Chimeric mice generated from cells reprogrammed for pluripotency (induced pluripotent stem cells, or iPS cells) show significant health problems, pointing to further challenges that must be overcome before such cells can be used in the clinic, noted iPS researcher Shinya Yamanaka said on Saturday (June 14).

Speaking at the meeting of the International Society for Stem Cell Research in Philadelphia, Yamanaka presented results from his group's experiments on three types of mouse chimeras generated from mouse iPS cells so far. One type was generated from fibroblasts using a cocktail of four retrovirally delivered transcription factors, Oct-3/4, SOX2, c-Myc, and Klf4. The second type of chimera was made without the use of c-Myc, which has been implicated in causing tumors. Finally, they also generated chimeras using iPS cells derived from liver and stomach cells.

Yamanaka reported that, not surprisingly, half of the mice generated with c-Myc developed tumors, most often in the thyroid. Normally, the researchers found, the expression levels of the four factors in the chimeras were silenced, but in tumors, c-Myc expression was reactivated. In contrast, only one of the c-Myc-minus chimeras out of 136 developed tumors.

Tumerogenicity wasn't the only safety issue the group uncovered, Yamanaka said. Regardless of whether the animals were generated with or without c-Myc, the researchers found, chimeras derived from adult cells -- whether they be fibroblasts or liver and stomach cells -- suffered a sharply increased rate of mortality. "We don't know the cause of death in these mice," he said. (The findings are not yet published.)

Gene expression profiles of iPS cells generated from stomach and liver cells suggest these cells are not fully pluripotent, Yamanaka said. "This kind of partial reprogramming may be the cause of mortality."

"In order to translate this technology to the clinic, we really have to understand the cause of this higher mortality," Yamanaka said, "because adult human cells are the cells we want to use."

Last year, Yamanaka's group was the first to reprogram human fibroblasts into pluripotent stem cells -- a landmark achievement that has since been replicated by several other teams and that has set off a whirlwind of research in the stem cell field.