Vascularized Stem Cell-derived β-cell Spheroids: A "Single Step" in the Right Direction for the Treatment of Type 1 Diabetes.

Abstract

Pancreatic islet transplantation represents an attractive therapeutic strategy to restore physiologic blood glucose control to individuals with type 1 diabetes (T1D). This treatment modality is established as an effective means to achieve normoglycemia, prevent hypoglycemia, improve quality of life, and potentially protect against vascular complications of T1D.1 Despite clear progress in clinical islet transplantation, this approach is limited to those with life-threatening hypoglycemic unawareness.2 While both auto- and alloimmune-mediated rejection clearly contribute to long-term islet graft failure, accumulating evidence suggests that acute islet cell death, in the peritransplant and posttransplant periods, severely compromises engraftment.3 As a consequence, multiple organ donors are routinely required to achieve insulin independence with chronic life-long toxic immunosuppression, restricting this therapeutic option to a narrow range of T1D patients. While transplanting islets within the liver has been demonstrated as an efficient means of restoring glycemic control, the procedure often results in acute or gradual graft attrition and carries procedural risks. Moreover, intrahepatic transplantation does not permit retrieval of donor islets; the ability to recover the graft is also important for safety monitoring in efforts to replace donor-derived islets with human stem cell– or animal cell–derived pancreatic cells. In recent years, numerous investigators have defined signaling pathways that allow the efficient generation of pancreatic progenitor cells and improved their commitment in vitro to β-like cells, thus serving as a potentially unlimited supply of surrogate islets.4 As a means to minimize potential recipient risk in early clinical trials, the transplant site for stem cell–derived cell-based therapies should ideally exploit an approach that encapsulates the stem cells, is retrievable, and provides vascular support.5 The subcutaneous tissue is an auspicious extrahepatic site, based on its ability to house large transplant volumes, minimal invasiveness, and the capacity for graft excision if required. Inopportunely, subcutaneous engraftment is limited by its innate hypovascularity, leading to poor oxygenation, inadequate metabolic exchange, and subsequent loss of transplanted tissue.6 To address this challenge, researchers have used approaches to create a subcutaneous prevascularized bed through tissue engineering, which has enabled long-term islet engraftment. This technique preconditions the subcutaneous site into a more sustainable microenvironment, cloaking the graft in a vascular matrix while facilitating long-term reversal of diabetes posttransplant using rodent and human islets,7 and more recently human stem cell–derived pancreatic endoderm cells.8 However, a limitation of prevascularized strategies is the requirement of a 2-stage surgical procedure, one to prime the site and another to deliver the therapeutic cells. In contrast, cellular encapsulation technologies that do not rely on prevascularization are plagued by a delay in revascularization, reliance on acute passive diffusion for nutrient exchange, and the stimulation of a chronic foreign body reaction.9 In this issue of Transplantation, Takaichi et al10 present their findings exploring the efficacy of a vascularized human-induced pluripotent stem cell–derived β cells (hiPS β cells) spheroid modality, transplanted subcutaneously for the treatment of T1D. This present work is an expansion of their previous published observations with layer-by-layer constructed spheroids utilizing normal human dermal fibroblasts and human umbilical vein endothelial cells, now applied to pancreatic β cells. The topic of evaluating extrahepatic islet engraftment sites is of great importance as the feasibility of alternative cell sources (ie, stem cell–derived insulin producing cell products) are rapidly becoming a present reality. Again, while the infusion of islets into the liver continues to remain only transplant site to routinely reverse diabetes in clinical patients, this site may not indeed be suitable for alternative cells sources, namely due to the inability to retrieve the cellular graft should complications arise. Using either MIN-6- and hiPS-derived β-cell spheroids, the authors demonstrate that vascularized spheroids enhanced in vitro glucose-stimulated insulin secretion. Postsubcutaneous transplant, vascularized hiPS β-cell spheroid also significantly decreased daily nonfasting blood glucose levels as well as improved glucose tolerance during an intraperitoneal glucose tolerance test in diabetic immunodeficient mice compared with controls not implanted with the spheroid grafts. The authors make a persuasive argument that this improved metabolic outcome was the result of the hiPS β-cell spheroids increasing angiogenesis at the graft site without the need for prevascularization. A caveat to the author’s 3D vascularized spheroid approach is its inability to facilitate full engraftment and correction of diabetes, coupled with the limited biological replicates. We agree with the authors that the true translational potential of this cell replacement therapy can only be fully gauged with future optimized studies that demonstrate routine posttransplant normoglycemia in larger cohort of recipients. Nevertheless, this β-cell transplant modality does represent an important and innovative advancement as it demonstrates a “single step” approach to create a functional and vascularized subcutaneous β-cell transplant platform. While our expectations are tempered until future studies materialize, we remain optimistic that this innovation could lead to promising regenerative treatments for T1D.