Induced pluripotent stem cells, or iPS cells, are a hot commodity right now in biology. The cells, which are created when non-stem cells are reprogrammed to resemble embryonic stem cells, have many potential uses in therapy and drug development. They’re usually created by using a virus to add just four genes (identified because they are highly expressed in embryonic stem cells) to the cell to be reprogrammed.
However, the molecular minutiae of the transformation are not well understood, and the expression of one of the genes, called c-Myc, is frequently elevated in human cancers. This has given researchers and clinicians pause when considering the use of iPS cells in humans.
Now researchers in the laboratory of Helen Blau, PhD, Stanford’s Donald E. and Delia B. Baxter Professor, have found that fusing a mouse embryonic stem cell with a human skin cell, or fibroblast, to create two-nuclei, bi-species mongrel called a heterokaryon is an excellent way to study the earliest steps of reprogramming. That’s because factors in the developmentally flexible stem cell nucleus reprogram the more-staid skin cell nucleus — quickly and efficiently — giving researchers a ring-side seat to the intricate transformation.
In contrast, only about one in every one thousand would-be iPS cells ever complete their transformation to pluripotency: a pretty boring, uninformative show if you pick the wrong cell to follow. As Blau explained in an e-mail:
Studying these heterokaryons gives us a molecular snapshot of pluripotency that would otherwise have been missed and allows us to capture reprogramming in action. For the first time we’re able to identify critically important transient regulators that would be totally missed by current methods of study.
Blau is the senior author of the research, which was published Sunday in Nature Cell Biology (subscription required). Postdoctoral scholar Jennifer Brady, PhD, is the lead author.
As Blau predicted, the study of the heterokaryons paid off. The researchers found that a signaling molecule called IL-6 is highly expressed in the human fibroblast nucleus during the first few hours of reprogramming in the fused cells. They were then able to show that temporary exposure to IL-6 during the creation of iPS cells can replace c-Myc.
The hope is that the findings will lead to iPS cells that will be safer to use in human therapies. But there’s still much to be learned from the heterokaryon model, said Blau:
This method provides insights into the logic and timing of the reprogramming process that would not be possible by any other means. Really understanding this process is vital to getting better and more efficient reprogramming to make iPS cells.
Previously: Nobel Prize-netting iPS-cell discovery was initially a tough sell (for me, anyway), Making induced pluripotent stem cells a loopy process, say Stanford/VA researchers and Nature summarizes iPS challenges