Stem cells might not be the easiest way to clone animals: That’s what researchers at the University of Connecticut are saying after they recently cloned mice from fully differentiated blood cells.

Differentiation refers to the process by which young cells take on specialized roles and functions, becoming one particular cell type, such as blood cells or liver cells. Stem cells are undifferentiated and have the potential to turn into one of many different kinds of cells.

This flexibility has traditionally positioned stem cells as more promising tools for cloning than fully differentiated cells. 

“For the last 10 years,” said biologist Jerry Yang, leader of the new research effort, “no one could answer the question: Could the cloned animal be produced from one of those differentiated cells? And now we have.”

In 1996, Scottish scientists made Dolly, the famous cloned sheep, by removing the nucleus from an adult sheep’s udder cell and placing it into an unfertilized egg. Researchers then placed the egg in a surrogate womb to develop. This process reprogrammed the DNA of the udder cell, turning the egg into an embryo, rather than another udder cell.

But scientists don’t know much about what kind of udder cell helped to create Dolly. Like most tissues, sheep udder tissue contains a huge number of mature, differentiated cells, along with a handful of adult stem cells. 

Most scientists assumed that the udder cell that led to Dolly—as well as the cells used to clone over a dozen mammalian species since—were these rare adult stem cells.

Yang and his colleagues provide evidence that cloned animals can actually develop from the mature, differentiated cells. In the October issue of Nature Genetics, the researchers report their efforts to make mouse clones by plucking the DNA from cells in three stages of development: undifferentiated blood stem cells that could turn into all blood cell types; somewhat differentiated blood stem cells that could turn into a few blood cell types; and fully differentiated blood cells.

Surprisingly, the researchers found that not only could clones be created from fully differentiated cells, but that the differentiated cells were actually the easiest to clone—about 35 percent of the fully differentiated cells developed into early stage embryos known as blastocysts, while only four percent of stem cells did.

Clones made from the two types of stem cells never developed into full embryos. The differentiated cells, however, produced two live mouse pups. (Both died a few hours after birth.)

The findings are surprising, said David Scadden, co-director of the Harvard Stem Cell Institute.

“It was thought that as cells become more specialized, the genome would become much more restricted, and less plastic,” he said.

Yang’s research will change the direction of future cloning work, Scadden said, and presents an appealing alternative to using adult stem cells, which are rare and poorly understood.
“One of the nice things about this,” he said, “[is] we can get large numbers of differentiated cells.”

According to Yang, more research is necessary to determine whether clones can be made from other kinds of differentiated cells besides blood cells.

As for the mystery surrounding Dolly, Ian Wilmut, the embryologist who supervised the sheep cloning project, said the new findings don’t indicate whether the original udder cell was a stem cell or an already differentiated cell.

“These new results are very interesting,” Wilmut said in an email. “[They] show that we have to have an open mind about the developmental potential of nuclei from different types of cell.”

Originally published October 3, 2006

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