MHC-matched parthenogenetic embryonic stem cells created

Researchers have created major histocompatible complex (MHC)-matched parthenogenetic embryonic stem (pES) cells in mice that successfully engraft in an immunocompetent system, according to a report in Science.

The work is a "tremendous advance," Kent Vrana at Pennsylvania State University told The Scientist. Vrana, who was not involved in the study, explained that the successful transplantation of pES cells had previously only been accomplished in immunodeficient animals.

This is the first report to assess the MHC regions of pES cells, study author George Daley at the Children's Hospital Boston and Harvard Stem Cell Institute told The Scientist. Daley and his team selected for cells that contained heterozygous MHC genes to match the egg donor. MHC mismatch is a major reason for graft rejection, particularly in bone marrow transplant.

The team, led by Kitai Kim at the Children's Hospital Boston and Harvard Medical School, developed embryonic stem cells from an unfertilized embryo through parthenogenesis. The researchers inhibited mouse oocytes at the first and second meiotic divisions and found that after recombination, up to 81% of the genome was perfectly matched to the egg donor. That number is "a very promising surprise," Jose Cibelli at Michigan State University, who was not part of the study, told The Scientist.

To test compatibility, the researchers cultured and transplanted the MHC-matched pES cells into their respective female mice donors for up to three months. The protein analyses of tissues provided what Cibelli considers to be "proof of the principle that pES cells can be suitable transplant material." Teratoma tumor formation, which indicates an acceptance of the transplant, appeared in 100% of the immunocompetent mice.

The finding adds to the appeal of using parthenogenetic cells, which has been demonstrated to be a more efficient method of creating ES cells. Kim told The Scientist that his success rate of generating ES cells is almost 70% through parthenogenesis but less than 1% through somatic cell nuclear transfer (SCNT).

Parthenogenesis also presents "less severe ethical problems," said Azim Surani at the University of Cambridge, who was not part of the research team. He explained that "parthenogenetic embryos cannot develop into full organisms because you need both parental genomes for normal development. That takes away one key objection that people have."

Study of parthenogenetic embryonic stem cells has not been a popular approach because most people believe SCNT is the more rationale method since it uses the exact nuclei from the donor, but the new finding highlights the promise of using parthenogenesis, Cibelli said. Vrana agreed, adding that "we should be exploring the utility of all tools until we find the right one."

Surani said the next step would be to examine how the MHC-matched pES cells compare with ES cells from fertilized eggs. He and his colleagues previously reported that pES cells are "quite good" at differentiating into neurons but not into muscle tissues. How these findings would map onto MHC-matched pES cells is not yet clear.

To address the concern that pES cells do not contain paternal imprinted genes, some of which suppress tumors, Cibelli said researchers now need to "look at studies of imprinted genes and pay attention to the ones that are correlated with tumor formation and see how they are expressed."

Cathy Tran
ctran@the-scientist.com

Links within this article:

K. Kim et al., "Histocompatible Embryonic Stem Cells by Parthenogenesis," Science Express, Nov. 14, 2006
http://www.sciencemag.org/cgi/content/abstract/1133542

Kent Vrana
http://fred.psu.edu/ds/retrieve/fred/investigator/kev10

K. Vrana et al., "Nonhuman primate parthenogenetic stem cells," Proc Natl Acad Sci, 100: 11911-11916, 2003
PM_ID: 11823632

George Daley
http://daley.med.harvard.edu/

A. Harding, "Harvard has human cloning plans," The Scientist, Oct. 15, 2004
http://www.the-scientist.com/article/display/22452/

P. Hoglund et al., Host MHC class I gene control of NK-cell specificity in the mouse, Immunol Rev, 155:11-28, 1997
PM_ID: 9059879

Kitai Kim
http://daley.med.harvard.edu/lab_people.htm

B. Maher, "The Stem Cell-Cloning Plot Thickens," The Scientist, Feb. 18, 2002
http://www.the-scientist.com/article/display/12870/

Jose Cibelli
http://www.canr.msu.edu/dept/ans/community/people/cibelli_jose.html

A. McCook, "Stem cells: Ethics before science" (Blog), The Scientist, March 28, 2006
http://www.the-scientist.com/blog/display/23251/

Azim Surani
http://www.gurdon.cam.ac.uk/phd/groups/surani.html