Saturday Morning Research Review – July 1, 2017

Top options for beta cell replacement

by Josh Boyer, MS

The one thing that any cure for type 1 diabetes needs to accomplish is to replace the beta cells that have been destroyed by the autoimmune destruction of islets.  Beta cell replacement strategies are an important issue that applies to both the development of technology to manage diabetes (encapsulated islets) and potential cures (transplantation of islets; reviewed by Adam here).  Along with protection from immune attack and nutrient/oxygen delivery this is a very important aspect for the success of encapsulation or any cell based diabetes therapy.  Because of a limited supply of cadaverous donors for islets and difficulty in obtaining viable cells from donated organs, beta cells will have to come from alternative sources.  Two proposed options are stem cell-derived human beta cells or pig xenograft transplants.

The pig option is an interesting one that I will briefly touch on.  Pigs have a long history in the treatment of diabetes.  The first insulin developed to treat type 1 diabetics was sourced from pigs (first identified by the Nobel Laureate Frederick Banting in 1922) and used until recombinant DNA technology developed by Genentech replaced it in the 1970s. Pigs maintain similar physiologic levels of blood glucose to humans and transplanted porcine islets have shown success in non-human primate.  This indicates that pig insulin can function promote glucose uptake by human cells and that pig beta cells have the potential to maintain glucose levels at an optimal target.  In fact pigs have been used as a model animal to study the functionality of both closed-loop insulin pump systems and encapsulated islets.  The main drawback to this option is that the transplanted beta cells are foreign cells and have a high probability of being rejected by the immune system.  One interesting recent development is the work on genetically engineering donor pigs to develop ‘humanized’ cells.  This is a research area being explored not just for diabetes but multiple diseases that require transplanted organs or tissues.  While it seems fairly science fiction now and there have been recent setbacks, science can also sometimes move rapidly and this may be an option that warrant further investigation.

My current favorite choice for expanding beta cells is to use induced pluripotent stem cells (iPSCs).  A stem cell has the ability for both self-renewal (generating more of itself) and differentiation into functional cell types.  A pluripotent stem cell means that it can differentiate into any cell type in the body.  Induced pluripotent stem cells were first described in 2007 through simultaneous work by Shinya Yamanaka at Tokyo University and James Thomson at UW-Madison.  iPSCs are stem cells derived from cells that have already differentiated into specific functional cells.  They are returned to a pluripotent state through addition of signaling molecules and growth factors and from there can be coaxed to develop into a different cell type.  The expansion and differentiation of beta cells from stem cell progenitors has been well described and Adam has reviewed this strategy previously.  The main advantage that I see from this technique is that in theory you could take a diabetic’s skin cells, turn them into iPSCs and develop beta cells from those that will be a perfect match for transplanting as they are from the patient.  This doesn’t block the autoimmune response but avoids the chronic transplant rejection issues that allogeneic or xenograft transplantations face.

Within the beta cell replacement field, something I’ve come across regarding encapsulation are data showing that the ideal cells to transplant are not fully differentiated beta cells but rather beta cell progenitors.  Beta cells develop from the endoderm through a multipotent pancreatic progenitor cell that progresses to an endocrine progenitor.  It is these pancreatic progenitors that are being used within encapsulated devices.  One advantage to this design is that circumvents (ie avoids) the hypoxic stress that newly transplanted islets experience.  Following implantation, the progenitor cells appear to be able to expand and maintain a larger number of beta cells than transplanted whole islets.  Following transplantation into a diabetic recipient, these cell clusters differentiate into ‘islet-like cells’ that include insulin-producing cells.  Current work in several groups is trying to increase the number of beta-like cells within these progenitor populations.  One concern with this method is the risk of a tumorigenic cell population developing because of stem cells’ self renewal properties.

Beta cell replacement is a very important area of research for type 1 diabetes therapies and cures.  However, there is also a chance that these transplantations may not even be necessary.  Recent work has shown that undifferentiated beta cells persist in the islets even in diabetic patients.  This work demonstrates that there may be trans-differentiation from alpha cells (that produce glucagon) to beta cells.  These cell populations may not exist for all diabetics (there is variability in degree of beta cell destruction) and even then these cells may not be able to expand to form a functional beta cell mass.  However, it is worth investigating whether they may be driven to produce sufficient mass as this would be an ideal fix that requires no transplantation.  Once we fix that autoimmune issue, of course.

Posted in beta cells, Research Review, Transplant.