Immunoisolation of Human or Xenogeneic Insulin-Producing Cells

Islet transplantation alone (ITA) has been recognized as an adequate insulin replacement therapy in type 1 diabetes (T1D) patients. To date, however, ITA has only been approved as a clinical therapy in few European countries and in Canada. Indeed, the latest results have convincingly demonstrated that ITA and pancreas transplantation alone have equivalent clinical outcomes with a greater than 10 years' insulin-independence in some patients while costs have been comparable.1,2 Critical aspects of moving ITA forward include, (1) an optimized isolation of islet cells, (2) the reduction of the number of donor pancreata needed to achieve long-term results, and (3) optimization of immunosuppression long term. To overcome the lack of donors, alternative sources of insulin-producing cells need to be explored particularly as donor rates have not increased in parallel to the increasing demand for organ transplantation. Moreover, efforts to differentiate adult progenitor cells into fully competent endocrine cells appear promising. Experimentally, the differentiation into phenotypic β cells that have the capacity to secrete insulin has been demonstrated. However, these cell preparations have rarely achieved a significant in vivo response to hyperglycemia.3,4 In contrast, both induced pluripotent stem cells (iPSCs) and human embryonic stem cells (hESCs) have been shown to be capable in vivo of responding to hyperglycemia.5 More importantly, in this recent article, Vegas and colleagues were able to demonstrate, for the first time, that mature β cells derived from hESCs are able to correct diabetes in mice. Similarly, others have demonstrated that a human cell line could be obtained by viral transfection capable of correcting diabetes in vivo.6 As such, at least in theory, hESCs, iPSCs, and human β cell lines could be of great interest to cure T1D because an unlimited number of human insulin-producing cells could be obtained. Two main limitations, however, are associated with these approaches. First, these cells may carry an intrinsic risk of tumorigenicity, and it is yet unclear how to tightly regulate the growth of these cells to prevent the occurrence of malignant transformations.7 Second, allogeneic cells will require chronic immunosuppression because they are known to express major histocompatibility complex antigens. Vegas and coworkers have introduced interesting findings that may help to use human and potentially xenogenic islets in an effective way At this stage, xenogeneic cells, especially porcine islets, may need to be considered as an alternative source. Indeed, pigs secrete an insulin that is comparable to that of humans (differing by only 1 amino acid of 51) which has been used for decades to treat T1D patients worldwide. Obviously, pig islets would solve the dilemma of limited availability. Moreover, pig cells have already differentiated and matured and can promptly secrete insulin in response to hyperglycemia, both in vitro and in vivo. At least in theory, porcine islets carry the risk of zoonosis, although pigs that have been negative for porcine endogenous retrovirus (PERV) C while having low copy numbers of PERV A/B and can be regarded as a safe source, especially if pigs are raised in specific pathogen-free facilities including a continuous surveillance of viral, bacterial, and parasitic exposure. Of additional note, to date, there is no PERV-related infection reported subsequent to the clinical transplantation of pig tissues.8 With a large number of now available knockout or transgenic pigs, the model bears also significant immunological advantages.9 Micro/macroencapsulation potentially provides the opportunity to modify the need for immunosuppression, while providing an opportunity to recover transplanted islets. Of note, Vegas and coworkers5 were able to show experimentally that the intraperitoneal implantation of mature β-cells derived from hESCs encapsulated in alginate derivates provided glycemic control in the absence of immunosuppression. Of interest, immune competent cells were much lower in number at the site of islets encapsulated with the chemically modified alginate. Moreover, encapsulated islets also restored normoglycemia subsequent to a glucose challenging test performed 150 days after implantation. Clearly, those findings are of translational relevance. With many aspects for debate, the optimal site of transfer remains to be considered. The peritoneum as a site of implantation presents several advantages in both experimental and clinical models. However, recovering encapsulated cells from the peritoneum may represent a challenge in addition to a predisposition of proinflammatory responses. Alternative sites, such as subcutaneous tissues or intramuscular locations, are increasingly being considered as valid alternatives. Of additional relevance, microencapsulation with substances, such as alginate, will not protect from sensitization, because major histocompatibility complex molecules may leak out of the alginate capsule mounting alloimmune responses and impacting future allogeneic organ transplants. Moreover, microencapsulation may prevent cellular overgrowth of fully differentiated xenogeneic pig islets. However, it has yet to be evaluated whether prevention of overgrowth will also apply for microencapsulated hESCs or iPSCs. Thus, any immunoprotective approach needs to be designed and adapted to the source of cells that will ultimately be used. Although microencapsulation appears appropriate for fully differentiated and maturate cells, such as pig islets, more efficient immunoisolation strategies may be necessary when using cells that are still replicating or differentiating. Thus, using a device that allows cells to secrete insulin and survive but also prevents [over]growth beyond the device itself is a safe approach to protect both recipient and cells and the only way ahead for the future widespread application of the encapsulation technology. In this context, although the low level of oxygen or anoxia may represent a major obstacle to the mid-term to long-term islet survival, such a shortcoming can be averted by a daily oxygen delivery into the compartment, enabling β cell survival for months.10 Taken together, Vegas and coworkers have introduced interesting findings that may help to use human and potentially xenogenic islets in an effective way. Implications on minimizing or even eliminating immunosuppression appear interesting and need to be tested clinically. The research on finding a clinical solution for all T1D patients ideally within the next 5 years has a new impetus.

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