The Niche

Why Yamanaka’s new results don’t (necessarily) spell doom for most human iPS cells

The stem cell field needs developmental biologists not just to use iPS cells, but to pick the best ones. As Shinya Yamanaka finished his talk Saturday morning, I literally felt cold. He’d compared dozens of mouse ES cell lines with iPS cell lines generated from mouse embryonic fibroblasts, tail tip fibroblasts (TTFs), hepatocytes, and even a few lines from stomach tissue. The tail-tip fibroblasts were bad news: they resisted differentiation. Even after in vitro differentiation caused the cells to make neurospheres twice, tail tip fibroblasts injected into mouse brains did not persist calmly as brain cells but instead made big, scary teratomas. Other assays came to similar conclusions. Of course, not every line misbehaved, but the TTF lines were much more likely to do so than the others. (You can read more of the results in Nature Biotechnology )

Right now, Yamanaka said, the only certain conclusion from the results is that researchers need better ways to evaluate iPS cells. But the implications are disturbing: mouse non-embryonic fibroblasts behave badly as iPS cells, and most human iPS cells come from adult fibroblasts. Have researchers been making exactly the wrong sort of human iPS cells? Yamanaka said it was too early to draw this conclusion. “Humans don’t have tails,” he said.

It turns out that’s not such a trivial observation. Among the scientists I cornered after the talk was Juan Carlos Izpisua Belmonte, who has shown that keratinocytes make iPS cells more readily than fibroblasts. “Has everyone been making cells from the wrong tissues?” I asked him breathlessly. He was calm. The tail, it turns out, is one of the last structures to form during development. Cells there retain plasticity long after cells elsewhere have specialized. Like Yamanaka said, more work needs to be done.

Much of the insight for what this work should be will come from scientists’ instincts to eliminate variables. All the lines Yamanaka tested were generated independently. The number and places where the extra pluripotency genes inserted themselves could vary greatly. Making iPS lines from “reprogramming ready” mice might help to ascertain whether its the tissue of origin or the luck of insertion that determines cells’ behavior.

Other insight, like Belmonte’s, might come from developmental biology. It made a conversation I’d had just the day before with Allan Spradling ring even truer.

But I have no time to write about this right now. Nor can I discuss the barriers to reprogramming that are being identified and knocked down by Konrad Hochedlinger and others, nor the ever more companies springing up around iPS cells. I’ll do it (and more) in airports as I head home to San Francisco. I also have some posts written by young scientists to add. If you’ve got some other ISSCR links or tidbits, please let me know.

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