Ectonucleotidase Expression on Human Amnion Epithelial Cells: Adenosinergic Pathways and Dichotomic Effects on Immune Effector Cell Populations

Abstract

This study investigates the mechanism(s) underlying the immunoregulatory activities of placenta-derived human amnion epithelial cells (hAEC). The working hypothesis is that NAD + and ATP, along with ectoenzymes involved in their metabolism, play a significant role in hAEC-mediated immune regulation. Proof of principle of the hypothesis was obtained by analyzing the interactions between hAEC and the main human leukocyte populations. The results obtained indicate that hAEC constitutively express a unique combination of functional ectoenzymes, driving the production of adenosine (ADO) via canonical (CD39, CD73) and alternative (CD38, CD203a/PC-1, CD73) pathways. Further, the picture is completed by the observation that hAEC express A1, A2a, and A2b ADO receptors as well as ADO deaminase, the enzyme involved in ADO catabolism. The contribution of the purinergic mediator to immunomodulation was confirmed by exposing in vitro different immune effector cells to the action of primary hAECs. B cells showed an enhanced proliferation and diminished spontaneous apoptosis when in contact with hAEC. T cell proliferation was partially inhibited by hAEC through ADO production, as confirmed by using specific ectoenzyme inhibitors. Further, hAEC induced an expansion of both T and B regulatory cells. Last, hAEC inhibited NK cell proliferation. However, the involvement of ADO-producing ectoenzymes is less apparent in this context. In conclusion, hAEC exert different in vitro immunoregulatory effects, per se, as a result of interactions with different populations of immune effector cells. These results support the view that hAEC are instrumental for regenerative medicine as well as in therapeutic applications for immune-related diseases.

Human Amniotic Epithelial Cells Affect the Functions of Neutrophils

“…In the case of phagocytosis, of note, by decreasing the ratio of HAECs：neutrophils, the phagocytic activity increased, as we observed the lowest and highest level of phagocytosis, respectively at the highest and lowest ratio of HAECs to neutrophils. These incompatible findings may be due to the fact that HAECs differentially regulate different populations of immune cells as it has been presented recently (26,27).…”

CD38, a Receptor with Multifunctional Activities: From Modulatory Functions on Regulatory Cell Subsets and Extracellular Vesicles, to a Target for Therapeutic Strategies

“…In that seminal study, hAECs were proven able to suppress T-cell proliferation in vitro through a mechanism, at least in part, related to ADO production (as witnessed by the recovery of T cell proliferation when specific inhibitors of adenosinergic ecto-enzymes were provided). Moreover, ADO may be responsible for the expansion of regulatory T and B cells induced by co-culture of hAEC with PBMNC from normal donors [68]. Thus, we delineated a novel role for CD38 in the context of hAEC-mediated modulation of immune response; that needs to be taken into account in the view of clinical applications for the latter cells.…”

Evaluation of different routes of administration and biodistribution of human amnion epithelial cells in mice

“…We analyzed the ectoenzymes expressed by hAEC; CD39, CD38, and CD73, ectoenzymes that play vital roles in modulation of the host immune system (85). Along with the other immune-suppressive molecules, adenosine (ADO) has been identified as an important immunomodulator.…”