Editorial: Cellular replacement therapy for diabetes

Abstract

Diabetes mellitus (DM) is a metabolic disorder with chronic hyperglycemia due to insulin deficiency and/or impaired insulin action. DM is a common disease, but it often threatens a patient’s quality of life. Cellular replacement therapy using insulin-producing cells is a promising therapy for severe DM because of the proper provision of internal insulin according to a change in blood glucose concentrations. This Special Collection, “Cellular Replacement Therapy for Diabetes,” was planned to appeal the current status and present novel translational trials of this therapy. Ten specialists presented their research, which attempted to overcome three limitations of the current cellular replacement therapy, including the regulation of immunity, limited donor supplies, and establishment of a preferable transplant site for cellular replacement therapy. Regarding regulation of immunity, potential of mesenchymal stem cells and immunomodulatory splenocytes is clarified. Regarding alternative donors, the current status of porcine islet xenotransplantation and therapy using multipotent stem cell–derived cells is introduced. And regarding transplant site, possibility of liver surface and subcutaneous tissue is elucidated.

Diabetes mellitus (DM) is a metabolic disorder with chronic hyperglycemia due to insulin deficiency and/or impaired insulin action ¹ . DM is a common disease, but it often threatens a patient’s quality of life, potentially leading to a coma, ketoacidosis, or nonketotic hyperosmolar syndrome under poor control of blood glucose concentrations ² . Furthermore, chronic hyperglycemia accompanied by the progression of DM induces irreversible vascular complications such as nephropathy, cardiomyopathy, and retinopathy, which can also impair a patient’s quality of life.

Cellular replacement therapy using insulin-producing cells is a promising therapy for severe DM because of the proper provision of internal insulin according to a change in blood glucose concentrations. In particular, islet transplantation is a representative diabetic cellular replacement therapy with high safety and good therapeutic effects. A recent multicenter, clinical trial performed in the United States (Clinical Islet Transplantation [CIT]-07) showed that 71% of the enrolled patients achieved hemoglobin A1C values <7.0% and were free from severe hypoglycemic events at 2 years after islet transplantation ³ .

This Special Collection, “Cellular Replacement Therapy for Diabetes,” was planned to appeal the current status and present novel translational trials of this therapy. Ten specialists presented their research, which attempted to overcome the limitations of the current cellular replacement therapy. The first limitation is the regulation of immunity. Using immunosuppressants is an essential strategy for the success of islet transplantation, but some immunosuppressants have a risk of impairment of transplanted islets. Perrier et al. ⁴ showed that glucose-stimulated insulin secretion of rat islets was impaired by exposure to tacrolimus, a calcineurin inhibitor. Recently, the regulation of immunity by cell therapy has been discussed. Two publications in this Special Collection dealt with this concept. One study focused on mesenchymal stem cells (MSCs). Mei et al. ⁵ reviewed the possibility of co-transplantation of MSCs in relation to immunosuppressive and anti-apoptotic aspects. Co-culture/co-transplantation of MSCs improve the viability and endocrine function of islets and promote angiogenesis. Regarding the regulation of immunity, MSCs affect T cells by preventing contact of antigen-presenting cells, including dendritic cells. In addition, MSCs regulate T cells by inhibiting the reactivity of T, B, and natural killer T cells via production of growth factors, including hepatic growth factor and transforming growth factor b1 ⁶ . Forgioni et al. ⁷ determined the potential of immunomodulatory splenocytes (immunomodulatory cells) produced by exposure of anti-CD80/CD86 monoclonal antibodies. Immunomodulatory cells promoted the transformation of M1 inflammatory macrophages to M2 anti-inflammatory macrophages. The co-transplantation of immunomodulatory cells suppressed inflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β, and inhibited the infiltration of macrophages into transplanted islets ⁷ . Transplantation of regulatory immune cells is a novel strategy for regulating immunity in islet transplantation. Chimeric antigen receptor regulatory T cell is one of the candidates for this purpose because it can protect transplanted islets by suppressing effector cells, as demonstrated by Wardell et al. ⁸

The second limitation is limited donor supplies. According to the International Diabetes Federation Diabetes Atlas 11th Edition, there are approximately 9.5 million people with type 1 DM worldwide ⁹ . Approximately 10% of these patients are considered as candidates for recipients of islet transplantation because of unstable blood glucose concentrations. However, the number of donors cannot cover the possible recipients. Indeed, less than one-third of the 8000 donor donations provided annually are used for islet transplantation ¹⁰ . The establishment of new donor candidates is an important issue. Xenotransplantation of porcine islets and multipotent stem cell–derived cells are possible candidates. Regarding the former candidate, Matsumoto et al. reviewed the current status and future directions of porcine islet xenotransplantation. They introduced preclinical and clinical trials of porcine islet xenotransplantation using fetal, neonatal, and adult porcine islets, including the preparation of designated pathogen-free pigs, immunosuppressants for achieving xenotransplantation, and the possibility of gene-modified pigs ¹¹ . Regarding gene modification, alpha 1,3-galactosyltransferase knock out, human CD46 (inhibition of complement activation) knock in, human tissue factor pathway inhibitor knock in, human CD39 (decreased platelet activation) knock in, and CTLA4-Ig (inhibition of cellular immune responses) knock in porcine islets can be engrafted for a long time under immunosuppression using anti-thymocyte globulin, anti-CD154mAb, and mycophenolate mofetil ¹² . Furthermore, an appropriate recipient model is required to promote preclinical trials for porcine islet xenotransplantation. Sakata et al. ¹³ evaluated the potential of Japanese monkeys as a recipient model using immunosuppressants, which are used for islet allotransplantation.

Regarding multipotent stem cell–derived cells, Keidai et al. ¹⁴ showed the possibility of human-induced pluripotent stem cell–derived adipocytes for treating metabolic diseases. In this review article, various methods of inducing white, beige, and brown adipocytes from induced pluripotent stem cells via the embryonic body or mesoderm are discussed^15,16. Previous studies showed that induced pluripotent stem cell–derived adipocytes are useful for assessing the mechanism of insulin sensitivity and resistance in type 2 diabetes^17,18 and to improve thermogenic and antidiabetic conditions by transplantation ¹⁹ . The reconstruction of insulin-producing cells is also a strategy for solving the problem of limited donor supplies. Gozalez et al. ²⁰ produced pseudo-islets from the C57BL/6 insulinoma cell line (MIN6) and non-obese diabetic insulinoma cell line (NIT-1) under a three-dimensional culture method for monitoring graft survival in autogeneic and allogeneic islet transplant models.

The preferable transplant site for islet transplantation is also an important issue. Katano et al. ²¹ and Endo Kumata et al. ²² suggested the liver surface as a novel transplant site for hepatocytes and islets. In summary, hepatocytes/islets seeded onto a biodegradable three-dimensional gelatin fiber sheet were placed onto the liver’s surface. The efficacy of islet transplantation was improved by using the gelatin fiber sheet. A histological assessment of the liver showed that the transplanted islets were successfully engrafted around the liver surface. The liver surface transplant method is useful for preventing an immediate blood-mediated inflammatory reaction and a nonspecific inflammatory and thrombotic reaction induced by contact between islets and blood. Finally, Emoto et al. ²³ showed the potential of a bioabsorbable medical device characterized by a collagen-gelatin sheet loaded with basic fibroblast growth factor for promoting vascularization of subcutaneous tissue. Subcutaneous tissue is the ideal transplant site regarding the safety and simplicity of transplantation. However, the transplant efficacy of this tissue is considered the worst because of poor vascularization ²⁴ . Subcutaneous islet transplantation under prevascularization using a collagen-gelatin sheet loaded with basic fibroblast growth factor shows a similar transplant efficacy to intraportal islet transplantation. This prevascularization treatment using a bioabsorbable medical device might be a good strategy for achieving subcutaneous islet transplantation, especially stem cell–derived islet cell transplantation. Stem cell–derived islet cell transplantation may be useful when performing it at the timing of completing prevascularization.