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CONCISE REVIEW |
a Centre for Stem Cell Biology and Developmental Genetics and
b Institute of Human Genetics, University of Newcastle, Central Parkway, Newcastle upon Tyne, United Kingdom;
c Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, United Kingdom
Key Words. Embryonic stem cells • Genome reprogramming • Epigenetic modification • Somatic cell nuclear transfer
Correspondence: Lyle Armstrong, Ph.D., Centre for Stem Cell Biology and Developmental Genetics, University of Newcastle, International Centre for Life, Newcastle NE1 3BZ, U.K. Telephone: 44 0191 241 8695; Fax: 44 0191 241 8666; e-mail: lyle.armstrong{at}ncl.ac.uk
Received July 29, 2005;
accepted for publication November 2, 2005.
The recent high-profile reports of the derivation of human embryonic stem cells (ESCs) from human blastocysts produced by somatic cell nuclear transfer (SCNT) have highlighted the possibility of making autologous cell lines specific to individual patients. Cell replacement therapies have much potential for the treatment of diverse conditions, and differentiation of ESCs is highly desirable as a means of producing the ranges of cell types required. However, given the range of immunophenotypes of ESC lines currently available, rejection of the differentiated cells by the host is a potentially serious problem. SCNT offers a means of circumventing this by producing ESCs of the same genotype as the donor. However, this technique is not without problems because it requires resetting of the gene expression program of a somatic cell to a state consistent with embryonic development. Some remodeling of parental DNA does occur within the fertilized oocyte, but the somatic genome presented in a radically different format to those of the gametes. Hence, it is perhaps unsurprising that many genes are expressed aberrantly within "cloned" embryos and the ESCs derived from them. Epigenetic modification of the genome through DNA methylation and covalent modification of the histones that form the nucleosome is the key to the maintenance of the differentiated state of the cell, and it is this that must be reset during SCNT. This review focuses on the mechanisms by which this is achieved and how this may account for its partial failure in the "cloning" process. We also highlight the potential dangers this may introduce into ESCs produced by this technology.
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