Reprogramming pancreatic cells
New research is showing that cells in the pancreas, that normally make digestive juices, can be permanently reprogrammed to turn them into insulin, somatostatin, and even glucagon secreting cells, just by exposing them briefly to three reprogramming factors. Harvard's Qiao Zhou spoke to Chris Smith...
Qiao - We are very interested to regenerate insulin secreting beta cells. That's important in the disease diabetes. A few years back, we published a paper and showed quite remarkably, using three factors to convert a pancreatic acinar cells into insulin secreting beta cells. Now, the acinar cells, their job is to synthesise digestive enzymes. So, we have followed up on these published work.
Chris - What were the factors that you found could do this?
Qiao - The official name, neurogenin 3, Pdx1 and MafA. So, these are the three so-called transcription factors. These factors had been known through years of studies that they are very important in the development of pancreas and beta cells. That has been known. But people don't know that these factors can work together to actually convert an entirely different cell type to beta cells.
Chris - So, it wasn't necessary to initially turn these acinar cells into IPS cells - these induced pluripotent cells and then reprogramme them. You can go from acinar cells directly with just these factors.
Qiao - Exactly. So, that is a very important point you brought up. The standard method nowadays to create some of these endocrine cells is to go through the IPS cells - the pluripotent stem cells and then we differentiate them to these cell types. And this method is basically some kind of - you can view that as short cut, that you can go directly from now acinar cells to this endocrine cell types.
Chris - Do you regard this as a permanent change of fate for these cells? In other words, if you convert these acinar cells in this way and then you keep culturing them or re-implant them into an animal, do they retain that reprogrammed fate indefinitely?
Qiao - That we believe is indeed the case. We have tracked animal models for over 7 to 8 months and when we go back and look at these cells, they're still there and they're still functional. So, we think they have reached the stable state.
Chris - Do you have a feel for how these factors are achieving this reprogramming effect?
Qiao - So, that is a mystery that we're trying to resolve. We don't have all answers yet, but as far as we can tell, these factors, when they enter the cells, it will go via specific places on the DNA importing genes and they can turn on genes that's important for hormone secreting phenotypes and they will shut down these digestive enzymes secreting phenotype.
Chris - And is that without the factors continuing to be expressed? Can you just put them in in a pulse once and then you get this reprogramming effect?
Qiao - Yes. So, that is a very interesting point and that indeed is what we discovered that the factors we put in have a transient expression. They are expressed extremely at very high levels during the first few days. And then their level drops dramatically in about a week. In the end, I think the cells that you made, these hormone secreting cells, no longer have these exogenous factors expressing them. And they reach a stable state.
Chris - What happens if you put these same factors in the same cocktail into a cell that isn't an acinar cell?
Qiao - Very fascinating question and very important one. So, we actually tried this. We made inducible genetic system. Basically, we now can express the same three factors in almost every cell type in the body. We have found the various different cell types. Cells in the liver, various different parts of the body can now express insulin, but are they really beta cells. You could have a cell that's insulin expressing cell, but they may not be a beta cell because they have to have many other properties that are unique to the beta cells. But one place that we study in detail that's quite remarkable is the stomach and the intestine. Some cells in the GI tract can give rise to insulin positive cells and we can secrete insulin. They also have many other properties that look just like beta cells. So, we are very confident at this moment that the stomach and the intestine can also give rise to beta cells or beta-like cells that are remarkably similar to the real beta cells.