The future of stem cell islet transplantation: from ‘shelf’ to ‘self’?

In October, Wang et al. reported a breakthrough in the field of type 1 diabetes (T1D) research: a functional cure after transplantation of patient- specific iPSC-derived islets. Promising results, that raise the discussion if patient-specific or off-the-shelf stem cell based therapies for T1D patients are the way forward. reNEW Leiden Professor Eelco de Koning and Associate Professor Françoise Carlotti at Leiden University Medical Center (LUMC) discuss the study, its implications and the future of stem cell islets in Cell Stem Cell.

T1D is an auto-immune disease affecting 9 million people worldwide that leads to irreversible loss of insulin producing cells in cellular structures of the pancreas called islets of Langerhans. Patients require life-long insulin therapy to manage symptoms and survive. Only a small subset of patients qualify for a curative treatment. They receive a so-called islet transplantation, which is dependent on the availability of scarce donor organs. The group of De Koning at LUMC has specialized in this complex procedure and is now working towards stem cell-based solutions that make a transplantation of insulin-producing islets available to T1D patients without the need for donor organs.

A two horse race
In the field, two different approaches are currently explored to generate stem cell islets and achieve this goal. First, several research groups have initiated clinical trials with ‘off the shelf’ stem cell islets. These islets can be generated in large numbers, which also offers financial advantages. However, currently patients in clinical studies that receive such transplantsrequire lifelong immunosuppression to avoid rejection of these foreign islets.

“The authors from this study took a different approach which provides a potential alternative to these clinical studies. They generated ‘self’ islets from the patient’s own induced pluripotent stem cells (iPSCs). Although more expensive, the advantage of this approach could be that recipients don’t require immunosuppressive medication that prevents rejection as the islets are endogenous to the patient,” explains De Koning.

Unique in many ways
Besides the ‘self’ approach, the study is unique in other ways. Carlotti: “The authors generated iPSCs from adipose tissue through addition of a cocktail of small molecules, instead of the ‘Yamanaka factors’. This procedure holds promise for the future, but is still very new and requires independent studies.” Carlotti and De Koning add that other elements of the successful study, such as the islet transplantation site and manufacturing workflow, are unconventional as well.

The remaining question
Although promising, the study was not yet able to answer a major question in the field: can ‘self’ islets be transplanted and result in long-term insulin independence without immunosuppressive medication? “The patient described in this study was already on immunosuppressants for a previous liver transplant. This means it remains elusive whether ‘self’ islets can lead to a long-term cure in the absence of such medication in patients with autoimmune destruction of insulin producing cells as the cause of their disease. It will be interesting to see how other patients in the trial, without immunosuppressive medication, react to these ‘self’ islets. This will provide valuable insights for the development and clinical implementation of stem cell islets in the future,” concludes De Koning.