targeting lysophosphatidic acid signaling retards culture-associated senescence of human marrow stromal cells针对lysophosphatidic酸信号阻碍culture-associated人类骨髓基质细胞的衰老.pdf

Targeting Lysophosphatidic Acid Signaling Retards Culture-Associated Senescence of Human Marrow Stromal Cells 1 2 2 1 1 Masahiko Kanehira , Toshiaki Kikuchi *, Shinya Ohkouchi , Taizou Shibahara , Naoki Tode , Arif 1 1 2 2 1,2 Santoso , Hisayoshi Daito , Hiromitsu Ohta , Tsutomu Tamada , Toshihiro Nukiwa 1 Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan, 2 Department of Respiratory Medicine, Tohoku University Hospital, Sendai, Japan Abstract 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 p16Ink4a, Rb, p53, and p21Cip1, which have been associated with cellular senescence, were all reduced i