Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury

Abstract

Regenerative processes in brain pathologies require the production of distinct neural cell populations from endogenous progenitor cells. We have previously demonstrated that oligodendrocyte progenitor cell (OPC) proliferation is crucial for oligodendrocyte (OL) regeneration in a mouse model of neonatal hypoxia (HX) that reproduces diffuse white matter injury (DWMI) of premature infants. Here we identify the histone deacetylase Sirt1 as a Cdk2 regulator in OPC proliferation and response to HX. HX enhances Sirt1 and Sirt1/Cdk2 complex formation through HIF1α activation. Sirt1 deacetylates retinoblastoma (Rb) in the Rb/E2F1 complex, leading to dissociation of E2F1 and enhanced OPC proliferation. Sirt1 knockdown in culture and its targeted ablation in vivo suppresses basal and HX-induced OPC proliferation. Inhibition of Sirt1 also promotes OPC differentiation after HX. Our results indicate that Sirt1 is an essential regulator of OPC proliferation and OL regeneration after neonatal brain injury. Therefore, enhancing Sirt1 activity may promote OL recovery after DWMI.

Non-Canonical Targets of HIF1a Drive Cell-Type-Specific Dysfunction

“…HIF1a was enriched at canonical target genes Vegfa and Bnip3 and globally peaks were enriched for HIF motifs and motifs of transcription factors that have been shown to interact with HIF1a including Sp1, c-Myc, and Bmal1 (Huang, 2008; Kaluz et al, 2003; Wu et al, 2017) (Figures S2A and S2B). HIF1a was not found proximal to Sirt1, Wnt7a , or Wnt7b (Figures S2C-S2E), which have previously been suggested as putative HIF effectors in OPCs (Jablonska et al, 2016; Yuen et al, 2014). Moreover, neither sgVhl OPCs nor wild type OPCs exposed to hypoxia exhibited increased expression of Sirt1, Wnt7a , or Wnt7b transcripts, suggesting that other targets are likely functioning to block oligodendrocyte formation (Figures S2F-S2I) (Zhang et al, 2020).…”

“…White matter of the CNS is formed by oligodendrocytes, which wrap neuronal axons in a lipid-rich protective sheath called myelin, allowing for rapid transmission of action potentials and maintenance of axonal integrity (Chang et al, 2016; Emery, 2010; Nave, 2010). Oligodendrocytes arise from oligodendrocyte progenitor cells (OPCs), which are prevalent in the developing and adult CNS, and HIF1a accumulation has been shown to be sufficient to impair oligodendrocyte formation from OPCs (Jablonska et al, 2016; van Tilborg et al, 2018; Yuen et al, 2014). However, the mechanism of the HIF1a-mediated block in oligodendrocyte formation from OPCs remains unclear.…”

Rapid modulation of the silent information regulator 1 by melatonin after hypoxia‐ischemia in the neonatal rat brain

“…We hypothesize that the differential expression of SIRT1 in neurons and glial cells found after melatonin treatment in the damaged brain may contribute to save neurons but may also direct the differentiation of NPCs toward a neuronal phenotype. In contrast to this hypothesis, however, it has been recently reported that in a model of white matter damage induced by hypoxia in the neonatal rat brain, SIRT1 activation regulated glial cell proliferation and promoted oligodendrocytes recovery . Further studies are therefore required to better define the role of SIRT1 and the effects of its modulators, including melatonin, in the regulation of the differentiation of NPCs after brain injury.…”

“…Deacetylation of p53 by SIRT1 provides a quick acting mechanism to stop its function once transcriptional activation of target genes is no longer needed and it inhibits apoptosis . A role of SIRT1 in differentiation of neuronal progenitor cells (NPCs) and promotion of oligodendrocyte progenitor cell proliferation has also been reported . By influencing chromatin structure, gene transcription, metabolism, inflammation, apoptosis, and NPCs differentiation, SIRT1 may play a key role in neurodegeneration and neuroprotection and may also modulate the scar formation associated with the neurodegenerative process …”

Melatonin Acts in Synergy with Hypothermia to Reduce Oxygen-Glucose Deprivation-Induced Cell Death in Rat Hippocampus Organotypic Slice Cultures

“…Additional indirect antioxidant effects of melatonin include the upregulation of antioxidant enzymes and crucially the preservation of mitochondrial integrity [12,31]. In addition, new emerging evidence suggests that, via SIRT1 modulation, melatonin could activate molecular pathways determining the fate of neuronal progenitor cells in response to injury [32,33].…”