Pluripotent Stem Cell-Derived Hepatocytes Inhibit T Cell Proliferation In Vitro through Tryptophan Starvation

Abstract

Regenerative medicine aims to replace damaged tissues by stimulating endogenous tissue repair or by transplanting autologous or allogeneic cells. Due to their capacity to produce unlimited numbers of cells of a given cell type, pluripotent stem cells, whether of embryonic origin or induced via the reprogramming of somatic cells, are of considerable therapeutic interest in the regenerative medicine field. However, regardless of the cell type, host immune responses present a barrier to success. The aim of this study was to investigate in vitro the immunological properties of human pluripotent stem cell (PSC)-derived hepatocyte-like cells (HLCs). These cells expressed MHC class I molecules while they lacked MHC class II and co-stimulatory molecules, such as CD80 and CD86. Following stimulation with IFN-γ, HLCs upregulated CD40, PD-L1 and MHC class I molecules. When co-cultured with allogeneic T cells, HLCs did not induce T cell proliferation; furthermore, when T cells were stimulated via αCD3/CD28 beads, HLCs inhibited their proliferation via IDO1 and tryptophan deprivation. These results demonstrate that PSC-derived HLCs possess immunoregulatory functions, at least in vitro.

The immunological profile of RC17 hESC-derived dopaminergic neural progenitor cellsin vitro: implications for the STEM-PD clinical trial

“…However, NPC-mediated suppression of T-cells was not inhibited by the addition of TFGβR1 or TFGβR2 inhibitors (Sup Figure 6J). IDO-1/TDO-mediated catabolism of tryptophan to kynurenine is a well-reported mechanism of suppression in other PSC-derived products 55,56 . While the NPCs did not express IDO-1 or TDO at baseline, they did upregulate IDO-1 expression following exposure to IFNγ (Sup Figure 6K) so this mechanism was tested, in case IFN-treated NPCs employ a different mechanism of suppression to the untreated cells.…”

Generation of Highly Functional Hepatocyte-like Organoids from Human Adipose-Derived Mesenchymal Stem Cells Cultured with Endothelial Cells

“…Similar to other stem cell-derived products, H-organoids express MHC-I molecules. However, in the study by Romano et al, although these cells expressed MHC class I molecules, CD8+ T cells were not activated, possibly due to the lack of immune co-recognition molecules [ 22 ]. In contrast to the increased immunogenicity reported with the differentiation of MSCs into cardiomyocytes, chondrocytes, and osteocytes [ 23 , 24 , 25 ], our H-organoids still lack the expression of the immune co-recognition molecules CD40, CD80, and CD86.…”

“…Of course, further evaluation of the immunomodulatory capacity of H-organoids is still needed. In addition, because in vivo environments will be significantly different from in vitro environments, experiments in in vivo models should be carried out to further test the immune properties of these cells [ 22 , 26 , 27 ].…”

Soluble Collectin 11 (CL-11) Acts as an Immunosuppressive Molecule Potentially Used by Stem Cell-Derived Retinal Epithelial Cells to Modulate T Cell Response

“…Lightly pigmented areas of RPE appeared as early as week three in culture, and RPE cell cultures were fed every two days. For some experiments, RPE cells were treated with 500 IU/mL of recombinant hIFN-γ (rhIFN- γ, R&D System, Minneapolis, MN, USA) for three days or under hypoxic conditions for 24 h as previously described [ 24 , 31 ]. For detection of cell surface markers, RPE cells were treated with TrypLE Express enzyme solution (Thermo Fisher Scientific, Waltham, MA, USA) for 10 min, and single-cell suspensions were stained with LIVE/DEAD™ Fixable Near-IR Dead Cell Stain Kit according to the manufacturer’s instructions (Thermo Fisher Scientific, Waltham, MA, USA).…”