Stem cell-derived β-cells in diabetes: The role of transplant sites in controlling off-target cell growth.

Abstract

Type 1 diabetes (T1D) results destruction of pancreatic β-cells by the immune system, leading to chronic hyperglycaemia and reliance on insulin therapy. Current treatments, including insulin replacement, islet transplantation, and pancreas transplantation, do not fully restore normoglycemia and have their own complications and limitations. Stem cell-derived β-cells offer a promising alternative by providing a potentially unlimited source of insulin-producing cells. However, the safety is challenged by the risk of off-target cell growth, including teratoma formation, non-endocrine off-target cell differentiation, and oncogenic mutations. This review examines the role of transplant sites in minimizing off-target cell growth in stem cellderived β-cell therapies for T1D. The microenvironment of each transplant site influences the safety of the cell product with factors such as oxygen tension, extracellular matrix (ECM) composition, vascularization, and local cell signalling. Evaluated sites include the liver, subcutaneous space, intramuscular tissue, subfascial region, gonadal fat pad, omentum, intrabone marrow, and gastric submucosa. Among the analysed sites, subfascial implantation under the anterior rectus sheath, gives the most promising outcomes. This site supports vascularization and β-cell maturation while exhibiting a low incidence of off-target cell growth. Both animal and human studies confirm its efficacy in preventing teratoma formation and off-target cell differentiation, making it a good candidate for clinical application. The intramuscular space is also a promising site due to its capacity to support cell survival and minimize tumour formation, although some cases of teratoma formation have been found at this site. Conversely, intrahepatic transplantation, despite being a common choice, poses significant risks due to the liver’s regenerative and immune-modulating properties, which can foster tumour growth and teratoma formation. The subcutaneous space, while accessible, presents challenges related to low vascularization and hypoxia, increasing the likelihood of off-target cell persistence and impaired β-cell function. This essay concludes that careful selection of the transplant site is crucial to enhance the safety of stem cell-derived β-cell therapy in T1D. The subfascial and intramuscular sites provide optimal environments for reducing off-target cell growth and ensuring the functional integration of transplanted cells.