Department of Developmental, Molecular and Chemical Biology, School of Medicine, Tufts University, Boston, MA 02111, USA; Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
Department of Developmental, Molecular and Chemical Biology, School of Medicine, Tufts University, Boston, MA 02111, USA; Program in Neuroscience, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
Cell Stem Cell. 2017 Dec 7;21(6):761-774.e5. doi: 10.1016/j.stem.2017.09.008. Epub 2017 Nov 22.
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.
成体嗅上皮中的神经发生在稳态和修复过程中通常被描绘为一个单向途径。我们通过显示上皮损伤释放了 Ascl1+祖细胞和 Neurog1+指定的神经元前体分化为多能干细胞/祖细胞的潜力，从而挑战了这个模型的单向性，这些细胞对小鼠嗅上皮（OE）的组织再生有重要贡献。我们使用几种谱系追踪株和单细胞 mRNA-seq 来表征这些去分化细胞，并表明 Sox2 对于启动去分化是必需的，而抑制 Ezh2 可促进多能祖细胞的扩增。这些结果表明，神经元分化的明显层次并不是不可逆转的，并且谱系决定可以在严重的组织损伤后被超越。我们通过高度再生的神经上皮阐明了一个以前未被认识的内源性组织修复途径，并引入了一个研究 OE 中可塑性的机制的系统，该系统可以适应其他组织。
