By Ewen Callaway
Human skin cells can be transformed into blood without first being sent through a primordial, stem-cell-like state, according to a ground-breaking study.
The breakthrough, published online today in Nature, follows work earlier this year showing that fibroblast cells from mouse skin, treated with the right cocktail of chemicals, can be transformed into neurons and heart muscle. However, it is the first study to accomplish this feat with human cells, and the first to create progenitor cells -- in this case for blood.
"It takes us a step along the line to believing that you can produce anything from almost anything," says Ian Wilmut, an embryologist and director of the MRC Centre for Regenerative Medicine in Edinburgh, UK. Such 'direct conversions' also offer a potentially safer, simpler tool for creating patient-specific cell therapies than is promised by adult cells reprogrammed to become stem cells (known as induced pluripotent stem cells, or iPS cells).
Mickie Bhatia, a stem-cell researcher at McMaster University in Hamilton, Canada, and his colleagues chose to make blood progenitors from skin cells because red blood cells created from stem cells do not make the adult form of haemoglobin. "Those cells, because they think they're embryonic, make embryonic and fetal blood," he says.
Creating a bloodline
To make blood progenitor cells, Bhatia and his team collected skin fibroblasts from several volunteers. They infected the cells with a virus that inserted the gene OCT4, and then grew them in a soup of immune-stimulating proteins called cytokines.
OCT4 is one of a handful of Yamanaka factors used to transform fibroblasts into iPS cells, but Bhatia's team found no evidence that the blood progenitor cells that they had made went through an embryonic state. The cells' gene-expression patterns never resembled those of embryonic stem cells, and the blood progenitor cells didn't cause mice to develop teratomas -- tumours that are characteristic of pluripotent cells.
"Everybody has their favourite cell type. There is a lot of this kind of alchemy going on."
The progenitors did, however, produce all three classes of blood cells -- white blood cells, red blood cells and platelets -- all of which seemed to function as they should, according to a battery of experiments. The red blood cells made adult haemoglobin, not the fetal form.
The ultimate test would be transplanting the cells into humans, says Bhatia, but that isn't on the cards -- at least not yet. "The clinical side is going to be a lot of work," he says. "At least from our estimation, this is the most encouraging result we've seen for using blood cells for cell-replacement therapy."
Sanguine about the possibilities
The potential for therapy is very much on the minds of Bhatia and other scientists who are converting cells directly. Because the progenitor cells bypass pluripotency, there is little risk of them forming tumours when implanted into patients, says Wilmut, who is working on creating other progenitor cells in his own lab.
Deepak Srivastava, a developmental biologist and director of the Gladstone Institute of Cardiovascular Disease in San Francisco, California, led the team responsible for making heart muscle from mouse fibroblasts3. He says that directly converted cells could also offer simpler treatments than iPS cells: the fibroblasts that surround the heart could be transformed into new heart muscle using a stent that delivers drugs to reprogram the cells.
Converted cells aren't without their drawbacks, though. Unlike iPS and embryonic stem cells, they cannot easily multiply in the lab, so producing the large quantities needed for applications such as screening drugs could prove tough, says Wilmut.
Despite lab experiments establishing that the converted blood cells are indistinguishable from adult blood cells, it is still too early to tell whether they will be as good as the real thing once they are inside patients, says George Daley, a stem-cell biologist at Children's Hospital Boston in Massachusetts.
In particular, epigenetic modifications -- changes that modify gene expression without altering the DNA sequence -- could differ between blood cells produced naturally and those created by direct conversion. "The journey from a zygote to a specialized blood cell is very long. The journey from a fibroblast to a blood cell in a petri dish may take a very different route," says Daley.
Even with these caveats, direct conversion is gaining in popularity. "Everybody has their favourite cell type," says Daley. "There is a lot of this kind of alchemy going on."