Histone deacetylase controls adult stem cell aging by balancing the expression of polycomb genes and jumonji domain containing 3

Aging is linked to loss of the self-renewal capacity of adult stem cells. Here, we observed that human multipotent stem cells (MSCs) underwent cellular senescence in vitro. Decreased expression of histone deacetylases (HDACs), followed by downregulation of polycomb group genes (PcGs), such as BMI1, EZH2 and SUZ12, and by upregulation of jumonji domain containing 3 (JMJD3), was observed in senescent MSCs. Similarly, HDAC inhibitors induced cellular senescence through downregulation of PcGs and upregulation of JMJD3. Regulation of PcGs was associated with HDAC inhibitor-induced hypophosphorylation of RB, which causes RB to bind to and decrease the transcriptional activity of E2F. JMJD3 expression regulation was dependant on histone acetylation status at its promoter regions. A histone acetyltransferase (HAT) inhibitor prevented replicative senescence of MSCs. These results suggest that HDAC activity might be important for MSC self-renewal by balancing PcGs and JMJD3 expression, which govern cellular senescence by p16INK4A regulation

Impaired functions of neural stem cells by abnormal nitric oxide-mediated signaling in an in vitro model of Niemann-Pick type C disease

Nitric oxide (NO) has been implicated in the promotion of neurodegeneration. However, little is known about the relationship between NO and the self-renewal or differentiation capacity of neural stem cells (NSCs) in neurodegenerative disease. In this study, we investigated the effect of NO on self-renewal of NSCs in an animal model for Niemann-Pick type C (NPC) disease. We found that NO production was significantly increased in NSCs from NPC1-deficient mice (NPC1- /- ), which showed reduced NSC self-renewal. The number of nestin-positive cells and the size of neurospheres were both significantly decreased. The expression of NO synthase (NOS) was increased in neurospheres derived from the brain of NPC1- /- mice in comparison to wild-type neurospheres. NO-mediated activation of glycogen synthase kinase-3 (GSK3) and caspase-3 was also observed in NSCs from NPC1- /- mice. The self-renewal ability of NSCs from NPC1- /- mice was restored by an NOS inhibitor, L-NAME, which resulted in the inhibition of GSK3 and caspase-3. In addition, the differentiation ability of NSCs was partially restored and the number of Fluoro-Jade C-positive degenerating neurons was reduced. These data suggest that overproduction of NO in NPC disease impaired the self-renewal of NSCs. Control of NO production may be key for the treatment of NPC disease.This work was supported by a grant from the Korean Science & Engineering Foundation (R01-2005-000-10190-0) and the BK21 Program for Veterinary Science

The tumor suppressor Pml regulates cell fate in the developing neocortex

The control of cell fate in neural progenitor cells is critical for nervous system development. Nevertheless, the processes involved are only partially known. We found that the expression of the tumor suppressor Pml was restricted to neural progenitor cells (NPCs) in the developing neocortex of the mouse. Notably, in Pml-/- cortices, the overall number of proliferating NPCs was increased and transition between the two major progenitor types, radial glial cells and basal progenitors, was impaired. This in turn resulted in reduced differentiation and an overall decrease in the thickness of the cortex wall. In NPCs, Pml regulated the subcellular distribution of the retinoblastoma protein (pRb) and the protein phosphatase 1, triggering pRb dephosphorylation. Together, these findings reveal an unexpected role of Pml in controlling the function of NPCs in the CNS