2012年
Targeting lysophosphatidic acid signaling retards culture-associated senescence of human marrow stromal cells.
PloS one
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- 巻
- 7
- 号
- 2
- 開始ページ
- e32185
- 終了ページ
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1371/journal.pone.0032185
- 出版者・発行元
- PUBLIC LIBRARY SCIENCE
Marrow stromal cells (MSCs) isolated from mesenchymal tissues can propagate in vitro to some extent and differentiate into various tissue lineages to be used for cell-based therapies. Cellular senescence, which occurs readily in continual MSC culture, leads to loss of these characteristic properties, representing one of the major limitations to achieving the potential of MSCs. In this study, we investigated the effect of lysophosphatidic acid (LPA), a ubiquitous metabolite in membrane phospholipid synthesis, on the senescence program of human MSCs. We show that MSCs preferentially express the LPA receptor subtype 1, and an abrogation of the receptor engagement with the antagonistic compound Ki16425 attenuates senescence induction in continually propagated human MSCs. This anti-aging effect of Ki16425 results in extended rounds of cellular proliferation, increased clonogenic potential, and retained plasticity for osteogenic and adipogenic differentiation. Expressions of p16(Ink4a), Rb, p53, and p21(Cip1), which have been associated with cellular senescence, were all reduced in human MSCs by the pharmacological inhibition of LPA signaling. Disruption of this signaling pathway was accompanied by morphological changes such as cell thinning and elongation as well as actin filament deformation through decreased phosphorylation of focal adhesion kinase. Prevention of LPA receptor engagement also promoted ubiquitination-mediated c-Myc elimination in MSCs, and consequently the entry into a quiescent state, G(0) phase, of the cell cycle. Collectively, these results highlight the potential of pharmacological intervention against LPA signaling for blunting senescence-associated loss of function characteristic of human MSCs.
- リンク情報
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- DOI
- https://doi.org/10.1371/journal.pone.0032185
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/22359668
- PubMed Central
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281120
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000302796200137&DestApp=WOS_CPL
- ID情報
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- DOI : 10.1371/journal.pone.0032185
- ISSN : 1932-6203
- PubMed ID : 22359668
- PubMed Central 記事ID : PMC3281120
- Web of Science ID : WOS:000302796200137