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Ectonucleotidase Expression on Human Amnion Epithelial Cells

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Ectonucleotidase Expression on Human Amnion Epithelial Cells Ectonucleotidase Expression on Human Amnion Epithelial Cells: Adenosinergic Pathways and Dichotomic Effects on Immune Effector Cell Populations This information is current as of September 28, 2021. Fabio Morandi, Alberto L. Horenstein, Valeria Quarona, Angelo Corso Faini, Barbara Castella, Raghuraman C. Srinivasan, Stephen C. Strom, Fabio Malavasi and Roberto Gramignoli J Immunol published online 26 December 2018 Downloaded from http://www.jimmunol.org/content/early/2018/12/23/jimmun ol.1800432 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2018/12/23/jimmunol.180043 Material 2.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published December 26, 2018, doi:10.4049/jimmunol.1800432 The Journal of Immunology Ectonucleotidase Expression on Human Amnion Epithelial Cells: Adenosinergic Pathways and Dichotomic Effects on Immune Effector Cell Populations Fabio Morandi,*,1 Alberto L. Horenstein,†,‡,x,1 Valeria Quarona,† Angelo Corso Faini,† Barbara Castella,† Raghuraman C. Srinivasan,{ Stephen C. Strom,{ Fabio Malavasi,†,x,2 and Roberto Gramignoli{,2 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 Downloaded from 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 http://www.jimmunol.org/ 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. The Journal of Immunology, 2019, 202: 000–000. tem cells have gained acceptance in cell-based therapies, medicine. The placental membrane in direct contact with the fetus and their “off-the-shelf” availability has been recognized is a tissue of fetal origin (amnion) and has been used in a variety S as being essential for the emerging field of regenerative of disorders (1, 2). Amnion tissue consists of cuboidal epithelial by guest on September 28, 2021 cells firmly adherent to a thick basal membrane and an abundant extracellular matrix with interspersed fibroblast-like cells. To our *UOC Laboratorio Cellule Staminali post natali e Terapie Cellulari, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; †Laboratory of Immunogenetics, Department knowledge, our group was the first to identify and describe the of Medical Sciences, University of Torino, 10126 Torino, Italy; ‡Immunologia dei nature of stem cells of human amnion epithelial cells (hAEC) (3). Trapianti, Citta` della Salute e della Scienza, 10126 Torino, Italy; xCentro di Ricerca { We developed efficient techniques to isolate hAEC with epithelial in Medicina Sperimentale, Universita` di Torino, 10126 Torino, Italy; and Depart- ment of Laboratory Medicine, Division of Pathology, Karolinska Institutet, SE-171 characteristics and a heterogeneous expression of membrane sur- 76 Stockholm, Sweden face Ags (4). The hAEC phenotype includes classic epithelial 1F. Morandi and A.L.H. equally contributed as first authors. adhesion molecules, such as EpCAM (CD325) and integrin sub- 2F. Malavasi and R.G. equally contributed as last authors. units (CD29 and CD49f). On the contrary, markers routinely used ORCIDs: 0000-0002-2849-7595 (F. Morandi); 0000-0002-0382-0595 (A.L.H.); to define and identify stromal cells are not detectable (4, 5). 0000-0003-2193-4577 (A.C.F.); 0000-0002-5880-2263 (B.C.); 0000-0003-3378- The surface markers commonly observed on embryonic stem cells 5169 (R.C.S.); 0000-0002-1844-174X (F. Malavasi); 0000-0003-3362-4170 (R.G.). (e.g., globoseries glycolipids SSEA-3 and -4 and keratansulfate- Received for publication March 28, 2018. Accepted for publication November 20, associated Ags TRA 1-60 and 1-81) are consistently expressed, 2018. perhaps contributing to their multilineage differentiation potential This work was supported by a grant from the National PKU Alliance and Ruth and Richard Julins Foundation to R.G. and a grant from the Compagnia di San Paolo to (1, 3, 6). Unlike pluripotent cells, hAEC are not immortal; they do F. Malavasi. Work in Genoa was supported by the Ministero del Lavoro, della not express telomerase and maintain a normal karyotype, without Salute e delle Politiche Sociali (Progetti di Ricerca Corrente). Work in Torino resulting in tumor formation upon transplantation (3, 7). hAEC have was supported by the Fondo per gli Investimenti della Ricerca di Base (Rome, Italy), Fondazione Ricerca Molinette, and Fondazione CRT (both in Torino, Italy). shown preclinical and clinical efficacy (1, 8). Over the past years, Address correspondence and reprint requests to Dr. Fabio Morandi, UOC Laboratorio hAEC have been suggested as a useful cell type for the treatment of Cellule Staminali post natali e Terapie Cellulari, Istituto Giannina Gaslini, Via Gaslini 1, different life-threatening models of inborn error of diseases (9–11). 16148 Genoa, Italy. E-mail address: [email protected] The results on transplants confirmed that hAEC are capable of a The online version of this article contains supplemental material. functional maturation into hepatic cells in addition to their char- Abbreviations used in this article: ACN, acetonitrile; ADA, ADO deaminase; ADO, acteristic immune-modulatory and anti-inflammatory properties adenosine; ADOR, ADO receptor; ADPR, ADP ribose; Breg, regulatory B cell; EICC, enzyme immunocytochemical; b-GP, b-glycerophosphate; hAEC, human am- (12). In fact, the same cells maintain immunosuppressive properties nion epithelial cell; MRFI, mean relative of fluorescence intensity; PB, peripheral in animal models of autoimmune/inflammatory disease (13–15). blood; rhEGF, recombinant human epidermal growth factor; TPP, thiamine pyrophos- Their safety and the absence of immune rejection were confirmed phate; Treg, regulatory T cell. after transplantation in immune-competent mouse models as well as Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$37.50 in human volunteers and patients (16–18). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800432 2 REGULATORY FUNCTION OF AMNION EPITHELIAL CELLS Mismatches in HLA expression are recognized by immune Flow cytometry cells and are generally followed by rejection. The characteristic Evaluation of surface expression of ectoenzymes was performed on expression of noncanonical HLA-Ib (i.e., HLA-G) was proposed as hAEC by means of anti-CD39 PE-Cy7 mAb (eBiosciences) and a a possible explanation for long-term engraftment and survival of panel of mAbs generated in our laboratory and FITC or allophycocyanin hAEC in allogenic or xenogenic settings (12). Among immuno- conjugates by Aczon (Bologna, Italy): anti-CD38 (clone IB4), anti- suppressive molecules, adenosine (ADO) has been recently iden- CD73 (clone CB73), anti-CD203a/PC-1 (clone 3E8, kindly pro- vided by J. Goding), and anti-CD157 (clone SY/11B5). FITC- or tified to play an important role in different physiological and allophycocyanin-conjugated irrelevant isotype-matched mAbs were pur- pathological settings. ADO is produced from the catabolism of chased from Beckman Coulter. Expression of ADO deaminase (ADA)/ mono- and di-nucleotides (ATP and NAD+) and from their CD26 complex was evaluated using PE-conjugated anti-CD26 mAb byproducts (ADP, ADP ribose [ADPR], and AMP). The canonical (clone CB26), locally generated. Expression of ADOR was evaluated on hAEC as well
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