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

Area of Science:

• Endocrinology and Metabolism
• Regenerative Medicine
• Diabetes Research

Background:

• Stem-cell-derived islets (SC-islets) show promise for type 1 diabetes therapy but exhibit metabolic immaturity compared to human islets.
• This immaturity, particularly aberrant pyruvate reactivity, may impair insulin secretion and clinical efficacy.
• Investigating SC-islet maturation post-engraftment is crucial for assessing their therapeutic potential.

Purpose of the Study:

• To determine if the immature metabolic phenotype of SC-islets persists after in vivo engraftment.
• To assess the metabolic and functional maturation of SC-islets in a murine model.
• To evaluate the safety and efficacy of SC-islets for cell-based diabetes therapy.

Main Methods:

• Human embryonic stem cells were differentiated into SC-islets.
• SC-islets were implanted into immunocompromised mice for 1-4 months.
• Metabolic and functional analyses (metabolomics, electron microscopy, insulin secretion assays) were performed pre- and post-implantation.

Main Results:

• Engrafted SC-islets improved glucose control in mice within 3 months.
• Metabolic maturation was observed, with increased mitochondrial content and enhanced glucose-sensitive insulin secretion.
• Aberrant pyruvate reactivity decreased, and pyruvate/lactate transporter (MCT1) expression was downregulated.

Conclusions:

• The in vivo environment promotes significant metabolic maturation of SC-islets.
• Engraftment diminishes aberrant metabolite trafficking, making SC-islets more similar to human islets.
• Metabolic dysregulation is unlikely to be a safety concern for SC-islet therapy after prolonged engraftment.