Quantifying stem cell derived islet graft volume and composition with FDOPA positron emission tomography

Abstract

Stem cell derived islets (SC-islets) are being developed as a novel source of beta cells that would enable large scale cell replacement therapy for insulin dependent diabetes. Therapeutic use of SC-islets carries an inherent risk of unwanted growth; and multiple strategies are being explored for optimizing long-term SC-islet graft effectiveness. However, a method for noninvasive in vivo monitoring for SC-islet graft safety and efficacy is lacking, as current insulin secretion measurements are inadequate. Here, we demonstrate the potential of positron emission tomography (PET) for monitoring SC-islet grafts using two tracers: GLP1-receptor binding [18F]F-DBCO-exendin and dopamine precursor [18F]FDOPA. We could detect and longitudinally monitor human SC-islet grafts in calf muscles of immunocompromised mice. Importantly, graft volume quantified with PET strongly correlated with actual graft volume (r2=0.91 for [18F]F-DBCO-exendin). PET using [18F]F-DBCO-exendin allowed delineation of cystic structures and its uptake correlated with graft beta cell proportion, enabling study of SC-islet graft purity noninvasively. [18F]FDOPA performed similarly to [18F]F-DBCO-exendin, but with slightly weaker sensitivity. Uptake of neither tracer was biased in SC-islet grafts genetically rendered hyper- or hypoactive. Insulin secretion measurements under fasted, glucose-stimulated or hypoglycemic conditions did not correlate with graft volume. In conclusion, [18F]F-DBCO-exendin and [18F]FDOPA PET constitute powerful approaches to noninvasively assess SC-islet graft volume and composition regardless of their functionality. PET imaging could therefore be leveraged for optimizing safety and effectiveness of SC-islet grafts in patients with insulin dependent diabetes.