Divergent cell-type specific hypoxia responses in human stem cell-derived and primary islets

Area of Science:

• Cell biology
• Regenerative medicine
• Diabetes research

Background:

• Type 1 diabetes treatment relies on replacing lost insulin-producing beta cells.
• Stem cell-derived islets (SC-islets) offer a promising alternative to primary islets for transplantation.
• Graft survival is a major hurdle in SC-islet therapy, particularly in the low-oxygen (hypoxic) environment after transplantation.

Purpose of the Study:

• To comparatively analyze the response of human SC-islets and primary human islets to acute hypoxia.
• To identify transcriptomic and functional differences in islet responses to hypoxic stress.
• To understand the mechanisms underlying SC-islet vulnerability in transplantation.

Main Methods:

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

Main Results:

• Primary islets adopted an energy-conserving, quiescent state under hypoxia.
• SC-islets displayed lineage instability, increased glycolysis, and activated pro-apoptotic pathways.
• Both islet types lost glucose-stimulated insulin secretion, but via distinct mechanisms.

Conclusions:

• SC-islets are uniquely vulnerable to acute hypoxic stress, showing a plastic and unstable phenotype.
• Hypoxia-induced dysfunction in SC-islets differs significantly from primary islets.
• Targeted strategies are needed to improve SC-islet resilience to hypoxia for effective diabetes cell therapy.