ISSCR: It takes a neighborhood to get a cell to grow up and behave well

Early stage progenitor cells from embryonic stem cells are allowed to mature into insulin producing cells (blue cells) lost in type 1 diabetes. The cells are inside a permeable protective pouch that would fit under the skin of diabetes. (image courtesy of Viacyte, Inc.)

Some years ago, it became a political adage that it takes a village to help a child grow up and become a well-functioning adult. At this year’s meeting of the International Society for Stem Cell Research it is clear that researchers are coming to realize that if you want to grow a stem cell in a lab and have it mature into an adult cell that functions like the ones in you and me, you really need to think about the environment it would grow up in naturally and try to recreate part of that in a lab.

That seems to increasingly mean that you cannot just grow the cell by itself in a dish in two dimensions. In yesterday’s plenary scientific sessions, two of the founding members of ISSCR eleven years ago presented work showing major progress on long-term obstacles in the field through addressing the cells’ environment—the neighborhood—where the cell would normally mature. Both were colleagues of mine back in the early days of ISSCR and members of the then fledgling Harvard Stem Cell Institute.

Both presenters, Doug Melton and George Daley, were starting with stem cells that were pluripotent, those that are able to make all the tissue types of the body. The beauty of those cells, whether embryonic stem cells or reprogrammed IPS cells, is that besides being multi-talented, you can grow vast quantities of them in the lab. For the areas they study, diabetes for Melton and blood diseases for Daley, this vast production becomes key to scaling up any potential therapies. Melton estimated that it would take one billion insulin-producing beta cells to replace the ones a single patient loses in type 1 diabetes.

While many labs have matured stem cells into beta cells, they generally can’t do it in large quantities, and while the cells that result can produce insulin in response to sugar, they don’t do it in proper amounts. Melton used two different approaches to make the cells feel more at home. He overcame most of the quantity problem by growing them in three dimensional “spinner” cultures that came closer to the dynamic environment of the developing embryo. Then to better educate the cells in how to function, he co-cultured them with type of endothelial cells that would be their natural neighbors.

The result was half a billion cells that produce insulin in appropriate levels. He said the team was not yet where they needed to be for a therapy, but they were close. He put out a call to bio-engineers in the room to help him figure out how to protect those cells from the immune attack that destroys beta cells in diabetics.

A CIRM Disease team at the company Viacyte has taken a different approach, not trying to mature the cells fully into beta cells in the lab. Instead they insert earlier stage progenitor cells into a protective pouch and implant them—so far only into mice—where they mature inside the animal into beta cells that seem to function normally. Melton suggests growing the needed cells in the lab may be more efficient, but the Viacyte team has a leg up on protecting the cells from immune system attack. You can read more about that team here.

Daley’s team works on one of the longest running and most puzzling problems in the stem cell field, how to grow large quantities of blood-forming stem cells from pluripotent stem cells, and have them able to engraft into a patient and produce fully functional components of our blood system. This could help us overcome the constant shortage of donors for bone marrow stem cells, and with iPS cells, could allow us to provide patients with genetically matched blood stem cells and avoid some of the devastating side effects of bone marrow stem cell transplants from donors. It would also make it much more feasible to use gene altering technologies to correct genetic defects in blood stems cells such as the ones in sickle cell disease. You can read about a CIRM team working on this approach here.

Up to this point, most blood forming stem cells created from pluripotent stem cells have either failed to engraft in the animal patient, or if they did, they produced hemoglobin and other components that were like those seen in early embryo development, not the type we need as adults. Daley’s group has come a long way to getting past this obstacle, by looking at the environment of the stem cells in the embryo, and trying to make the lab conditions more like those.

The embryo is not a static place. It has a very dynamic flow of fluids, traffic through its street if you will. So, his team developed a system to mimic this “shear” tension. A member of his team also meticulously looked at the genes active in 2,500 mouse embryos at various times in development to see which were turned on. They arrived at a set of four, that when activated in the cell culture, with the shear force, were able to create functional blood stem cells. Again, he said they were not quite where they needed to be for therapy, but certainly much closer than teams in the past.

More to come soon, we hope.

Here’s a video that describes type 1 diabetes and the Viacyte CIRM Disease team’s stem cell-based therapeutic strategy:


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