Subcutaneous cell sheet transplantation as a superior strategy to intraportal route for induced pluripotent stem cell-derived pancreatic islet cells therapy

Introduction: Stem cell–derived islets are a promising alternative cell source for transplantation therapy in insulin-dependent diabetes mellitus; however, the optimal transplantation strategy remains unclear. Subcutaneous transplantation has attracted attention due to its favorable safety profile. Orizuru Therapeutics, Inc. developed a unique sheet method using induced pluripotent stem cell–derived pancreatic islet cells (iPICs) designed for subcutaneous transplantation. We aimed to compare the method with conventional method and elucidate the underlying mechanism.
Methods: Streptozotocin-induced diabetic NOD-SCID mice received iPICs. We compared subcutaneous sheet transplantation (SQ-sheet group) with intraportal transplantation (PV group). We measured blood glucose, serum human C-peptide (hCp), ketone levels, and performed histological analyses. To assess the roles of scaffold support and angiogenesis in subcutaneous transplantation, we additionally performed subcutaneous injection of iPICs suspension without a sheet (SQ-cell group) and sheet transplantation combined with anti-human VEGFA antibody treatment (anti h-VEGFA group).
Results: Normoglycemia was achieved in all mice in the SQ-sheet group and in 81.8% of mice in the PV group, indicating a higher functional success rate with subcutaneous sheet transplantation. The SQ-sheet group also showed higher circulating hCp levels. Blood ketone levels decreased from the early post-transplant period in both groups, reflecting metabolic recovery. In subcutaneous comparison experiments, normoglycemia was achieved in 22.2% of mice in the SQ-cell group and in 60% of mice in the anti h-VEGFA group. Histological analysis showed VEGFA-positive iPICs adjacent to mouse CD31-positive endothelial cells, suggesting intrinsic angiogenic potential.
Conclusion: Subcutaneous sheet transplantation of iPICs demonstrated superior engraftment efficiency compared with intraportal transplantation. Enhanced angiogenesis and effective scaffold support may underlie these findings. This strategy may contribute to improved diabetes therapy and broader applications of stem cell–based regenerative medicine.