Divergent Cell-Type Specific Hypoxia Responses in Human Stem Cell-Derived and Primary Islets

Area of Science:

• Endocrinology
• Regenerative Medicine
• Cell Biology

Background:

• Type 1 diabetes (T1D) therapies using stem cell-derived islets (SC-islets) face challenges due to poor graft survival in the low-oxygen (hypoxic) post-transplantation environment.
• Previous studies focused on chronic hypoxia; a direct comparison of SC-islets and primary human islets during acute hypoxia was lacking.

Purpose of the Study:

• To comparatively analyze the transcriptomic and functional responses of human SC-islets and primary islets to acute hypoxia.
• To identify differences in cellular behavior and vulnerability under hypoxic stress.

Main Methods:

• Single-cell transcriptomic analysis of SC-islets and primary islets.
• Functional assessment of glucose-stimulated insulin secretion.
• Exposure to acute hypoxia (1% O2) for 48 hours.

Main Results:

• Primary islets adopted an energy-conserving response, downregulating identity genes and pro-apoptotic factors, shifting towards metabolic quiescence.
• SC-islets displayed lineage instability, increased glycolysis, and activated pro-apoptotic pathways.
• Both islet types lost glucose-stimulated insulin secretion, but primary islets showed suppressed secretion while SC-islets had dysregulated, unresponsive release.

Conclusions:

• SC-islets are uniquely vulnerable to hypoxic stress, exhibiting unstable and plastic phenotypes.
• The findings highlight the need for source-specific strategies to mitigate hypoxic damage and enhance cell replacement therapy for T1D.