Induced pluripotent stem cells

It was one of the top science stories of 2007: number 2 on Science's list – reprogramming ordinary adult body cells (of mice and humans) to act like embryonic stem cells.

The riddle of Dolly the Sheep has puzzled biologists for more than a decade: What is it about the oocyte that rejuvenates the nucleus of a differentiated cell, prompting the genome to return to the embryonic state and form a new individual? This year, scientists came closer to solving that riddle. In a series of papers, researchers showed that by adding just a handful of genes to skin cells, they could reprogram those cells to look and act like embryonic stem (ES) cells.

The story really began in October 2006, when a team at Kyoto University in Japan, led by Shinya Yamanaka, announced that they had reprogrammed mouse skin cells into cells that closely resembled embryonic stem cells, based on certain characteristic genes that were expressed. The reprogramming was done by introducing genes for four important stem cell transcription factors (Oct4 (or sometimes the similar Oct3), Sox2, c-Myc, and Klf4) into the skin cells with the help of a genetically engineered retrovirus.

But the team could not at that time demonstrate that these reprogrammed cells would differentiate into a variety of adult cells after having been introduced into a mouse embryo which then developed into an adult mouse. Being able to do this would verify the pluripotency of the reprogrammed cells. (Pluripotency is the ability of a cell to develop into any type of fetal or adult cell. It is characteristic of embryonic stem cells.) The reprogrammed cells are called induced pluripotent stem (iPS) cells.

However, in June 2007 Yamanaka's team, along with two others, reported that they had been able to provide the missing demonstration of pluripotency. The second team that joined in reporting this accomplishment was led by Rudolf Jaenisch at MIT's Whitehead Institute for Biomedical Research. The third team was led jointly by Konrad Hochedlinger of the Harvard Stem Cell Institute and Kathrin Plath of the UCLA Institute for Stem Cell Biology and Medicine.Recently (mid-February), Kathrin Plath's team at UCLA has also announced success in reprogramming human skin cells, using the same techniques as previously reported. They have also verified that the induced pluripotent cells are very similar to embryonic stem cells:
Human Skin Cells Reprogrammed Into Embryonic Stem Cells

                                                       The reprogrammed cells were not just functionally identical to embryonic stem cells. They also had identical biological structure, expressed the same genes and could be coaxed into giving rise to the same cell types as human embryonic stem cells.

As we've noted, there have been some potential problems with the work already mentioned. First, any process that activates c-Myc (directly or indirectly) runs risks of promoting cancerous tumors. Second, the processes have used retroviruses to introduce the necessary genetic material into cells to be reprogrammed. This also runs the risk of inducing cancer.

So Konrad Hochedlinger's team has come along with work in mice to reduce or remove these cancer-causing risks:
Discovery Could Help Reprogram Adult Cells To Embryonic Stem Cell-like State

                                                 Harvard Stem Cell Institute (HSCI) and Massachusetts General Hospital (MGH) researchers have taken a major step toward eventually being able to reprogram adult cells to an embryonic stem cell-like state without the use of viruses or cancer-causing genes.

In a paper released online today by the journal Cell Stem Cell, Konrad Hochedlinger and colleagues report that they have discovered how long adult cells need to be exposed to reprogramming factors before they convert to an embryonic-like state, and have “defined the sequence of events that occur during reprogramming.”

This work on adult mouse skin cells should help researchers narrow the field of candidate chemicals and proteins that might be used to safely turn these processes on and off. This is particularly important because at this stage in the study of these induced pluripotent (iPS) cells, researchers are using cancer-causing genes to initiate the process, and are using retroviruses, which can activate cancer genes, to insert the genes into the target cells. As long as the work involves the use of either oncogenes or retroviruses, it would not be possible to use these converted cells in patients.

And hard on their heels, other teams are announcing similar findings:

Stem cell breakthrough may reduce cancer risk

                       The main obstacle to using "reprogrammed" human stem cells – the danger that they might turn cancerous – has been solved, claims a US company.

PrimeGen, based in Irvine, California, says that its scientists have converted specialised adult human cells back to a seemingly embryonic state – using methods that are much less likely to trigger cancer than those deployed previously.

The company also claims to be able to produce reprogrammed cells faster and much more efficiently than other scientists.