title: Mesenchymal stem cells cultured under hypoxia escape from senescence via down-regulation of p16 and extracellular signal regulated kinase.
abstract: Hypoxia has been considered to affect the properties of tissue stem cells including mesenchymal stem cells (MSCs). Effects of long periods of exposure to hypoxia on human MSCs, however, have not been clearly demonstrated. MSCs cultured under normoxic conditions (20% pO(2)) ceased to proliferate after 15-25 population doublings, while MSCs cultured under hypoxic conditions (1% pO(2)) retained the ability to proliferate with an additional 8-20 population doublings. Most of the MSCs cultured under normoxic conditions were in a senescent state after 100days, while few senescent cells were found in the hypoxic culture, which was associated with a down-regulation of p16 gene expression. MSCs cultured for 100days under hypoxic conditions were superior to those cultured under normoxic conditions in the ability to differentiate into the chondro- and adipogenic, but not osteogenic, lineage. Among the molecules related to mitogen-activated protein kinase (MAPK) signaling pathways, extracellular signal regulated kinase (ERK) was significantly down-regulated by hypoxia, which helped to inhibit the up-regulation of p16 gene expression. Therefore, the hypoxic culture retained MSCs in an undifferentiated and senescence-free state through the down-regulation of p16 and ERK.
authors.affiliation: Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Japan.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Jin
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Kato
authors.forename: Moritoshi
authors.initials: M
authors.lastname: Furu
authors.forename: Akira
authors.initials: A
authors.lastname: Nasu
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kajita
authors.forename: Hiroto
authors.initials: H
authors.lastname: Mitsui
authors.forename: Michiko
authors.initials: M
authors.lastname: Ueda
authors.forename: Tomoki
authors.initials: T
authors.lastname: Aoyama
authors.forename: Tomitaka
authors.initials: T
authors.lastname: Nakayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Junya
authors.initials: J
authors.lastname: Toguchida
mesh_terms: D000693:Anaerobiosis; D018929:Cell Culture Techniques; D015687:Cell Hypoxia; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D048049:Extracellular Signal-Regulated MAP Kinases