Durable Control of Autoimmune Diabetes in Mice Achieved by Intraperitoneal Transplantation of “Neo-Islets,” Three-Dimensional Aggregates of Allogeneic Islet and “Mesenchymal Stem Cells”

Abstract

Novel interventions that reestablish endogenous insulin secretion and thereby halt progressive end‐organ damage and prolong survival of patients with autoimmune Type 1 diabetes mellitus (T1DM) are urgently needed. While this is currently accomplished with allogeneic pancreas or islet transplants, their utility is significantly limited by both the scarcity of organ donors and life‐long need for often‐toxic antirejection drugs. Coadministering islets with bone marrow‐derived mesenchymal stem cells (MSCs) that exert robust immune‐modulating, anti‐inflammatory, anti‐apoptotic, and angiogenic actions, improves intrahepatic islet survival and function. Encapsulation of insulin‐producing cells to prevent immune destruction has shown both promise and failures. Recently, stem cell‐derived insulin secreting β‐like cells induced euglycemia in diabetic animals, although their clinical use would still require encapsulation or anti‐rejection drugs. Instead of focusing on further improvements in islet transplantation, we demonstrate here that the intraperitoneal administration of islet‐sized “Neo‐Islets” (NIs), generated by in vitro coaggregation of allogeneic, culture‐expanded islet cells with high numbers of immuno‐protective and cyto‐protective MSCs, resulted in their omental engraftment in immune‐competent, spontaneously diabetic nonobese diabetic (NOD) mice. This achieved long‐term glycemic control without immunosuppression and without hypoglycemia. In preparation for an Food and Drug Administration‐approved clinical trial in dogs with T1DM, we show that treatment of streptozotocin‐diabetic NOD/severe combined immunodeficiency mice with identically formed canine NIs produced durable euglycemia, exclusively mediated by dog‐specific insulin. We conclude that this novel technology has significant translational relevance for canine and potentially clinical T1DM as it effectively addresses both the organ donor scarcity (>80 therapeutic NI doses/donor pancreas can be generated) and completely eliminates the need for immunosuppression. Stem Cells Translational Medicine 2017;6:1631–1643

Stem Cell Therapy: Recent Success and Continuing Progress in Treating Diabetes

“…Simultaneously, re-expression of other islet-specific hormones occurred. Identical injection of Nis into nondiabetic animals resulted in omental engraftment without causing hypoglycemia, further demonstrating regulated islet hormone secretion [14]. Both allo-and auto-immune protection was also achieved [16,17].…”

“…This approach will ensure improved success rates in transplantation and sustained insulin independence [13]. In 2017, Westenfelder, et al, [14] reiterated the need for re-establishing endogenous insulin secretion without being limited by both the scar- 2. Generate all the cell types of the organ from which they originate.…”

“…This treatment led to long-term glycemic control in non-obese diabetic mice [14]. The NIs survived, engrafted and re-differentiated into functional insulin secreting cells in the well-vascularized omentum (via intraperitoneal administration), delivering insulin into the hepatic portal system.…”

“…In these, euglycemia was readily and durably induced and intraperitoneal Glucose Tolerance Tests (i.p. GTTs) were normalized by the exclusive release of canine-specific insulin [14].…”

Cure of Insulin-Dependent Diabetes Mellitus by an Autologous Hematopoietic Stem Cell Transplantation Performed to Control Multiple Myeloma in a Patient with Chronic Renal Failure on Regular Hemodialysis

“…However, despite being considered highly innovative therapeutic modalities, cellular therapies are still experimental and they should be performed only by highly experienced centers worldwide [79]. Additionally, the combination of islet cell transplantation and stem cell therapeutics is another promising approach that may ultimately become curative for type 1 DM [81,89,90].…”