2429-P: Unlicensed vs. Licensed Mesenchymal Stromal Cells: Impact on Subcutaneous Vascularization and Neonatal Porcine Islet Engraftment and Function

Introduction and Objective: Islet transplantation can reverse hyperglycaemia, but poor engraftment limits long-term success. The subcutaneous (SC) space is accessible but poorly vascularized, limiting islet survival. Mesenchymal stromal cells (MSCs) enhance angiogenesis; cytokine exposure (licensing) further enhances their potential. We aimed to determine if unlicensed or licensed MSCs improve SC vascularization and neonatal porcine islet (NPI) engraftment and diabetes reversal. Methods: Human pancreatic MSCs were unmodified or licensed for 24h with TNF-α, IL-1β, and IFN-γ (10 ng/mL). PLGA+gelatin (PLGA+G) scaffolds were implanted SC as controls or coated with 5×106 MSCs: unlicensed (PGM) or licensed (PGSM). Vascularization was assessed 2 weeks post-implantation by FITC-lectin injection. Streptozotocin-diabetic immunodeficient mice received 3000 NPIs into the pre-vascularized niche. Efficacy outcomes included vascular metrics and diabetes reversal; ANOVA and log-rank tests were applied. Results: Licensing increased MSC expression of CXCL1/5/6/8, FGF2, and VEGF (all p<0.01). PGM and PGSM increased vessel area/mm² (PGM p=0.0138; PGSM p<0.0001) and vessel number/mm² (PGM p=0.0011; PGSM p<0.0001) versus PLGA+G, with PGSM being significantly higher than PGM for all metrics. Lectin+ (PGM p=0.0029; PGSM p<0.0001), CD31+ (PGM p<0.0001; PGSM p<0.0001), and SMA+ cells (PGM p<0.0001; PGSM p<0.0001) followed the same pattern. PGM improved diabetes reversal (10/12 vs 4/12 in PLGA+G; p=0.0139) and reduced reversal time (14 vs 22 weeks; p=0.0177). PGSM did not improve diabetes reversal (p>0.05) compared to PLGA+G. Conclusion: Both PGM and PGSM enhanced SC vascularization, with PGSM producing the highest vascular density. However, only PGM improved NPI engraftment and diabetes reversal, indicating that further work is needed to translate vascular gains into functional improvements. These findings support the use of MSCs to enhance SC transplantation for diabetes therapy. Disclosure N. Cuesta Gomez: None. A. Bose: None. P. Kuppan: None. J. Paramor: None. C. Castro: None. M. Rosko: None. A. Pepper: Consultant; Current; Encellin, Inc. Stock/Shareholder; Current; Transcyto Therapeutics. G.S. Korbutt: None.