Overexpressed ATP7B protects mesenchymal stem cells from toxic copper

被引:20
作者
Sauer, Vanessa [1 ]
Siaj, Ramsi [1 ]
Todorov, Theodor [1 ]
Zibert, Andree [1 ]
Schmidt, Hartmut H. -J. [1 ]
机构
[1] Univ Klinikum Munster, D-48149 Munster, Germany
关键词
Mesenchymal stem cells (MSC); Copper; ATP7B; Regeneration; Wilson's disease; WILSON DISEASE GENE; MOUSE MODEL; IN-VITRO; LIVER; HEPATOCYTES; TRANSPLANTATION; EXPRESSION; ATPASE; LINE; VIVO;
D O I
10.1016/j.bbrc.2010.03.158
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Wilson's disease (WD) is characterized by accumulation of high levels of copper in liver due to malfunction of copper transporter ATP7B which is central for copper homeostasis. Here we report for the first time that mesenchymal stem cells (MSC) derived from bone marrow express detectable levels of ATP7B. The role of ATP7B overexpression for MSC survival and selection in high copper was investigated. Hepatoma cell line HepG2 that has a high intrinsic expression of ATP7B served as a control. Using retroviral vector a significant higher expression level of ATP7B could be achieved in MSCs. Whereas copper treatment resulted in cell death in untransduced MSCs, viability assays demonstrated a unique copper resistance of ATP7B overexpressing MSCs that outcompeted HepG2. In long-term cell culture stable transgene expression for up to 9 weeks was shown for ATP7B overexpressing MSCs which rapidly overgrew untransduced cells. Our findings suggest that ATP7B overexpression provides an important selection advantage to MSCs in high copper microenvironments, and may represent novel cell transplants for therapy of WD. (C) 2010 Elsevier Inc. All rights reserved.
引用
收藏
页码:307 / 311
页数:5
相关论文
共 28 条
  • [1] The potential of bone marrow stem cells to correct liver dysfunction in a mouse model of Wilson's disease
    Allen, KJ
    Cheah, DMY
    Lee, XL
    Pettigrew-Buck, NE
    Vadolas, J
    Mercer, JFB
    Ioannou, PA
    Williamson, R
    [J]. CELL TRANSPLANTATION, 2004, 13 (7-8) : 765 - 773
  • [2] Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers
    Aurich, Ines
    Mueller, Lutz P.
    Aurich, Hendryk
    Luetzkendorf, Jana
    Tisljar, Kai
    Dollinger, Matthias M.
    Schormann, Wiebke
    Walldorf, Jens
    Hengstler, Jan G.
    Fleig, Wolfgang E.
    Christ, Bruno
    [J]. GUT, 2007, 56 (03) : 405 - 415
  • [3] Britton RS, 1996, SEMIN LIVER DIS, V16, P3, DOI 10.1055/s-2007-1007214
  • [4] THE WILSON DISEASE GENE IS A PUTATIVE COPPER TRANSPORTING P-TYPE ATPASE SIMILAR TO THE MENKES GENE
    BULL, PC
    THOMAS, GR
    ROMMENS, JM
    FORBES, JR
    COX, DW
    [J]. NATURE GENETICS, 1993, 5 (04) : 327 - 337
  • [5] Mesenchymal stem cells as trophic mediators
    Caplan, Arnold I.
    Dennis, James E.
    [J]. JOURNAL OF CELLULAR BIOCHEMISTRY, 2006, 98 (05) : 1076 - 1084
  • [6] Chan HW, 2008, INT J CLIN EXP MED, V1, P76
  • [7] COSTA M, 1982, RES COMMUN CHEM PATH, V38, P405
  • [8] Mesenchymal stem cells reside in virtually all post-natal organs and tissues
    da Silva Meirelles, Lindolfo
    Chagastelles, Pedro Cesar
    Nardi, Nance Beyer
    [J]. JOURNAL OF CELL SCIENCE, 2006, 119 (11) : 2204 - 2213
  • [9] Retrovirus-mediated gene transfer and expression cloning: Powerful tools in functional genornics
    Kitamura, T
    Koshino, Y
    Shibata, F
    Oki, T
    Nakajima, H
    Nosaka, T
    Kumagai, H
    [J]. EXPERIMENTAL HEMATOLOGY, 2003, 31 (11) : 1007 - 1014
  • [10] Human mesenchymal stem cells maintain transgene expression during expansion and differentiation
    Lee, K
    Majumdar, MK
    Buyaner, D
    Hendricks, JK
    Pittenger, MF
    Mosca, JD
    [J]. MOLECULAR THERAPY, 2001, 3 (06) : 857 - 866