Intrasplenic Transplantation of Islets With a Platelet Shielding System Restores Glycemic Control

Area of Science:

• Regenerative Medicine
• Transplantation Biology
• Diabetes Research

Background:

• Intraportal islet transplantation is clinically validated for diabetes but limited by liver's hypoxic environment and sinusoidal structure.
• Transplanted islets face poor survival and loss of therapeutic effect within one year in the liver.
• The spleen offers a more oxygen-rich environment but suffers from instant blood-mediated inflammatory reactions (IBMIRs) and low extracellular matrix (ECM).

Purpose of the Study:

• To develop a novel strategy for enhancing islet survival and engraftment in the spleen for long-term diabetes treatment.
• To overcome the limitations of the spleen's inflammatory environment and low ECM for islet transplantation.
• To reduce the critical islet dose required for successful transplantation.

Main Methods:

• Developed constructs of islets encapsulated by hepatocytes and fibroblasts.
• Utilized low von Willebrand factor expression in hepatocytes to form a protective coating, reducing IBMIRs.
• Leveraged ECM production by fibroblasts to support islet survival and vascularization.

Main Results:

• Hepatocyte-fibroblast encapsulation significantly reduced islet mortality during the posttransplantation stress period.
• Achieved rapid islet engraftment and vascularization in the mouse spleen.
• Demonstrated long-term (>1 year) islet survival and sustained glycemic regulation in the spleen's high-oxygen environment.
• Significantly lowered the critical islet dose required for transplantation.

Conclusions:

• The live cell-shielding strategy using hepatocyte-fibroblast encapsulation is a novel approach for islet transplantation.
• This method effectively mitigates IBMIRs and supports islet survival in the spleen.
• The technique shows promising clinical potential for functional islet regeneration and long-term diabetes management.