Editorial: Xenotransplantation for the therapy of diabetes: A new look

and >2 years in a heterotopic non-life-supporting cardiac xenograft model (7) (8) (9) (10) (11) . However, it is not clear which gene manipulations are essential for successful xenogeneic islet transplantation. In addition, although > 1 year survival of porcine islets in non-human primate models have been reported, continuous administration of multiple immunosuppressive drugs is required (12) (13), and recipients typically succumb to complications associated with chronic immunosuppression. Attempts to taper immunosuppression have been unsuccessful in islet xenoTx in preclinical models. Moreover, life-long multiple immunosuppressive drugs constitute a substantial limitation to the clinical application of islet xenoTx, providing a compelling rationale to pursue a clinically applicable strategy for the induction of tolerance.The recent news from New York announcing kidney xenotransplantation in two brain death patients (14) and subsequently, the world first Tx of a genetically modified pig heart in a human patient have caught the public's attention (15). It is now timely to review and discuss the current status and potential of clinical islet xenoTx.In the Research Topic entitled "Xenotransplantation for the Therapy of Diabetes: a New Look" we present four articles. Two of them focus on characterizing porcine islets and the other two introduce complementary or alternative strategies for islet replacement, such as via blastocyst complementation technology or human stem cell derived beta cells.The article (First author Dr. Arefanian) by Dr. Rayat's groups from the University of Alberta assessed yield, cell composition and function of islets isolated from neonatal pigs at different ages. For previous experimental studies two sources of pig islets have historically being used: neonatal pigs (16) or adult pigs (13,17,18,19). It is generally accepted that adult pig islets are fragile, and that their isolation is technically more challenging than human Islet Isolation; only a limited number of facilities are proficient in the provision of adult pig islets. Neonatal pig islet Isolation is technically less complicated and therefore more broadly replicable. However, the islet yields are lower thus requiring multiple donors versus one adult, to generate an islet mass sufficient to reverse diabetes in large mammals and potentially in human recipients. Neonatal islets compared to adult islets requires longer time to produce insulin following Tx (16). Thus, it is not yet clear whether to use neonate or adult pig as islets donors, and this decision, therefore, to the individual institutions. Optimizing pig donor age for multi-organ retrieval for xenoTx, poses a significant practical problem for companies seeking to raise pigs for xenotransplantation.Arefranian/Rayat et al present a study that compares functional performance of neonatal pig islets at age, 3, 5, 7 or 10 days, with the aim to identify a preferable donor age. They concluded that among, islets from 7-day old donors offer higher yields and better function.Most studies focusing on porcine islet physiology examine beta cell function and insulin secretion, but less is known about glucagon responses by porcine alpha cells. Dr. Gianello's group at the University Catholique de Louvain (First author Dr. Nizar Mourad) assessed glucagon secretion comparing neonatal with adult porcine islets. Glucagon and insulin were assessed both in vitro through dynamic perifusion of isolated islets, and in vivo with glucose tolerance tests. Porcine beta cells have been known to be less responsive to glucose stimulation than human beta cells, however, Dr. Gianello's group demonstrated that porcine alpha cells are particularly responsive to glucose changes. These findings suggest a critical role of glucagon in porcine islet physiology and underscore the importance of characterizing species-specific differences in endocrine cell function. The combination of low insulin response to glucose by beta cells and potent glucosemediated inhibitory response of glucagon secretion by alpha cells may explain the supraphysiologic blood glucose levels in recipients after porcine islet transplantation, even if adequate numbers of islets are transplanted.The other studies included in this Research Topic introduce new and emerging strategies for islet replacement. Dr. Nakauchi's team describes progress led by his group and others in organogenesis using blastocyst complementation. Since it was first proposed in 2010, substantial technical improvements have led to notable successes in rat-to-mouse islet xenotransplantation (19). This technology is still in its infancy, and challenges remain that limit rapid translation of these results from small animal studies to large animal interspecies studies. While it is not clear that this approach will be applied to islet transplantation, given advances in genetic engineering of source animals, blastocyst complementation may be a particularly attractive strategy for the development and transplantation of complex organs such as lung and liver, where current genetic modification strategies of the organs/tissues have proven insufficient. Lastly, Dr. Layden's group at the University of Illinois (First author Dr. Raza Naqvi) provides a comprehensive review of challenges and potential solutions in the field of islet xenotransplantation. In particular, this paper highlights an emerging (and directly applicable to xenotransplantation) strategy for the generation of human beta cells using iPSCs. If fully successful, this approach may theoretically obviate the need for xenotransplantation. The results of in vitro testing suggest that iPSC-derived beta cells function similarly to primary human islet cells; whether this function is preserved in vivo after transplantation is the subject of ongoing clinical trials. The prospect of using either human (allogeneic) or patient-derived (autologous) iPSCs is particularly attractive, as overcoming xenogeneic barriers in pig-to-human islet transplantation remains a challenge. However, stem cell therapy is also a new field with its own potential drawbacks including the theoretical risk of oncogenesis from the viral vector technology used to insert transcription factors. Both stem cell therapy and xenotransplantation remain therefore promising new technologies while requiring additional research.

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