Hyaluronan substratum induces multidrug resistance in human mesenchymal stem cells via CD44 signaling.
Little information is available concerning multidrug resistance (MDR) in mesenchymal stem cells, although several studies have reported that MDR is associated with hyaluronan in neoplastic cells. We have evaluated whether a hyaluronan-coated surface modulates MDR in placenta-derived human mesenchymal stem cells (PDMSCs). We have found that PDMSCs cultured on a tissue-culture polystyrene surface coated with 30 microg/cm(2) hyaluronan are more resistant than control PDMSCs to doxorubicin. Inhibiting PI3K/Akt signaling has shown that the PI3K/Akt pathway modulates both P-glycoprotein activity and doxorubicin resistance. In addition, 10 microM verapamil dramatically suppresses the doxorubicin resistance induced by the hyaluronan-coated surface, indicating that P-glycoprotein activity is necessary for MDR. We have further found that PDMSCs treated with CD44 small interfering RNA (siRNA) and grown on a polystyrene surface coated with 30 microg/cm(2) hyaluronan have fewer P-glycoprotein(+) cells and lower CD44 expression levels (less than 60% in both cases) than PDMSCs not treated with CD44 siRNA and grown on the hyaluronan-coated surface. Moreover, treatment with CD44 siRNA suppresses the hyaluronan-substratum-induced doxorubicin resistance. We conclude that a hyaluronan substratum induces MDR in PDMSCs through CD44 signaling.
Liu
Chi-Mou
CM
Institute of Biotechnology, National Cheng Kung University, 1 University Road, Tainan, 70101, Taiwan.
Chang
Chiung-Hsin
CH
Yu
Chen-Hsiang
CH
Hsu
Chao-Chin
CC
Huang
Lynn L H
LL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010920:Placenta / Q000166:cytology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering; D004317:Doxorubicin; D006820:Hyaluronic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt