Harnessing cellular therapeutics for type 1 diabetes mellitus: progress, challenges, and the road ahead

Abstract

Type 1 diabetes mellitus (T1DM) is a growing global health concern that affects approximately 8.5 million individuals worldwide. T1DM is characterized by an autoimmune destruction of pancreatic β cells, leading to a disruption in glucose homeostasis. Therapeutic intervention for T1DM requires a complex regimen of glycaemic monitoring and the administration of exogenous insulin to regulate blood glucose levels. Advances in continuous glucose monitoring and algorithm-driven insulin delivery devices have improved the quality of life of patients. Despite this, mimicking islet function and complex physiological feedback remains challenging. Pancreatic islet transplantation represents a potential functional cure for T1DM but is hindered by donor scarcity, variability in harvested cells, aggressive immunosuppressive regimens and suboptimal clinical outcomes. Current research is directed towards generating alternative cell sources, improving transplantation methods, and enhancing cell survival without chronic immunosuppression. This Review maps the progress in cell replacement therapies for T1DM and outlines the remaining challenges and future directions. We explore the state-of-the-art strategies for generating replenishable β cells, cell delivery technologies and local targeted immune modulation. Finally, we highlight relevant animal models and the regulatory aspects for advancing these technologies towards clinical deployment.

Fig. 1 ∣. Pluripotent stem cell differentiation into stem cell-derived islets through modulation of different genes.

Stem cell-derived islets (SC-islets) are functionally, transcriptionally and epigenetically different to native pancreatic islets. Enhancing cellular identity to generate optimal functional potency and safety profile is an active area of investigation along with methods for scalable manufacturing.

Fig. 2 ∣. Microencapsulation approaches for islet transplantation.

Microencapsulation strategies (most notably alginate with modifications including hyaluronic acid or collagen) for islet transplantation. Surface modifications and immunomodulatory molecules can promote islet survival. Co-encapsulation of immune modulatory cells (including mesenchymal stem cells (MSCs), amniotic epithelial cells (AECs) and other accessory cells and factors) as well as extracellular matrix (ECM) proteins can aid immune isolation and islet survival. DAMP, damage-associated molecular pattern; NK cell, natural killer cell; T_reg cell, regulatory T cell.

Fig. 3 ∣. Direct vascularization scaffolds and open devices.

a, Simultaneous implant–transplant methods involve placing islets in permeable matrices or open scaffolds, relying on the host’s vascular connections. Approaches include embedding islets in matrices that deliver pro-angiogenic factors and accessory cells such as endothelial cells and mesenchymal stem cells in hydrogels or collagen matrices. Some methods utilize microvascular fragments for faster integration, while 3D printing creates structures that mimic natural tissue architecture. Decellularized tissues can also be used as scaffolds. b, Prevascularization techniques establish a vascular network prior to transplantation to improve outcomes. Both temporary and permanent devices are being explored, with some using methacrylic acid to reduce hypoxia and fibrosis, while minimizing immune response.