Integrated Transcriptomic, Phenotypic, and Functional Study Reveals Tissue-Specific Immune Properties of Mesenchymal Stromal Cells Cédric Ménard, Joelle Dulong, David Roulois, Benjamin Hebraud, Léa Verdière, Céline Pangault, Vonick Sibut, Isabelle Bezier, Nadège Bescher, Céline Monvoisin, et al. To cite this version: Cédric Ménard, Joelle Dulong, David Roulois, Benjamin Hebraud, Léa Verdière, et al.. Inte- grated Transcriptomic, Phenotypic, and Functional Study Reveals Tissue-Specific Immune Prop- erties of Mesenchymal Stromal Cells. STEM CELLS, AlphaMed Press, 2020, 38 (1), pp.146-159. 10.1002/stem.3077. hal-02282131 HAL Id: hal-02282131 https://hal-univ-rennes1.archives-ouvertes.fr/hal-02282131 Submitted on 10 Sep 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Stem Cells Integrated transcriptomic, phenotypic, and functional study reveals tissue-specific immune properties of mesenchymal stromal cells Journal: Stem Cells Manuscript ID Draft Wiley - Manuscript Type: Original Research Date Submitted by Forthe Peer Review n/a Author: Complete List of Authors: Menard, Cedric; UMR U1236 MICMAC, INSERM, Université Rennes 1, Etablissement Français du Sang; SITI Laboratory, Etablissement Français du Sang, CHU Rennes Dulong, Joëlle; SITI Laboratory, Etablissement Français du Sang Bretagne, CHU Rennes; UMR U1236 MICMAC, INSERM, Université Rennes 1, Etablissement Français du Sang Roulois, David; UMR U1236 MICMAC HEBRAUD, Benjamin; STROMALAB VERDIERE, Lea; UMR U1236 MICMAC PANGAULT, Celine; UMR U1236 MICMAC; CHU Rennes, Pole Biologie SIBUT, Vonick; UMR U1236 MICMAC Isabelle, Bezier; SITI Laboratory, Etablissement Français du Sang Bretagne, CHU Rennes; UMR U1236 MICMAC Bescher, Nadège; SITI Laboratory, Etablissement Français du Sang Bretagne, CHU Rennes; UMR U1236 MICMAC MONVOISIN, Celine; UMR U1236 MICMAC Gadelorge, Mélanie; STROMALAB Bertheuil, Nicolas; SITI Laboratory, Etablissement Français du Sang Bretagne, CHU Rennes; UMR U 917 INSERM, Université Rennes 1; Centre Hospitalier Universitaire de Rennes, Plastic, reconstructive and aesthetic surgery Flecher, Erwan; Centre Hospitalier Universitaire de Rennes, Thoracic and cardiac surgery Casteilla, Louis; UMR UPS/CNRS/EFS 5273 Inserm U1031 , STROMALab Collas, Philippe; University of Oslo, Institute of Basic Medical Sciences, Department of Biochemistry SENSEBE, Luc; STROMALAB Bourin, Philippe; CSA21, Direction Espagnolle, Nicolas; STROMALAB Tarte, Karin; UMR U1236 MICMAC, INSERM, Université Rennes 1, Etablissement Français du Sang; SITI Laboratory, Etablissement Français du Sang, CHU Rennes adipose stem cells, Bone marrow stromal cells (BMSCs), Keywords: Immunosuppression, Immunogenicity, Gene expression, Cell interactions Journal Section: Translational and Clinical Research Cell Types: Bone Marrow Stem Cells, Adipose Stem Cells/VSF ScholarOne Support: (434) 964-4100 Page 1 of 97 Stem Cells 1 2 3 Genomics / Epigenomics / Metabolomics, Immunomodulation, Clinical 4 Diseases/Processes/Areas: Application / Translation, Cell Culture Advances 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 For Peer Review 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ScholarOne Support: (434) 964-4100 Stem Cells Page 2 of 97 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 For Peer Review 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ScholarOne Support: (434) 964-4100 Page 3 of 97 Stem Cells 1 2 3 Integrated transcriptomic, phenotypic, and functional study 4 5 reveals tissue-specific immune properties of mesenchymal stromal cells 6 7 8 Cédric Ménard1,2, Joëlle Dulong1,2, David Roulois1, Benjamin Hébraud3, 9 10 Léa Verdière1, Céline Pangault1,4, Vonick Sibut1,2, Isabelle Bezier1,2, Nadège 11 12 Bescher1,2, Céline Monvoisin1, Mélanie Gadelorge3, Nicolas Bertheuil2,5, 13 6 3 7 3 8 14 Erwan Flécher , Louis Casteilla , Philippe Collas , Luc Sensebé , Philippe Bourin , 15 Nicolas Espagnolle3, and Karin Tarte1,2 16 17 18 1 19 UMR 1236, Univ Rennes, INSERM, Etablissement Français du Sang Bretagne, F- 20 35000, Rennes, France 21 For Peer Review 22 2 SITI Laboratory, Etablissement Français du Sang Bretagne, CHU Rennes, F-35000 23 24 Rennes, France 25 3 26 STROMALab, Etablissement Français du Sang-Occitanie (EFS), Inserm 1031, 27 University of Toulouse, National Veterinary School of Toulouse (ENVT), ERL5311 28 29 CNRS, Toulouse, France. 30 31 4 Pôle Biologie, CHU Rennes, F-35000 Rennes, France 32 5 33 Department of Plastic Surgery, CHU Rennes, F-35000 Rennes, France 34 6 Department of Thoracic and Cardiac Surgery, CHU Rennes, F-35000 Rennes, 35 36 France 37 7 38 Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of 39 Medicine, University of Oslo, 0317 Oslo, Norway 40 41 8 Cell-easy, Place Pierre Potier, F-33000, Toulouse, France 42 43 44 45 CONTACT INFORMATION 46 Karin Tarte, INSERM U1236, Faculté de Médecine, 2 Avenue du Pr Léon Bernard, 47 48 35043 RENNES, France. e-mail: [email protected] Phone: +33 2 23 23 45 49 50 12, fax: +33 2 23 23 49 58 51 52 53 RUNNING TITLE: MSC properties rely on their tissue of origin 54 55 56 57 AUTHOR'S CONTRIBUTIONS: 58 C.M.: collection and assembly of data, data analysis and interpretation, manuscript 59 60 writing and final approval; J.D., B.H., L.V., I.B., N.B., M.G., P.C: collection and 1 ScholarOne Support: (434) 964-4100 Stem Cells Page 4 of 97 1 2 3 assembly of data; D.R: data analysis and interpretation, manuscript writing; C.P., 4 5 V.S.: data analysis and interpretation; B.H., N.B., E.F.: provision of study material or 6 7 donors; L.S.: contribution to data interpretation and manuscript writing; L.C., P.B., 8 N.E.: conception and design of the study; K.T.: conception and design of the study, 9 10 financial support, data analysis and interpretation, manuscript writing and final 11 12 approval. 13 14 15 16 17 18 19 20 21 For Peer Review 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 ScholarOne Support: (434) 964-4100 Page 5 of 97 Stem Cells 1 2 3 ABSTRACT 4 5 Clinical-grade mesenchymal stromal cells (MSCs) can be expanded from bone 6 7 marrow and adipose tissue to treat inflammatory diseases and degenerative 8 disorders. However the influence of their tissue of origin on their functional 9 10 properties, including their immunosuppressive activity, remains unsolved. In this 11 12 study, we produced paired bone marrow-derived stromal cell (BM-MSC) and 13 14 adipose-derived stromal cell (ASC) batches from 14 healthy donors. We then 15 compared them using transcriptomic, phenotypic, and functional analyses and 16 17 validated our results on purified native MSCs to infer which differences were really 18 19 endowed by tissue of origin. Cultured MSCs segregated together owing to their 20 tissue of origin based on their gene expression profile analyzed using differential 21 For Peer Review 22 expression and weighted gene co-expression network analysis. This translated into 23 24 distinct immune-related gene signatures, phenotypes, and functional cell interactions. 25 26 Importantly, sorted native BM-MSCs and ASCs essentially displayed the same 27 distinctive patterns than their in vitro-expanded counterparts. As a whole, ASCs 28 29 exhibited an immune profile consistent with a stronger inhibition of immune response 30 31 and a lower immunogenicity, supporting the use of adipose tissue as a valuable 32 33 source for clinical applications. 34 35 36 SIGNIFICANCE STATEMENT 37 38 Numerous clinical trials are evaluating the therapeutic potential of mesenchymal 39 stromal cells (MSCs) in degenerative and inflammatory diseases. Whereas their 40 41 tissue of origin has been proposed as a crucial determinant influencing MSC 42 43 biological function, the comparison of adipose-derived (ASCs) versus bone marrow- 44 45 derived (BM-MSCs) stromal cells has been essentially performed using MSC batches 46 obtained from different donors, with the confounding influence of inter-individual 47 48 variability. By evaluating transcriptomic, phenotypic, and functional features of paired 49 50 ASCs and BM-MSCs expanded from the same donors, and analyzing their native 51 purified counterpart, we highlighted an imprinting of tissue source on MSC immune 52 53 properties and proposed adipose tissue as a source of MSCs for the treatment of 54 55 immune-mediated diseases. 56 57 58 59 60 3 ScholarOne Support: (434) 964-4100 Stem Cells Page 6 of 97 1 2 3 INTRODUCTION 4 5 Mesenchymal stromal cell (MSC) therapy has gained tremendous interest over the 6 7 past decade, since the seminal proof of concept of its beneficial effect in steroid- 8 resistant graft-versus-host disease [1,2]. MSCs have thereafter been proposed as a 9 10 valuable innovative approach in a wide array of inflammatory diseases, acute tissue 11 12 injury syndromes, and chronic degenerative disorders, and more than 900 clinical 13 14 trials involving MSCs have been registered (http://www.clinicaltrials.gov). 15 Nevertheless, the limited evidence of their effectiveness in prospective randomized 16 17 phase III trials, the lack of defined in vivo mechanism of action allowing the design of 18 19 relevant potency assays and patient monitoring strategies, together with the high cost 20 of regulatory approved cell productions have hampered their development in the 21 For Peer Review 22 clinic [2,3].