Stem-cell-derived beta cells mature metabolically upon murine engraftment.

aims/hypothesisThe use of stem-cell-derived islets (SC-islets) as a source for cell-based therapy of type 1 diabetes shows great potential. However, SC-islets have a metabolically immature phenotype compared with primary human islets, the current 'gold standard' cell therapy. SC-islet metabolic immaturity is most evident in their aberrant reactivity to pyruvate, which could be associated with clinically significant dysregulation of insulin secretion. We thus aimed to study whether this immature metabolic phenotype persists upon engraftment in mice.

methodsThis study was conducted by differentiating the H1 human embryonic stem-cell line into pancreatic islets (SC-islets) using a well-established seven-stage differentiation protocol. SC-islets were implanted under the kidney capsule of immunocompromised NOD-scid-gamma mice for 1-4 months. Metabolic and morphological assays of SC-islets pre- and post-implantation were performed (in parallel to cadaveric donor islets) using LC-MS metabolomics, electron microscopy, immunohistochemistry analyses and dynamic insulin secretion assays.

resultsSC-islets had the capability of dynamically controlling mouse blood glucose levels by 3 months post-implantation. Murine engraftment led to maturation of various metabolic aspects of SC-islets, leading them to resemble human donor islets more closely. Mitochondrial number increased from a mean of 0.38 mitochondria/µm CONCLUSIONS/

interpretationAn in vivo environment is beneficial for the metabolic maturation of SC-islets, leading them to more closely resemble human donor islets. We show that the aberrant metabolite trafficking pathways seen in SC-islets are robustly diminished following engraftment. Our results suggest that metabolic dysregulation is not a major safety concern for clinical SC-islet implantation after prolonged periods of engraftment.