Fas Ligand-Modified Scaffolds Protect Stem Cell Derived β-Cells by Modulating Immune Cell Numbers and Polarization.

Abstract

Stem cell derived β-cells have demonstrated the potential to control blood glucose levels and represent a promising treatment for Type 1 diabetes (T1D). Early engraftment post-transplantation and subsequent maturation of these β-cells are hypothesized to be limited by the initial inflammatory response, which impacts the ability to sustain normoglycemia for long periods. We investigated the survival and development of immature hPSC-derived β-cells transplanted on poly(lactide-co-glycolide) (PLG) microporous scaffolds into the peritoneal fat, a site being considered for clinical translation. The scaffolds were modified with biotin for binding of a streptavidin-FasL (SA-FasL) chimeric protein to modulate the local immune cell responses. The presence of FasL impacted infiltration of monocytes and neutrophils and altered the immune cell polarization. Conditioned media generated from SA-FasL scaffolds explanted at day 4 post-transplant did not impact hPSC-derived β-cell survival and maturation in vitro, while these responses were reduced with conditioned media from control scaffolds. Following transplantation, β-cell viability and differentiation were improved with SA-FasL modification. A sustained increase in insulin positive cell ratio was observed with SA-FasL-modified scaffolds relative to control scaffolds. These results highlight that the initial immune response can significantly impact β-cell engraftment, and modulation of cell infiltration and polarization may be a consideration for supporting long-term function at an extrahepatic site.