The effect of mesenchymal stem cells and surgical angiogenesis on immune response and revascularization of acellular nerve allografts in a rat sciatic defect model

Abstract

Increasing evidence demonstrates an interplay between neoangiogenesis and immune cells. We investigated the immune response and revascularization of acellular nerve allografts (ANA) after combined stem cell delivery and surgical angiogenesis in a rat model. Unilateral sciatic nerve defects in 60 Lewis rats were repaired with (I) autografts, (II) ANAs, and (III) ANAs wrapped within a pedicled superficial inferior epigastric artery fascial flap to induce surgical angiogenesis, combined with seeding of either (IV) undifferentiated mesenchymal stem cells (uMSCs) or (V) MSCs differentiated into Schwann cell-like cells. Immune cell phenotyping was performed on days 7 and 14. The vascular volume of nerves was measured by microcomputed tomography at 12 and 16 weeks. On day 7, helper T cells (CD4+) were significantly increased in groups IV and V compared to group I. Regulatory T cells (CD4+CD25+) were significantly higher in groups III-IV, and cytotoxic T cells (CD8+) were significantly reduced in groups IV and V compared to group II, respectively. Group II demonstrated the highest levels of natural killer cells (CD161+) compared to groups III-V. On day 14, group IV demonstrated the highest CD4/CD8 ratio. Vascular volume was significantly higher in groups III-V compared to group II at 12 weeks and groups IV and V compared to group II at 16 weeks. The CD4/CD8 ratio demonstrated a positive correlation to vascular volumes at 12 weeks. Early favorable immune responses were observed in ANAs treated with surgical angiogenesis with or without stem cell delivery and demonstrated improved vascularity at longer follow-up.