Project description:Iron deficiency is a common nutritional deficit that can lead to organ damage or dysfunction. Research is increasingly linking iron deficiency to dysfunction of bone metabolism, although the exact mechanisms remain unclear. Some studies suggest that iron-dependent methylation-erasing enzyme activity regulates cell proliferation and differentiation under physiological or pathological conditions. Whether iron deficiency inhibits the activation of quiescent mesenchymal stem cells (MSCs) by affecting histone demethylase activity is unclear. In our study, we discovered that KDM4D plays a pivotal role in the activation of quiescent MSCs. Under conditions of iron deficiency, the H3K9me3 demethylase activity of KDM4D significantly decreased. This change led to increased heterochromatin with H3K9me3 near the PIK3R3 promoter, hindering the expression of PIK3R3. Subsequently, the activation of quiescent MSCs was inhibited via the PI3K-Akt-Foxo1 pathway. Iron-deficient mice exhibited significantly inhibited bone marrow MSC activation and reduced bone mass compared to normal mice. Modulating the PI3K-Akt-Foxo1 pathway could reverse iron deficiency-induced bone loss.
Project description:Iron deficiency is a common nutritional deficit that can lead to organ damage or dysfunction. Research is increasingly linking iron deficiency to dysfunction of bone metabolism, although the exact mechanisms remain unclear. Some studies suggest that iron-dependent methylation-erasing enzyme activity regulates cell proliferation and differentiation under physiological or pathological conditions. Whether iron deficiency inhibits the activation of quiescent mesenchymal stem cells (MSCs) by affecting histone demethylase activity is unclear. In our study, we discovered that KDM4D plays a pivotal role in the activation of quiescent MSCs. Under conditions of iron deficiency, the H3K9me3 demethylase activity of KDM4D significantly decreased. This change led to increased heterochromatin with H3K9me3 near the PIK3R3 promoter, hindering the expression of PIK3R3. Subsequently, the activation of quiescent MSCs was inhibited via the PI3K-Akt-Foxo1 pathway. Iron-deficient mice exhibited significantly inhibited bone marrow MSC activation and reduced bone mass compared to normal mice. Modulating the PI3K-Akt-Foxo1 pathway could reverse iron deficiency-induced bone loss.
Project description:Adult hippocampal neurogenesis is important for certain forms of cognition and failing neurogenesis has been implicated in neuropsychiatric diseases. The neurogenic capacity of hippocampal neural stem/progenitor cells (NSPCs) depends on a balance between quiescent and proliferative states. However, how this balance is regulated remains poorly understood. Here we show that the rate of fatty acid oxidation (FAO) defines quiescence vs. proliferation in NSPCs. Quiescent NSPCs show high levels of carnitine palmitoyltransferase 1a (Cpt1a)-dependent FAO, which is downregulated in proliferating NSPCs. Pharmacological inhibition and conditional deletion of Cpt1a in vitro and in vivo leads to altered NSPC behavior, showing that Cpt1a-dependent FAO is required for stem cell maintenance and proper neurogenesis. Strikingly, experimental manipulation of malonyl-CoA, the metabolite that regulates levels of FAO, is sufficient to induce exit from quiescence and to enhance NSPC proliferation. Thus, the data presented here identify a shift in FAO metabolism that governs NSPC behavior and suggest an instructive role for fatty acid metabolism in regulating NSPC activity.
