl1+ progenitors and Neurog1+ specified neuronal precursors to dedifferentiate into multipotent stem/progenitor cells that contribute significantly to tissue regeneration in the murine olfactory epithelium (OE). We characterize these dedifferentiating cells using several lineage-tracing strains and single-cell mRNA-seq, and we show that Sox2 is required for initiating dedifferentiation and that inhibition of Ezh2 promotes multipotent progenitor expansion. These results suggest that the apparent hierarchy of neuronal differentiation is not irreversible and that lineage commitment can be overridden following severe tissue injury. We elucidate a previously unappreciated pathway for endogenous tissue repair by a highly regenerative neuroepithelium and introduce a system to study the mechanisms underlying plasticity in the OE that can be adapted for other tissues.

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Teaser

Lin et al. demonstrate that Ascl1+ and Neurog1+ neuronal progenitors can acquire cell fate plasticity after injury using genetic lineage trace and transplantation assays. Injury-induced multipotency occurs through a developmentally reminiscent endogenous upregulation of Sox2, KLF4, and Pax6, and dedifferentiation efficiency can be enhanced by Ezh2 inhibition.


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