Hyaluronan substratum induces multidrug resistance in human mesenchymal stem cells via CD44 signaling

Abstract

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.

Receptor for hyaluronic acid-mediated motility (RHAMM, CD168) expression is prognostically important in both nodal negative and nodal positive large cell lung cancer

“…CD44 can bind to CD95 and inhibit apoptosis as well 6. Finally, hyaluronate can induce multidrug resistance (MDR) mediated through P-glycoprotein (P-gp, also known as multidrug resistance protein MDR1) via CD44 signalling 7. The receptor for hyaluronic acid-mediated motility (RHAMM, CD168) has been identified as an important antiapoptotic factor of prognostic significance in carcinomas and leukaemias 8 9.…”

Metastatic suppressor CD44 is related with oxidative stress in breast cancer cell lines

“…Hyaluronan, known as hyaluronic acid, is a determinant of cellular behavior and promotes multiple processes like anchorage-independent growth, survival, migration, cytotoxicity resistance, among others characteristics that promote metastasis (60)(61)(62). HA is able to induce CD44 expression (63) and fragment formation of HA that can induce the cleavage of CD44 (64). It was found that CD44 expression was diminished between 200-800 µM of hydrogen peroxide treatment.…”

Insulin-Signaling Pathway

“…Our first objective was to determine which would be the preferable source of placenta MSCs. Since these cells can be isolated from two different regions, the chorionic plate [23][24][25][26] or the chorionic villi [13][14][15]20], a full characterization of MSCs derived from these two regions was performed. At first, one might think that cp-MSCs and cv-MSCs are equivalent given that the chorionic villi arise from the chorionic plate during human development.…”

“…Additional file 1: Methods of isolation for mesenchymal stem cells (MSCs) from different regions of the human term placenta [13][14][15][16][17][18][19][20]22,23,25,26,[61][62][63][64][65][66].…”

“…Several reports have shown that it is possible to extract MSCs from both the chorionic villi (cv) [13][14][15][16][17][18][19][20][21][22] and chorionic plate (cp) [22][23][24][25][26][27] of the term placenta. However, it remains undetermined whether there is any difference between cv-MSCs and cp-MSCs or which placental region is a better source of extra-embryonic MSCs.…”