Transplantation of pancreatic beta cells represents a possible treatment for diabetes. However, the supply of primary tissue from organ donors is too low to meet the demand of tissue that would be needed if the treatment were to become widely utilized. Regeneration of insulin producing cells would make a virtually unlimited supply to be made available. Protocols to differentiate stem cells and other progenitor cells into fully functional beta cells that sense and respond to changes in glucose with the appropriate secretion of insulin are under development by group within ISCRM and around the world. A major challenge is to be able confirm that cells produced in vitro function normally relative to a native beta cell. To do this requires 1. identification of the intrinsic and indispensible characteristics that beta cells require for function; and 2. methods to measure these characteristics.
We have developed novel microphysiological systems (MPS) that both culture tissue for extended periods of time needed for differentiation to occur, while continually assessing various functional and biochemical parameters. The MPS incorporates microfluidic systems, 3D printing and sophisticated optical methods to non-invasively interrogate tissue within the fluidics chamber. Using this system, we have characterized intracellular biochemical mechanisms that are critical to the control of insulin secretion. These involve metabolic pathways, calcium and a novel role for the transformation and translocation of the mitochondrial protein cytochrome c. The real time changes of these parameters in response to nutrients and hormonal stimulation of the beta cell are used as quantitative and objective criteria to evaluate the success of the differentiation protocol. The approach complements the use of animal model transplant recipients by reducing the length of time and cost it takes to evaluate the protocols, and by indicating specific biochemical inadequacies of the differentiated cells. Ultimately, the MPS systems, and the detailed functional analysis of primary cell and tissue types that the systems provide, will quicken the time before transplantable, fully functional beta cells will become available for the treatment of diabetics. The MPS approach also has similar utility to the development and assessment of cells and tissue important to cancer, liver and retinal disease and thus has broad fundamental and clinical impact.