In a world’s first, researchers at Harvard have turned one form of fully formed adult cells of a mouse into another.
The Melton [Harvard Stem Cell Institute (HSCI) co-director Doug Melton] team reports in today’s online edition of the journal Nature that, using a technique it is calling "direct reprogramming," the team is able to turn mouse exocrine cells, which make up about 95 percent of the pancreas, into precious and rare insulin-producing beta cells. These beta cells, which comrpise [sic] about one percent of the pancreas, are the cells that die off in Type I diabetes.
In addition to its value for the field of regenerative medicine, the work also is a major step forward toward eventually developing a treatment for Type II – and eventually Type I – diabetes, a treatment that might someday eliminate the need for patients to constantly monitor their blood sugar and take insulin-adjusting medications, or even insulin. It is important to note, however, that there are numerous scientific hurdles that lay ahead before a treatment could be tested in humans.
Unlike the process involved in creating induced pluripotent stem cells (iPS), which have caused enormous excitement ever since their introduction two years ago by Japanese researcher Shinya Yamanaka, this direct reprogramming technique does not require turning adult cells into stem cells and then figuring out how to induce them to differentiate into a desired cell type. Melton emphasized, however, that direct reprogramming does not in any way eliminate the need for, or value of, work with iPS cells or human embryonic stem cells. "We need to attack problems from multiple angles," said Melton, stressing that his lab is using several approaches and will continue to work with iPS and hES cells.
Melton likened the the multi-step process a stem cell goes through during differentiation into a specific adult cell type to passing through a series of doors. "There are locks on all the doors," he said, "and the locks are transcription factors. We asked which ones are present in the beta cell, and that gave us 1,100 transcription factors to choose from. Eventually we learned that of the 1,100, only about 200 are actually expressed in cells that are involved in forming the pancreas.
"Next," Melton continued, "we decided that of the 200, we only cared about the ones that are expressed in the key part of the pancreas where the beta cells are – and that got us down to about 28. Then we did some lineage studies," he explained, "and we got it down to nine. Joe said, ‘my best guess is it’s these nine.’ And he were right. It was a messy experiment, mixing all nine and injecting them into the pancreas. Then we found out that it got better and better as we removed one gene at a time from the nine, and eventually we found that it actually works best with three transcription factors – that six of them aren’t that important. And that’s the fun of science!" Melton said, a grin spreading across his face.
But back to serendipity for a moment:
Suppose the experiment hadn’t worked with those nine transcription factors; what then? "If it hadn’t worked with those nine, we’d probably have dropped the experiment and gone onto something else; there would have been just too many possible combinations of transcription factors to wade through," Melton said.
Press release: Harvard Stem Cell Institute researchers turn one form of adult mouse cell directly into another.
Image: In this immunofluorescent image of an adult mouse pancreas, exocrine cells into which three transcription factors have been inserted are displayed in green. The red areas in the image are insulin. The blue streaks are blood vessels, which are remodeled by and lie close to the new, insulin-producing beta cells. Image courtesy Joe Zhou, Melton Lab
