Normal adult cells have been reprogrammed to become stem cells inside live mice for the first time.

As stem cells can be coaxed into developing into almost any kind of cell, being able to prompt this behaviour in the body could one day be used to repair ailing organs including the heart, liver, spinal cord and pancreas.

“By doing it in situ, the cells are already there in the tissue, in the right position,” says Manuel Serrano at the Spanish National Cancer Research Centre in Madrid, and co-leader of the new work.

The technique overcomes the difficulties inherent in making cells outside the body, grafting them into people, and then of potential rejection. It opens up new clinical opportunities, say the researchers.


Back to the start

Since 2006, when Nobel-prizewinning researcher Shinya Yamanaka first made adult cells return to a stem-cell-like state of being pluripotent – able to turn into almost any cell type – all such induced pluripotent stem (iPS) cells have been made in vitro. This is done by taking a sample of adult cells, such as skin cells, and treating them with four proteins that rewind the cells back to an embryonic-like state.

Serrano genetically altered mice to give them extra copies of the four genes that produce these proteins: Oct, Sox2, Klf4 and c-Myc. The genes were programmed to kick into action when exposed to doxycycline, an antibiotic.

When Serrano injected the mice with the antibiotic, the genes activated, and new iPS cells formed and matured at several sites in the body, including the stomach, intestine, pancreas and kidney.

In many cases, the iPS cells matured to form teratomas, clumps of cells containing a jumbled mix of adult tissue types. These also form when human embryonic stem cells and lab-grown iPS cells are injected into live animals.

Serrano says these tumour-like teratomas could pose dangers in people, so treatments would have to be temporary and localised to sites of tissue damage. And the genes, which would be delivered by a harmless virus, could be switched on or off with an injected chemical such as doxycycline so that the reprogramming could be aborted, either when repair is complete or if something goes wrong.

“We must provide proof of principle for regeneration in animals first,” says Serrano. “We will try in the heart and pancreas, but treatments will be years away.”

“I would not volunteer to have the factors expressed within me,” says Robin Lovell-Badge of the National Institute for Medical Research in London. “The paper highlights that we need to be careful how we handle the reprogramming factors, otherwise people exposed to them are very likely to develop teratomas.”

Making babies

The in vivo iPS cells also formed placental tissue within the teratomas, which has never been seen before in animals receiving other types of stem cells.

What’s more, the iPS cells formed strange cysts that resembled embryos when injected into the abdomens or chest cavities of normal mice. These cysts are unprecedented, and not seen when researchers transplant other types of stem cell into animals, such as lab-grown iPS cells or human embryonic stem cells.

“It’s like an attempt to make an embryo that’s pretty sophisticated,” says Serrano. “These embryo-like cysts are round, hollow, contain membranes and seem to have an organisation like that of an embryo, with its three main tissue layers,” he says. “They also include very sophisticated structures such as placental tissue and a yolk sac, from which the blood system originates.”

Further study could explain why some lab-generated iPS cells haven’t worked as well as hoped when injected into animal tissue. “It could help us identify criteria for what it means for an iPS cell to be truly reprogrammed,” says Robert Lanza, chief scientific officer at Advanced Cell Technology, a stem cell company in Santa Monica, California.

“We’ve been so focused on reprogramming cells in Petri dishes that we haven’t even considered the role the host biological environment might play in resetting cells,” he says.

Journal reference: Nature, DOI: 10.1038/nature12586