January 25, 2017

expert reaction to study reporting functional mouse pancreatic islets grown in rats and transplanted into mice

Scientists publishing in Nature have shown that is it possible to generate rat/mouse chimeric pancreatic tissue by injecting mouse stem cells into rat early embryos. The resulting tissue could be transplanted into diabetic mice, restoring normal control over blood glucose. These findings may have implication for the future treatment of diabetes in humans.

Dr Shareen Forbes, Reader in Diabetes and Endocrinology, University of Edinburgh, & Lead Physician for the Islet Transplantation Programme in Scotland, said:

“Type 1 diabetes is caused by damage to specific insulin-secreting cells found in specialised structures in the pancreas called islets. Transplanting healthy islets is a proven therapy for people with type 1 diabetes but the lack of donor tissue is a major limiting factor for widespread use of this approach. This study involving rats and mice raises the possibility that we may one day be able to grow donor islets in animals of another species. The findings are exciting but there are still many questions to answer. Much more research is needed before we could see this approach being applied in people.

“This article demonstrates proof of principle that organs generated in a xenogeneic environment by blastocyst complementation functionally rescues diseased hosts despite the presence of xenogeneic cells.

“Islet transplantation is of proven efficacy in type I diabetes however the lack of donor pancreata is an issue limiting islet transplantation in humans. The investigators used immunosuppression for just five days post-transplant, highlighting the potential of such an approach to diminish immunosuppression which ultimately may mean increasing the applicability of such an approach to a wider patient group. At present islet transplantation is indicated in those with type I diabetes associated with recurrent hypoglycaemia and impaired awareness of hypoglycaemia. If this approach was possible it would open this therapy up to others with type I diabetes and even perhaps those with type II diabetes.

“Importantly the researchers had conducted a number of experiments to account for potential confounders and the experiments are well conducted. One potential issue is the route of islet transplantation that they utilised in these rodent experiments. Whilst utilising the kidney capsule route is a common experimental route it does not reflect the clinical situation in humans where islets are transplanted into the liver. The kidney capsule route displays at least partial immune privilege unlike the hepatic niche. Additionally, the immunosuppression agents used, TNF Alpha antibodies, in fact may have immunosuppressive effects for many months and so the incidence of rejection in this report may be much lower than we would realistically expect to see if these techniques were potentially transferred to humans.

“This may have implications for human islet transplants – however since Type 1 diabetes is an autoimmune disease the use of patient specific iPSC may be an issue as the islets thus formed may be susceptible to autoimmune mediated cell death if there is no immunosuppression. However other patient specific iPSCs may certainly be useful.  Certainly this opens the possibility that other more complex organs may be grown in other species.”

Prof. Robin Lovell-Badge, Group Leader at The Francis Crick Institute, said:

“This is interesting and potentially important research, exploring the possibility of growing tissues of one species in another with the long term aim of providing human material for grafts to overcome both the shortage of donated organs and problems of immune rejection, if the tissues can be grown from the patient or closely matched cells. It is a very long way from practical applications for humans, but the work is a good demonstration of the principles involved and it points to both the successes of the approach and some of the problems likely to be encountered. There is currently much interest in these approaches, particularly with respect to animals containing human cells or tissues. Although not dealing with the latter, this study shows why it is important to carry out this research.

“This work suggests that this technique might be a viable approach in humans if appropriate large animals can be used for chimeras with the complementation approach. However, they need to establish these methods with a species with similar embryo development and size to humans – perhaps pigs. They also need to use patient-specific induced pluripotent stem cells (iPS cells) and to show that these can indeed make chimeras after blastocyst injection. However, scale up can be a problem with any of these approaches and particularly the immune issues will require a lot of attention.

“One thing to note is that some of the rats with mouse pancreata seemed to develop diabetes with infiltration of immune cells, suggesting that the immune system was beginning to recognise the mouse pancreatic cells as foreign – but this should not happen.  The immune system develops in the late embryo and everything present at this time should be recognised as self and not attacked.  Perhaps some mouse proteins are only expressed after birth and therefore escape the process by which tolerance arises in the embryo.”

* ‘Interspecies organogenesis generates autologous functional islets’ by Yamaguchi et al. published in Nature on Wednesday 25th January.

Declared interests

Dr Shareen Forbes: No conflicts of interest to declare.

Prof. Robin Lovell-Badge: Robin Lovell-Badge is a Senior Group Leader at the Francis Crick Institute in London. Some of his research touches on the methods used in the paper by Yamaguchi et al, but not on the specific topic, and he has no conflicts of interest or financial interest in the study. He was a member of the Academy of Medical Sciences Working Group on: “Animals containing human material” (2009 – 2011), whose recommendations were adopted into UK law in 2015.