Sperm-like cells made from human embryonic stem cells
But results are only preliminary, researchers caution.
Human embryonic stem cells have been coaxed into forming sperm-like cells, researchers report today1. The cells have some of the hallmarks of sperm — they can swim, for example — but require much more characterization before they can be embraced as an experimental model for the study of inherited diseases and infertility.
Meanwhile, the use of such cells to help infertile couples to have children remains a distant prospect; in several countries, including the UK, it would actually be illegal even if they were properly characterised.
With approximately one in seven couples experiencing fertility problems, there is a strong push to develop a robust method for generating sperm and eggs for research. But researchers have struggled for years to produce reproductive cells from stem cells. The task is particularly difficult because it requires a complex form of cell division called meiosis, which reduces the number of chromosomes per cell by half.
In addition, the DNA packaged in reproductive cells is wiped clean of a chemical modification known as methylation, which involves the attachment of methyl groups to certain regions of the genome. These modifications are then added back in patterns characteristic of either sperm or egg cells.
Methylation can affect gene expression, and if either demethylation or remethylation does not occur properly the results can be disastrous. "If these genes are not correctly modified, it's like you erased a hard drive but you didn't do it very well," says Renee Reijo Pera, director of the Center for Human Embryonic Stem Cell Research and Education at Stanford University School of Medicine in Palo Alto, California. "The embryo may develop and some offspring may be born, but there could be gross abnormalities."
Possible evidence of this was observed in 2006, when Karim Nayernia, now of the University of Newcastle Upon Tyne, UK, and his colleagues reported that they had produced sperm from mouse embryonic stem cells. When the sperm were used to fertilize mouse eggs, the few pups that were born died prematurely2. Nayernia says his lab is still working to determine what went wrong, but early results suggest that DNA in the sperm was not properly remethylated.
From mice to men
Now, Nayernia and his colleagues have used a similar technique to create sperm-like cells from human embryonic stem cells1. The team labelled embryonic stem cells with a fluorescent marker attached to a particular gene that is expressed during reproductive-cell development, and cultured the cells in a medium that encourages differentiation into sperm cells.
About 3% of the resulting cells contained enough DNA for only one set of chromosomes, suggesting that meiosis had occurred. Some of these cells also formed tails and were motile.
The work is "a good start", says Reijo Pera, who was not affiliated with the study, but additional characterization of these cells will be needed before they can be taken up as an experimental model for the study of sperm. Nayernia and his colleagues have not yet analysed methylation patterns in their sperm-like cells, or conducted a detailed study of the cells' morphology.
Robin Lovell-Badge, head of the Division of Stem Cell Biology and Developmental Genetics at the National Institute for Medical Research in London, notes that Nayernia's team looked only at the total DNA content of the cells, and did not confirm that they contained the right number of chromosomes. "He needs to identify putative haploid cells and check they really have all 23 chromosomes and no more," says Lovell-Badge.
But Nayernia says the work is a "proof-of-principle experiment". "We don't claim that it is fully normal sperm, but they do have some of the right characteristics."
These issues would need to be carefully addressed before any attempt could be made to fertilize a human egg with the cells, but some preliminary tests of the sperm-like cells' ability to behave like sperm could be performed. For example, sperm should be able to bind to the membrane that surrounds unfertilized egg cells regardless of whether there is an egg inside, Reijo Pera notes.
Meanwhile, Nayernia and his colleagues have also launched a project to produce sperm cells from induced pluripotent stem cells, which can be generated from adult cells. Such cells would make it easier to derive sperm cells from many individuals. "Then we can, for example, see whether environmental factors or genetic factors are affecting fertility, and which step of sperm production has been affected by those factors," he says.
- Lee, J. H. et al. Stem Cells Dev. doi:10.1089/scd.2009.0063 (2009).
- Nayernia, K. et al. Dev. Cell 11, 125-132 (2006).