Abstract
One of the main challenges in liver cell therapy (LCT) is the induction of a tolerogenic microenvironment to promote graft acceptance in the recipient. Little is known about the immunomodulatory potential of the hepatic cells used in liver cell therapy. In this work, we wanted to evaluate the immunosuppressive properties of human hepatocytes and adult-derived human liver stem/progenitor cells (ADHLSCs), as well as the potential involvement of the immunomodulatory molecule HLA-G. We demonstrated that both cell types were capable of inhibiting the proliferative response of PBMCs to an allogenic stimulus and that the immune inhibitory potential of ADHLSCs, although lower than that of hepatocytes, increased after hepatogenic differentiation. We demonstrated that liver cells express HLA-G and that the immune inhibition pattern was clearly associated to its expression. Interestingly, HLA-G expression increased after the third step of differentiation, wherein oncostatin M (OSM) was added. A 48 hr treatment with OSM was sufficient to induce HLA-G expression in ADHLSCs and result in immune inhibition. Surprisingly, blocking HLA-G partially reversed the immune inhibition mediated by hepatocytes and differentiated ADHLSCs, but not that of undifferentiated ADHLSCs, suggesting that additional immune inhibitory mechanisms may be used by these cells. In conclusion, we demonstrated that both hepatocytes and ADHLSCs present immunomodulatory properties mediated, at least in part, through HLA-G, which can be upregulated following hepatogenic differentiation or liver cell pretreatment with OSM. These observations open up new perspectives for the induction of tolerance following LCT and for potential therapeutic applications of these liver cells.
Highlights
One of the main challenges in cell therapy is the induction of a tolerogenic microenvironment which would help promote graft acceptance in the recipient
The adult-derived human liver stem/progenitor cells (ADHLSCs) used in this study presented the typical characteristics previously described by our group: expression of CD73, CD90 CD105, Human leukocyte antigen (HLA)-ABC, and albumin; absence of CD45, CD40, CD86, HLA-DR, cytokeratin 7 (CK7), and CK19; and the capacity to differentiate into hepatocyte-like cells, characterized by round- or polygonal-shaped cells reduced in size, containing cytoplasmic granulations and central nucleus with prominent nucleolus, when subjected to a specific differentiation protocol
Following hepatogenic differentiation in vitro, the level of immune inhibition induced by ADHLSCs reached a level similar to that seen with the hepatocytes
Summary
One of the main challenges in cell therapy is the induction of a tolerogenic microenvironment which would help promote graft acceptance in the recipient. Because of limited hepatocyte availability and viability, other cell sources are under development for liver cell transplantation, including adult-derived human liver stem/progenitor cells (ADHLSCs) [1] These cells, characterized by a hepatic origin and a mesenchymal phenotype, present the advantage of a high proliferative capacity and the ability to differentiate into functional hepatocyte-like cells in vitro and in vivo [2,3,4]. Several soluble factors have emerged as key molecules in MSCs’ immunomodulatory properties, including HLA-G, IL-10, IDO, PGE2, INOS, and TGF-β [8] Among these immunosuppressive factors, HLA-G has been described to play a role in both the induction of tolerance following allogeneic transplantation and in MSC-mediated immunosuppression [10, 11]
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