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Evaluation of vascularization and immunomodulation potential of islet/MSC scaffolds implanted in a nonhuman primate model

Cherie L. Stabler^1,2,3, Melissa A. Willman¹, Steven Sukert¹, Alexander Rabassa¹, Eileen Pedraza^1,2, Ann-Christine Brady³, Norman Kenyon¹, Camillo Ricordi^1,2,3,5, Dora M. Berman^1,3, Norma S. Kenyon^1,2,3,4,5

¹Diabetes Research Institute; ²Biomedical Engineering; ³Department of Surgery; ⁴Department of Microbiology and Immunology; ⁵Department of Medicine, University of Miami, Miami, FL, United States

Mesenchymal stem cells (MSC) have been demonstrated to modulate immunity, limit fibrosis, and enhance angiogenesis and tissue repair. Co-infusion of MSCs and islets into the liver has been shown to enhance islet engraftment and function in a nonhuman primate (NHP) model. To explore the potential of the co-localization of NHP MSCs with islets in improving islet engraftment, biomaterial scaffolds were employed. We pre-cultured MSCs onto macroporous PDMS scaffolds 4-5 days prior to islet loading, evaluated growth, viability, and phenotype of MSCs during pre-culture, and the effect of MSCs on islet viability (MTT assay) and function (glucose-stimulated-insulin-release). Finally, implantation of scaffolds with MSC + islets into baboons evaluated the effects of islet source (autologous or allogeneic), MSC source (autologous or 3rd party), and site (intramuscular, subcutaneous, or omental pouch) on the graft response. Scaffolds (islets + 3rd party MSCs, islets + recipient MSCs, islets only, 3rd party MSCs only, recipient MSCs only, and material only) were implanted into the three sites (n=3 each) for both an autologous and allogeneic (immunosuppressed) non-diabetic baboon. On day 21, scaffolds were explanted, sectioned, and stained. Particular focus was paid to extracellular matrix deposition (Masson’s Trichrome staining), local inflammation (CD3 and CD69 staining), and intra-implant vascularization (vWF and α-SMA staining). Preliminary assessment of engraftment at these three sites indicates a greater degree of cellular infiltration, fibrosis, and inflammation at the subcutaneous site. Overall, the presence of MSCs within the scaffold appears to dampen inflammation and fibrotic tissue deposition, when compared to scaffold only implants. Vascularization analysis for all found over a 7-fold increase in the 3rd party MSC+islets group vs empty silicone scaffold control. These results suggest a correlation between implantation site and positive engraftment and vascularization. Furthermore, localization of MSC to the site may enhance vascular tissue growth and engraftment. Authors acknowledge JDRF support.