Thomas Skutella, Centre for Regenerative Biology and Medicine in Tübingen, Germany

With all the headlines on embryonic stem cells and reprogrammed skin cells, it's easy to forget that there are other human cell types that might be capable of becoming any cell type in the body. Now, according to a paper published this month in Nature, cells derived from the human testes are among them1.

Thomas Skutella at the Centre for Regenerative Biology and Medicine in Tübingen, Germany, and colleagues showed that spermatogonial stem cells can convert over prolonged periods in culture to become pluripotent — meaning that they appear capable of forming all cell types.

The quest for a new source of pluripotent cells began, says Skutella, when his mother, who had Parkinson's disease, sent him a letter. She was interested in medical science and was in the habit of clipping articles she thought her son would like. One day she sent him information detailing how mouse gamete-producing cells could be manipulated to produce more cell types2. “Could these cells help me in the future?” she wrote.

Restrictions on working with human embryonic stem cells were particularly acute in Germany, recalls Skutella, and this had piqued scientists' interest in finding alternate sources of pluripotent cells. His position in regenerative medicine had already allowed him to establish collaborations with clinicians. His urologist colleague, Arnulf Stenzl, who was interested in using cells for bladder reconstruction, agreed to supply human samples, and Skutella began culturing cells, hoping that procedures that had proven successful in mice3 could be tweaked to apply to humans.

“The cells are easily derived, but you have to enrich them,” says Skutella. “What's frustrating is doing the same procedure over and over again, picking clones and transferring them for hours.” Stem cell characteristics would come in and fade out, and the chief problem was enriching cultures for reprogramming cells; otherwise, these cells would redifferentiate. The key to success was not so much a single strategy, says Skutella, but rather sticking with the project — particularly the devotion of medical technologist Sabine Conrad.

Using biopsies from testes of 22 patients, the researchers generated cells that express genes characteristic of embryonic stem cells but not spermatagonial stem cells. When injected into mice without immune systems, the cells form teratomas — the bizarre benign tumours that contain cells representing all the major categories of tissue and are considered standard practice for assessing pluripotency. However, Skutella says he's still working to perfect the technique. Though the cells form teratomas and can even be differentiated into insulin-producing cells, they express pluripotency genes at lower levels than embryonic stem cells do.

Skutella says he has several strategies for generating high-quality cells, but determining the mechanism that converts the cells from one state to another could be more interesting than making the cells.

The fact that the cytoplasm within an oocyte can reprogram a differentiated nucleus was established with the cloning of Dolly the Sheep. A different technique, which was famously discovered by Shinya Yamanaka of Kyoto University, induces pluripotency through a completely different mechanism than that used to create Dolly. Yamanaka instead added extra copies of pluripotency genes to cells to activate endogenous programs.

The process used by Skutella within the testes-derived cells seems different still and may be the most mysterious. It seems to require time plus the right culture conditions. “This is not understood at all,” says Skutella. Factors within the culture or high concentrations of cells within the culture might play a role. Further studies could yield clues for producing and maintaining high-quality pluripotent stem cells from a variety of sources.