A series of articles this week show that cultures of mouse fibroblasts (cells that make connective tissue) can be reprogrammed to make every kind of body tissue. The technique starts with retroviruses that insert a group of four genes into the cells. Next, a series of clever screens identifies cells that activate their own copies of embryonic stem cell (ESC) genes. The cells, called induced pluripotent stem (iPS) cells, contributed to all cell types when injected into mouse embryos that were grown into live pups. Related research shows that these modified fibroblast genes silence copies of the inserted genes and have genetic activity closely resembling that of ESCs.

If the technique works for adult human fibroblasts (which can be collected in skin biopsies), it could pave the way to create patient-specific “embryonic” stem cells. Such cells could be invaluable for disease research and, potentially, therapies, but no one has been able to make them yet.

Nature Reports Stem Cells spoke with Kyoto University's Shinya Yamanaka, who led the team that grew mice from these cells.

Nature Reports Stem Cells: What are the implications of these advances for drug discovery and clinical applications?

Yamanaka: Human iPS cells might enable tailor-made cell transplantation therapy and drug discovery.

Nature Reports Stem Cells: How is this work an advance on the work you published last year?

Yamanaka: In the first-generation iPS cells we published last year, reprogramming was partial. In the second-generation iPS cells, we obtained nearly full reprogramming.

Nature Reports Stem Cells: How do these three articles complement each other?

Yamanaka: We examined progenies obtained from iPS cells. The other two articles performed more thorough analyses of iPS cells.

Nature Reports Stem Cells: Why is it so important that the transgenes are silenced and that the endogenous pluripotency genes are reactivated?

Yamanaka: Continuous expression of transgenes is likely to inhibit proper differentiation of iPS cells.

Nature Reports Stem Cells: It seems that much of reprogramming relies on random events and luck. Why are the reprogramming rates so low (under 1%)?

Yamanaka: One possibility is that iPS cells originate from rare tissue stem cells coexisting in fibroblast cultures. Another possibility is that the additional genes should be modified by retroviral integration for iPS cell induction. Alternatively, proper levels and timing of the four factors is essential.

Nature Reports Stem Cells: Are you looking for other combinations of genes that don't include c-Myc or another oncogene? Or do you think that the current set of four is the best that could be found?

Yamanaka: We suspect that c-Myc and Klf4 can be replaced by other factors.

Nature Reports Stem Cells: What will be the major hurdles for reprogramming human somatic cells? What have you attempted so far?

Yamanaka: There are many hurdles, including transfection efficiency, selection systems for iPS cells induction and different reactions to oncogenes. All I can say is that we have been struggling to overcome these hurdles.

Nature Reports Stem Cells: If induced pluripotent cells can be made for humans, will work on ESCs still be useful for understanding disease and finding therapies?

Yamanaka: Human ESCs will serve as an important control to examine the ability and safety of human iPS cells.