Parthenogenetic embryonic stem cells (pES)—those derived exclusively from oocytes—may provide a more technically efficient and less ethically challenging method for generating embryonic stem cells to use in tissue transplants. HMS researchers, led by research fellow Kitai Kim and George Daley, HMS associate professor of biological chemistry and molecular pharmacology and associate director of the Children’s Hospital Boston Stem Cell Program, reported the findings online in Science on Dec. 14. Their study yielded pES cells that were both pluripotent and capable of engrafting into immunocompetent mice.
The possibility of generating tissue for transplantation has been one of stem cell research’s greatest promises. To fulfill this need, embryonic stem cells have to meet two requirements: they must be able to differentiate into a vast array of tissue types and to elude detection by the recipient’s immune system. Cells that accomplish the latter—those whose major histocompatibility complex (MHC) genes match the host’s—could mitigate the need to suppress the host’s immune system, a routine aspect of current transplant procedures, required to prevent transplant rejection. So far, only one method can generate stem cells that meet both needs.
As its name implies, somatic cell nuclear transfer (SCNT) involves transferring the nucleus from a somatic cell into an egg from which the nucleus has been removed. Ideally, this gives rise to a blastocyst that is genetically identical to the somatic cell donor. Ethical battles aside, SCNT has proven finicky at best, with some researchers reporting success rates as low as 1 percent. According to the recent study, parthenogenically derived embryonic stem cells could surpass this dismal statistic: Kim reports a success rate of almost 70 percent generating pES cells.
Kim, Daley, and their colleagues derived pES cells from unfertilized egg cells by arresting the first or second meiotic metaphase. After recombination and inheritance of the relevant sister chromatids, 81 percent of the embryonic stem cell genome—including the MHC loci responsible for tissue matching—was genetically identical to the oocyte donor genome. In immunodeficient mice, all transplants were accepted. In immunocompetent strains, MHC-homozygous mice accepted only MHChomozygous embryonic stem cells, rejecting MHChomozygous tissue that expressed only half the mice’s MHC antigens. MHC-heterozygous mice, on the other hand, accepted both exact MHC matches and MHC-homozygous donor cells. All pES cells demonstrated levels of multilineage tissue differentiation comparable to that found in embryonic stem cells derived from fertilized embryos.
Because mammalian embryonic development requires expression of a paternal genome, pES cells lack the potential to develop into a full organism. This could alleviate at least some concerns of those opposed to human cloning and those who want to protect any cells with the potential to develop into a full organism.
At the same time, lack of a paternal imprint presents its own set of obstacles. Some paternally imprinted genes, for example, are believed to have tumor suppressor activity, and there is no telling how tissue with two copies of maternally imprinted genes would function in the long term. Another caveat is that because pES cells are derived from oocytes, only females would benefit from any potential therapy, possibly giving rise to a new set of ethical dilemmas. Furthermore, some tissue types, especially bone marrow, could be subject to hybrid resistance, a phenomenon in which the host natural killer (NK) cells of MHC-heterozygous recipients reject transplanted tissues that lack both sets of MHC antigens.
Still, the new technique comes with its own advantages. Unlike embryonic stem cells generated via SCNT, all pES cells retain the mitochondrial genome of their oocyte donor and can therefore avoid immunologic rejection from antigens encoded by the mitochondrial genome. Although the authors point out that the long-term success of tissue engrafted from pES cells remains to be seen, they suggest that a cell bank of pES cells homozygous for the major MHC haplotypes could one day serve as a source of transplantable tissues.
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