Major step forward in understanding cell reprogramming

Harvard Stem Cell Institute and Massachusetts General Hospital (MGH) researchers have taken a major step toward 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 published by the journal Cell Stem Cell, Konrad Hochedlinger, PhD, 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 induced pluripotent stem (iPS) cells are created using cancer-causing genes called oncogenes. The process involves 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.

Up to this point, the reprogramming process has been a virtual black box - scientists have been able to turn back the developmental clock on adult skin cells by introducing four genes into the cells, but they have not known what steps were occurring during the process.

Doug Melton, PhD, Co-Director of HSCI, called the work “an impressive and thoughtful study” that “marks an important first step in finding ways to create pluripotent stem cells from adult cells without the need for viruses or oncogenes.”

Hochedlinger, an Assistant Professor in Harvard’s new cross-school Department of Stem Cell and Regenerative Biology, and a leader in the study of iPS cells, is, like others, converting adult cells to an embryoniclike state using four genes to bring about the conversion.

In this new paper, Hochedlinger and his colleagues at MGH’s Cancer Center and Center for Regenerative Medicine report that they have engineered new viral systems, which allow them to control the behavior of the four genes and identify what is happening during each day of the reprogramming process.

“The importance of this finding is that it will tell us how long we need to throw chemicals or proteins on the cells for the programming to be effective,” Hochedlinger said. “It could have been that these viruses are only necessary for two days or three weeks. And if you know a certain chemical, or protein, becomes dangerous after 10 days, but you’ll only need to use it for eight days, you have learned something important.”

The other message,” he said, “is that we found the molecular cornerstones of the reprogramming process. Up to this point it was unknown what the sequence of events occurring was. By using a series of surface markers we’ve defined the sequence of events that occurs during the reprogramming “