Development of an encapsulated stem cell-based therapy for diabetes

Abstract

Introduction: Islet transplantation can treat the most severe cases of type 1 diabetes but it currently requires deceased donor pancreata as an islet source and chronic immunosuppression to prevent rejection and recurrence of autoimmunity. Stem cell-derived insulin-producing cells may address the shortage of organ donors, whereas cell encapsulation may reduce or eliminate the requirement for immunosuppression, minimizing the risks associated with the islet transplantation procedure, and potentially prolonging graft survival.

Areas covered: This review focuses on the design principles for immunoisolation devices and on stem cell differentiation into insulin-producing cell products. The reader will gain understanding of the different types of immunoisolation devices and the key parameters that affect the outcome of the encapsulated graft. Progresses in stem cell differentiation towards mature endocrine islet cells, including the most recent clinical trials and the challenges associated with the application of immunoisolation devices designed for primary islets to stem-cell products, are also discussed.

Expert opinion: Recent advancements in the field of stem cell-derived islet cell products and immunoisolation strategies hold great promise for type 1 diabetes. However, a combination product including both cells and an immunoisolation strategy still needs to be optimized and tested for safety and efficacy.

Keywords: hydrogels; islet transplantation; macroencapsulation; microencapsulation; scaffold; vascular supply.

Fig. 1

Schematic of cell immunoisolation through microencapsulation for transplantation without immunosuppression. Before transplantation isolated islets are completely enclosed by a capsule. The capsule material allows transport of oxygen, nutrients, cytokines, glucose, insulin and waste products through the capsule. The capsule prevents contact between the enclosed cells and the host immune cells (immunoisolation), in turn preventing immunorejection. Key parameters that directly affect capsule performances are indicated.

Fig. 2

Schematic of limitations associated with traditional alginate (ALG) microencapsulation. A. Diffusion limitations imposed by large capsule size (600–1000μm) that results in core hypoxia, central necrosis and delayed insulin secretion in response to glucose; B. Large volumes of encapsulated cells that do not allow implantation in sites that might be more favorable to islet cell engraftment but that can accommodate only small volumes. 3. Instability of capsules that causes change in permselectivity and breakage after implantation, leading to rejection of enclosed cells.

Fig. 3

Schematic summarizing the most recent efforts in differentiating stem cells into beta cells. SC: stem cell; DE: definitive endoderm; PP: pancreatic progenitors; PH: polyhormonal; SC-b: stem cell-derived functional beta cells; GSIR: glucose-stimulated insulin release; T1D: type-1 diabetes

Fig. 4

Phase contrast microscope images of rat islets encapsulated with conformal capsules vs. microcapsules vs. non-encapsulated.

Fig. 5

Flowchart illustrating the step-wise strategy that we suggest should be undertaken for evaluating safety and efficacy of a new encapsulated stem cell product for T1D. TX: transplantation; NOD: non-obese diabetic mice; NHP: non-human primates.