Signals Blog
Menu

 

Dr. Bruce Verchere presenting at the Till & McCulloch Meetings

Another interesting talk, on the first morning of the Canadian Till & McCulloch Meetings, was from Dr. Bruce Verchere who spoke about possible routes to prevent graft rejection in the case of human β-cell and islet cell transplants for diabetes through engineering the β-cells.

As previously described, Type 1 diabetes (T1D) is an autoimmune attack on insulin producing β-cells in the pancreas. Cellular therapy has shown to be effective in reversing diabetes and eliminating insulin injection by replacing the β-cell through pancreatic islet transplantation. Only a few hundred thousand islets can normalize blood sugar levels. This transplant has become a routine procedure at the University of Alberta Hospital, in Edmonton. However, 2.1 million Canadians were affected by diabetes in 2016. Because there aren’t enough islet donors around, there is a need for new ways to regenerate these cells.

Additionally, some patients reject the islet transplants and their grafts fail over time. And, those who receive the transplants need to be on lifelong immunosuppressive regimens, which cause more complications for the patients. Dr. Verchere’s group has developed a novel method to derive β-cells from stem cells, and engineer those cells into better functional β-cells that are immune to graft rejection.

The technology has stemmed from a molecule that tumor cells use to avoid immune response cells. A protein called the chemokine CCL22 is produced by cancer cells, which, when released, reduces the allograft response (chance of rejection). If this protein is overexpressed in the transplanted β-cells, it will have a similar effect. This was evident in mouse models, and those with β-cells that overexpressed CCL22 lasted longer without a return of the diabetes compared to the control group.

Further research is needed to evaluate what will happen in humans. So far, Dr. Verchere’s lab has engineered human embryonic stem cells (hESCs) to express human CCL22, but this study is at the early stages. They are also in the process of developing a humanized mouse model for allograft rejection and graft vs. host disease (GVHD).

In Type 2 diabetes, the insulin producing β-cells die, mainly due to the accumulation of a protein called the islet amyloid polypeptide (IAPP or amylin), in the cells. Verchere’s group observed that the accumulation of the same protein happens in the transplanted human islets, which seems to contribute to graft failure. For future projects, they are working on engineering hESC-derived β-cells that would generate non-amyloidogenic (meaning they won’t generate amylin) islet polypeptides and transplanting these as another strategy to avoid immune rejection response.

One important factor to remember, though, is multiple types of immune cells are active during a graft rejection response. To have long-term tolerance to the grafts, we have to think about the other players involved, such as the other cells of the immune system (NK cells, macrophages and monocytes), since it is a really complex response.

Back speaking at TMM 2017 is Dr. Timothy Kieffer

Following Dr. Verchere’s talk, Dr. Timothy Kieffer discussed methods to expand and differentiate stem cells in vitro into islet cells. His group tries to mimic the developmental signals that differentiate the pluripotent stem cell to become pancreatic beta cells. They have discovered that there is no need to transplant fully differentiated cells, as islet progenitor cells, at the early stages of differentiation, can become mature in vivo and produce insulin after a few months. (In 2015, Dr. Kieffer was awarded the Till & McCulloch Award for his diabetes research. Read more about this here.)

Dr. Kieffer’s team tackles the problem of immune response post transplantation using macroencapsulation devices. These provide an immuno-isolation barrier to protect transplanted cells from the host immune system. Also, for cell transplant treatments for diabetes, there is no need to directly transplant into the pancreas. As long as the cells are close to a vascular system, the device can be implanted under the skin (subcutaneously).

The macroencapsulation device provides sufficient oxygen and nutrient diffusion, but the cells will not be in direct contact with the immune cells. The pancreatic progenitor cells were able to survive well and mature into insulin producing β-cells, which reversed diabetes in mice after four months post transplantation. This method has received approval from the U.S. FDA and Health Canada to go into clinical trials.

The caveat of relying on in vivo maturation with the immature progenitor cells is that it is not clear how environmental factors affect the maturation of the cells. Dr. Kieffer and his team have evaluated the effect of a high fat diet, thyroid hormones, pregnancy and sex of the transplant recipient. The diet did not impact maturation, whereas low thyroid hormones had dramatic effect on maturation of the cells. While pregnancy did not affect β-cell maturation, more cells in the female mice matured to β-cells compared to in males, which could be a result of hormonal differences.

Knowing all the contributing factors in maturation of the β-cell progenitor cells, the researchers were able to develop a more advanced protocol and further differentiated the cells before transplanting them in vivo. These more mature cells were still progenitor cells since they were moderately glucose responsive, meaning they would produce insulin when triggered by glucose increases in media. When transplanted, these later stage cells were able to reverse diabetes much faster than the less mature cells, and showed more robust insulin production. The group continues to work on developing protocols to produce robust numbers of more mature progenitor cells and identify the signaling pathways necessary to mature the cells in vitro.

 

 

The following two tabs change content below.
Hamideh Emrani

Hamideh Emrani

Hamideh is a scientific communicator and the founder of Emrani Communications, serving clients in Toronto (University of Toronto) and California (Stanford University). She earned her B.Sc. in Cell and Molecular Biology at UC Berkeley and finished her M.Sc. at the University of Toronto (U of T). She was an intern at the Carnegie Institute at Stanford University, honours research student at UC Berkeley and has won awards for best podium and best poster presentations at the Faculty of Dentistry and IBBME at U of T. She is passionate about science and loves to talk and write about it. You can follow Hamideh on Twitter at @HamidehEmrani.