Selective Ablation of Human Embryonic Stem Cells Expressing a “Suicide” Gene

Over the past few years, technological procedures have been developed for utilizing stem cells in transplantation medicine. Human embryonic stem (ES) cells can produce an unlimited number of differentiated cells and are, therefore, considered a potential source of cellular material for use in transp...

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Veröffentlicht in:Stem cells (Dayton, Ohio) Ohio), 2003-01, Vol.21 (3), p.257-265
Hauptverfasser: Schuldiner, Maya, Itskovitz‐Eldor, Joseph, Benvenisty, Nissim
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creator Schuldiner, Maya
Itskovitz‐Eldor, Joseph
Benvenisty, Nissim
description Over the past few years, technological procedures have been developed for utilizing stem cells in transplantation medicine. Human embryonic stem (ES) cells can produce an unlimited number of differentiated cells and are, therefore, considered a potential source of cellular material for use in transplantation medicine. However, serious clinical problems can arise when uncontrolled cell proliferation occurs following transplantation. To avoid these potential problems, we genetically engineered human ES cell lines to express the herpes simplex virus thymidine kinase (HSV‐tk) gene. Expression of the HSV‐tk protein renders the ES cells sensitive to the U.S. Food and Drug Administration‐approved drug ganciclovir, inducing destruction of HSV‐tk+ cells at ganciclovir concentrations that are nonlethal to other cell types. The reversion rate of engineered cells was low even under prolonged selection with ganciclovir. The HSV‐tk+ clones retained a normal karyotype and the ability to differentiate to cells from all three germ layers. Most importantly, tumors that arose in mice following subcutaneous injection of HSV‐tk+ human ES cells could be ablated in vivo by administration of ganciclovir. By utilizing these cell lines, safety levels can be improved in transplantations involving tissues derived from human ES cells.
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Human embryonic stem (ES) cells can produce an unlimited number of differentiated cells and are, therefore, considered a potential source of cellular material for use in transplantation medicine. However, serious clinical problems can arise when uncontrolled cell proliferation occurs following transplantation. To avoid these potential problems, we genetically engineered human ES cell lines to express the herpes simplex virus thymidine kinase (HSV‐tk) gene. Expression of the HSV‐tk protein renders the ES cells sensitive to the U.S. Food and Drug Administration‐approved drug ganciclovir, inducing destruction of HSV‐tk+ cells at ganciclovir concentrations that are nonlethal to other cell types. The reversion rate of engineered cells was low even under prolonged selection with ganciclovir. The HSV‐tk+ clones retained a normal karyotype and the ability to differentiate to cells from all three germ layers. Most importantly, tumors that arose in mice following subcutaneous injection of HSV‐tk+ human ES cells could be ablated in vivo by administration of ganciclovir. 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source MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection
subjects Animals
Antiviral Agents - pharmacology
Cell Culture Techniques - methods
Cell Death - drug effects
Cell Death - genetics
Cell Differentiation - genetics
Cell Division - drug effects
Cell Division - genetics
Cell Transformation, Neoplastic - genetics
Cells, Cultured
Clone Cells - cytology
Clone Cells - drug effects
Clone Cells - metabolism
Disease Models, Animal
Drug Resistance - genetics
Ganciclovir
Ganciclovir - pharmacology
Genes, Transgenic, Suicide - genetics
Genetic Engineering - methods
Genetic manipulation
Genetic Markers - drug effects
Genetic Markers - genetics
Humans
Karyotyping
Mice
Mice, SCID
Neoplasms - genetics
Neoplasms - prevention & control
Pluripotent Stem Cells - cytology
Pluripotent Stem Cells - metabolism
Stem Cell Transplantation - adverse effects
Stem Cell Transplantation - methods
Thymidine kinase
Thymidine Kinase - genetics
Transplantation
Tumors
Viral Proteins - genetics
title Selective Ablation of Human Embryonic Stem Cells Expressing a “Suicide” Gene
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