Despite improved treatment, diabetes remains a chronic disease with major health risks and heavy burden on patients and society. Serious forms are caused by depletion in pancreatic beta cells and subsequent loss of glucose control through regulated insulin release. Their cure requires replacement by a metabolically adequate beta cell mass. Islet cell grafts prepared from human donor pancreases can correct a diabetic state in patients, but variable quality and organ shortage indicates the need for large-scale sources of therapeutic cells as might be generated by human stem cells. The objective of this project was to identify conditions under which a functional beta cell mass can be established in device-encapsulated human pluripotent stem cell (hu-PSC)-derived implants in type 1 diabetes patients.
Studies in preclinical models served to identify components in grafts and in environment of implants that influence outcome. State-of-the art methods were used to investigate the biology of implants and assess their functional effect. The formation and maturation of the beta cell mass was followed in time and compared with characteristics of human donor pancreatic beta cells in clinical grafts. Markers for monitoring host immune and innate reactivity to the implants were defined. In the perspective of autografts, a preclinical study line with hu-PSC-derived cells produced from type 1 diabetes patients was included.
The preclinical studies guided phase 1 and phase 2 clinical trials with device-encapsulated hu-PSC-derived pancreatic endoderm that was placed in the subcutis of patients. This translational project led to the first report in literature on a beneficial effect of a stem cell product in type 1 diabetic patients, and thus provided proof-of-principle for its therapeutic potential. In vivo data on metabolic outcome were correlated with in situ analysis of retrieved implants. The combination of clinical and preclinical data indicated causes for failure and targets for improvement. It also contributed knowledge to the physio(patho)logy of human beta cells in an ectopic micro-organ and its use for developing beta cell replacement therapies.
