Cells Reprogrammed Using Only One Gene

Monya Baker

Taking neural stem cells to pluripotency with Oct4 alone

Cells that behave like embryonic stem cells can be made from cultured skin, liver and stomach cells. All techniques used so far require the addition of at least two pluripotency genes, which makes the cells much less attractive for use in cell therapy and drug screening. Now, researchers led by Hans Schöler of the Max Planck Institute for Molecular Biomedicine in Münster, Germany, show that cells can be reprogrammed to pluripotency using just one of the standard four genes¹. "With only one 'switch' — the gene Oct4 — we have turned adult somatic cells into stem cells that are very similar to embryonic stem cells", he explains.

Schöler's team began not with fibroblasts, the cultured skin cells most frequently used to make so-called induced pluripotent stem cells (iPS cells), but with mouse neural stem cells, which naturally express three of the four standard transcription factors. They were able to induce pluripotency by adding the gene for the missing factor, Oct4. Also called Pou5f1, this transcription factor is expressed in both embryonic stem cells and germ cells and has long been considered a key regulator of pluripotency. The team had previously been able to reprogram neural stem cells using two of the four factors. The trick to using just one was waiting longer for cells to reprogram. Reprogramming generally takes about three weeks, but Schöler and his colleagues cultured the Oct4-infected cells for four to five weeks. The resulting cells passed several tests of pluripotency, including germline transmission in chimeric mice. The efficiency was similar to that of reprogramming mouse embryonic fibroblasts with all four factors — about 0.014%.

However, practical implications may be a ways off. Unlike skin cells, brain cells cannot be obtained readily from a human biopsy. However, Schöler says these cells present a good model for reprogramming not only because they can be transformed readily but also because they can be grown easily in pure cultures, so researchers can be certain what type of cells are being reprogrammed.

"The study sets the basis to understand, at a mechanistic level, whether Oct4 alone, in the absence of other oncogenes, could be used to reprogram different adult stem cells", says Juan Carlos Izpisúa Belmonte of the Salk Institute in La Jolla, California, whose work has shown that cells from plucked human hair reprogram much more swiftly and efficiently than fibroblasts. If such an approach could be made to work with more easily obtained cell types, the therapeutic implications would be "extraordinary", he says. In the meantime, understanding what cell types are most susceptible to reprogramming "will surely help at unveiling the nuts and bolts of the process".

Other techniques will also be helpful to this understanding. Schöler and other researchers previously showed that fetal neural stem cells could be reprogrammed without inserting the Oct4 gene, although the cells then required insertion of the other pluripotency genes plus a small molecule that inhibits an enzyme known as G9a histone methyltransferase. Schöler says that because this small molecule turns on many genes, the other three factors must be added to focus the "crucial action" of Oct4.

Author affiliations

1. Monya Baker is editor of Nature Reports Stem Cells.