Title:
Neural stem/precursor cell senescence -related to the aging process and diseases.

Toru Kondo
Professor
Department of Stem Cell Biology, Ehime University Proteo-Medicine Research Center

Abstract:
Mammalian aging is thought to be partially caused by the diminished capacity of stem/precursor cells to undergo self-renewing divisions. Although many cell-cycle regulators are involved in this process, it is unknown to what extent cell senescence, first identified as irreversible growth arrest in vitro, contributes to the aging process. Using a serum-induced mouse oligodendrocyte precursor cell (mOPC) senescence model, we identified several uncharacterized genes involved in cell senescence. One of them is the esophageal cancer related gene 4 ( Ecrg4 ) : Ecrg4 was upregulated in the senescent OPCs, that its overexpression in OPCs induced senescence by accelerating the proteasome-dependent degradation of cyclins D1 and D3, and that its knockdown by a specific short hairpin RNA (shRNA) prevented these phenotypes. We also demonstrate that senescent OPCs secreted Ecrg4 and that recombinant Ecrg4 induced OPC senescence in culture. Moreover, increased Ecrg4 expression was observed in the OPCs and neural precursor cells (NPCs) in the aged mouse brain, accompanied by the expression of senescence-associated b -galactosidase activity, indicating the cells’ entrance into senescence. These results suggest that Ecrg4 is a novel factor linking neural-cell senescence and aging. Since we recently found that Ecrg4 is also up-regulated in CNS diseases, I would like to discuss about how stem cell senescence contributes to the aging process and diseases.