Stem Cell Rejuvenation by Restoration of Youthful Metabolic Compartmentalization

Abstract

Stem cell dysfunction is a hallmark of aging. Much recent study suggests that epigenetic changes play a critical role in the loss of stem cell function with age. However, the underlying mechanisms require elucidation. A recent report describes a process by which mild mitochondrial stress associated with aging causes lysosomal-mediated decreases in CiC, the mitochondrial citrate transporter, in bone marrow-derived mesenchymal stem cells (MSCs). This, in turn, results in a deficit of acetyl-CoA in the nucleus and hypoacetylation of histones. The altered epigenome results in skewered stem cell differentiation favoring adipogenesis and disfavoring osteogenesis, which is problematic given the role the MSCs play in maintaining the integrity of bone tissue. Restoration of nuclear acetyl-CoA by either ectopic expression of CiC or acetate supplementation of MSCs in culture rejuvenates the MSC, restoring the potential to efficiently differentiate along the osteogenic lineage. Citrate, which has recently been reported to extend lifespan in Drosophila, chemically incorporates acetyl-CoA and may prove useful to restore cytoplasmic and nuclear acetyl-CoA levels. The general applicability of the CiC defect in old cells, particularly stem cells, should be established.

Keywords: acetyl-CoA; citrate; epigenetics; mesenchymal stem cells; metabolic compartmentalization; rejuvenation.