Injury Induces Endogenous Reprogramming and Dedifferentiation of Neuronal Progenitors to Multipotency

Abstract

Summary 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.

Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia

“…Furthermore, work in mice suggests that injury can cause de-differentiation of neuronal progenitors, which may suppress ongoing neurogenesis and potentially abrogate olfactory function. 64 ACE2 and TMPRSS2 were also expressed in microvillar and Bowman's gland cells in the OE. Our analysis mapping cells in the nasal RE and OE to cells in the lower respiratory system suggest that the nasal mucosa microvillar cells in the Durante dataset are related to previously identified pulmonary ionocytes 56 .…”

Hepatocyte growth factor plays a dual role in tendon‐derived stem cell proliferation, migration, and differentiation

“…of tendon function (Bi et al, 2007). However, similar to other stem cells (Gadye et al, 2017;Lin et al, 2017), the detailed mechanisms underlying the self-renewal and differentiation potential of TDSCs are not fully understood (Lui & Chan, 2011;Zhou et al, 2010).…”

Age-dependent dormant resident progenitors are stimulated by injury to regenerate Purkinje neurons

“…The regenerative processes previously described in neuronal tissues involve adaptive reprograming of cells that are either actively proliferating or retain proliferative capacity and also have cell fate plasticity (Benner et al, 2013; Buffo et al, 2008; Jinnou et al, 2018; Lin et al, 2017; Llorens-Bobadilla et al, 2015; Lopez-Juarez et al, 2013; Marti-Fabregas et al, 2010; Robel et al, 2011; Samanta et al, 2015; Sirko et al, 2013; Wojcinski et al, 2017). Here we identified a distinct regenerative process that involves a local, unipotent and dormant progenitor.…”