Regenerative macrophages enhance stem cell-derived β cell function and engraftment.

Area of Science:

• Regenerative Medicine
• Stem Cell Biology
• Endocrinology

Background:

• Stem cell-derived beta cells (SC-β cells) show promise for type 1 diabetes treatment.
• Challenges remain in achieving functional maturity and insulin secretion comparable to endogenous cells.
• Macrophages play a crucial role in pancreatic islet development.

Purpose of the Study:

• To investigate the effect of macrophages on SC-β cell differentiation and function.
• To determine if polarized macrophages can enhance SC-β cell maturity and insulin secretion.

Main Methods:

• Human embryonic or induced pluripotent stem cells were differentiated into SC-β cells.
• Autologous SC-macrophages (unpolarized, inflammatory, or regenerative) were coaggregated during stage 7 differentiation.
• SC-β cell maturity markers, glucose-stimulated insulin secretion, and metabolic activity were assessed.
• SC-β cells coaggregated with SC-macrophages were transplanted into diabetic mice.

Main Results:

• Regenerative macrophages (SC-M_Regs) significantly improved SC-β cell maturity marker expression.
• SC-M_Regs enhanced glucose-stimulated insulin secretion and metabolic activity in SC-β cells.
• Transplantation of SC-β cells with SC-M_Regs led to faster glycemia normalization in diabetic mice compared to SC-β cells alone.

Conclusions:

• Co-aggregation with regenerative macrophages accelerates the functional maturation of stem cell-derived beta cells.
• This macrophage-assisted differentiation strategy represents a significant advancement for SC-β cell therapy in type 1 diabetes.
• Macrophages can be leveraged to improve the production of functional SC-β cells for regenerative medicine.