Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming

Abstract

Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-wide expression analysis confirmed that treatments promoting neuronal reprogramming elicit an anti-oxidative stress response. Importantly, co-expression of Bcl-2 and anti-oxidative treatments leads to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type in vitro and in vivo.

Injury Induces Endogenous Reprogramming and Dedifferentiation of Neuronal Progenitors to Multipotency

“…We also identified significant differences in metabolic processes, which comport with studies showing that altered metabolism is required and plays an active role in cell fate conversion (Folmes et al, 2012; Gascón et al, 2015; Ryall et al, 2015). However, testing other upstream signaling pathways via small molecule inhibition yielded mixed results.…”

Small Molecules Modulate Chromatin Accessibility to Promote NEUROG2-Mediated Fibroblast-to-Neuron Reprogramming

“…The morphological complexity of these neurons can be significantly enhanced with ISL1 and LHX3 overexpression (Liu et al., 2015). As adult fibroblast lineages exhibit highly defined epigenetic signatures that make these cells less poised for reprogramming, mechanistic studies have predominantly relied on embryonic or fetal fibroblasts (Masserdotti et al., 2015, Wapinski et al., 2013, Gascón et al., 2016). Our proposed mechanism suggests that SOX4 reduces epigenetic barriers to reprogramming to facilitate fate conversion of adult cell lineages.…”

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

“…These inhibitors are also protective in models of degenerative brain disorders, including Parkinson's, Huntington's, and Alzheimer's Diseases, as well as in other forms of neurodegeneration and traumatic and hemorrhagic brain injury (Chen et al, 2015; Do Van et al, 2016; Gascon et al, 2016; Guiney et al, 2017; Hambright et al, 2017; Li et al, 2017; Skouta et al, 2014; Zille et al, 2017). Ferroptosis in some other tissues and diseases has been examined, including liver hemochromatosis (Wang et al, 2017).…”