Overexpressed ATP7B protects mesenchymal stem cells from toxic copper.
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 9weeks 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.
Sauer
Vanessa
V
Klinische und Experimentelle Transplantationshepatologie, Universitätsklinikum Münster, Domagkstr 3a, 48149 Münster, Germany.
Siaj
Ramsi
R
Todorov
Theodor
T
Zibert
Andree
A
Schmidt
Hartmut H-J
HH
D000251:Adenosine Triphosphatases / Q000096:biosynthesis* / Q000235:genetics; D027682:Cation Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D002470:Cell Survival; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism / Q000633:toxicity*; D000073840:Copper-Transporting ATPases; D004351:Drug Resistance; D006527:Hepatolenticular Degeneration / Q000378:metabolism / Q000628:therapy; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D014161:Transduction, Genetic
D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases