Assistant Professor Hematology, Immunology and Biotherapy
Phone: 01 56 24 55 00
MCU, hématology, Immunology et Biothérapy, Paris Descartes University – Assistant Professor Hematology, Immunology and Biotherapy.
Fields: Onco-immunology, haemostasis, angiogenesis and vascular differentiation
Key words: hematology, vascular biology, immunology, immunotherapy, oncology, biotherapy, stem cells, microenvironment, innovation
Diagnostic and therapeutic innovation through the study of stem or progenitor cells as circulating biomarkers and the associated cellular microenvironment in biotherapy context in vascular biology and onco-immunology.
In the critical limb ischemia (CLI), one of the research focuses on the development of a cell therapy product capable of inducing the formation of neo-vessels. Faced with the difficulty of obtaining and amplifying endothelial progenitor cells (EPCs) in healthy adults and, even more so, in patients, one hypothesis suggests the use of other cell types with vasculogenic properties. In patients with cardiovascular disease, and AOMI in particular, bone marrow mononuclear cells and CPEs show diminished angiogenic properties. We have demonstrated the ability of mesenchymal stem cells (MSCs) isolated from patients with AOMI to induce reperfusion by recruitment of endothelial cells in situ by acting paracrine (Smadja DM, Audigier C, Guerin CL , Bone Marrow Transplant, 2011).
The second hypothesis for obtaining an autologous angiogenic cell therapy product is to sort more immature cells than the CPE in order to differentiate them secondarily towards the endothelial line in the image of the pathological model of the CD133 + hemangioma stem cell (Smadja DM, Guerin CL Stem Cells, 2013) which suggests the Very Small Embryonic Like Stem Cells (VSEL), a CD133 + multipotent stem cell, as a candidate for post-natal cells with vascular potential. We have derived, in culture under angiogenic conditions, VSELs which acquire a mesenchymal phenotype but have a secretory profile close to that of CPE. VSELs promote post-ischemic revascularization and acquire an endothelial phenotype in vitro and in vivo suggesting that they may be at the ontogeny of the endothelial lineage (Guerin CL et al., Thromb Haemost, 2015) but are also able to act in synergy with EPCs by acting as vascular support cells in the context of therapeutic revascularization (Guerin CL et al., Stem Cell Reviews and Reports, 2017a). VSELs are a biomarker of mobilized endothelial dysfunction from bone marrow to peripheral blood in patients with CLI.
Circulating cellular biomarkers are not only non-invasive markers of the endothelium but can also provide relevant information for the prognosis, diagnosis and therapeutic follow-up of patients with pathologies associated with endothelial dysfunction. A change in the number of CPE, VSEL and circulating endothelial cells (CEC) in the circulation has been reported in various pathological situations respectively associated with regeneration and endothelial damage such as increased CEC level in patients with hypertension. pulmonary arterial (PAH) (Smadja DM, …, Guerin C. et al Eur Respir J. 2010) (Guerin CL et al., Stem Cell Reviews and Reports, 2017b).
In the context of biotherapy in vascular biology, such as onco-immunology, the mobilization and differentiation of stem cells as well as the microenvironment of the lesion or tumor site play a major role in maintaining the architecture and in the functional organization.
Chronic lymphocytic leukemia (CLL) is a hematological malignancy that originates in the bone marrow of a patient whose bone marrow cells acquire a mutation leading to an excessive accumulation of B cells in the bone marrow, blood, lymph nodes and spleen. These cells infiltrate the tissues and come into direct contact with the stromal and immune cells that make up the tumor microenvironment. Thus, the extensive and detailed mapping of the cells that populate the LLC microenvironment in a mouse model shows that the development of CLL creates a highly immunosuppressive environment in C57BL / 6 mice after adoptive transfer of Eμ-TCL1 splenocytes. (Wierz M, …, Guerin C et al., Blood 2018) Therapeutic treatment by combined blockade of PD1 and LAG3 immune control receptors effectively limits CLL progression by correcting immune cell imbalance and promoting effective anti-tumor immunity. In conclusion, the current knowledge of the immune cell populations present in the CLL microenvironment demonstrates that dual targeting of the PD1 and LAG3 immune control points controls the development of the disease in mice and could therefore constitute an effective immunotherapy treatment.
In-depth knowledge of the cells surrounding the tumor cell as well as structural and functional interactions with these partners is therefore essential to elucidate the mechanisms of escape to the immune response, a critical step for the development of immunotherapies aimed at restoring / stimulating anti-tumoral immunity effectively.
Natural killer cells (NK) are lymphocytes of the innate immune system with a cytotoxic activity which, unlike cytotoxic T8 lymphocytes, contribute to the elimination of cancer cells (Mgrditchian T, …, Guerin C et al PNAS 2017) by the very rapid establishment of an immunological synapse with the target cell that does not require pre-activation by prior exposure to the antigen. The direct and convincing demonstration of the key role of the actin cytoskeleton of breast cancer cells in the resistance to NK-induced cell death shows that certain breast cancer cells respond to attacks rapidly by significantly accumulating the tumor. actin at the immunological synapse (Al Asbi, Guerin C et al., Cancer Res 2018). Breast cancer cell lines contain two subpopulations that differ in their ability to respond to NK cell attack via an actin response, and the relative abundance of these determines the overall susceptibility of the cell line to induce lysis by NK cells. Thus, the epithelio-mesenchymal transition induces the actin response and promotes resistance to cancer cell destruction by cell mediation. Conversely, the prevention of actin response by genetic modification or pharmacological approach restores the sensitivity of cancer cells.
From a diagnostic and therapeutic point of view, my work thus opens new perspectives in the detection of circulating cellular biomarkers and in the study of their differentiation, offering a better understanding of the interactions between the immune system and tumor cells and allows to consider new possibilities of therapeutic interventions in patients regarding immunotherapy treatment.
Major publications 2020 / 2007
(H) : Haemostasis, angiogenesis and vascular differentiation in red n=31
(OI) : Onco-immunology in green – n=6
(R) : Review in blue n=1
(H) Valproic Acid Decreases Endothelial Colony Forming Cells Differentiation and Induces Endothelial-to-Mesenchymal Transition-like Process. Nathalie Nevo, Severine Lecourt, Ivan Bièche, Magda Kucia, Audrey Cras, Adeline Blandinieres, Sophie Vacher, Nicolas Gendron, Coralie L Guerin, Mariusz Z Ratajczak, David M Smadja – 2020 Apr – PMID: 31898801 DOI: 10.1007/s12015-019-09950-y
(H) Hemocompatibility and safety of the Carmat Total Artifical Heart hybrid membrane. Ulysse Richez, Hector De Castilla, Coralie L Guerin, Nicolas Gendron, Giulia Luraghi, Marc Grimme, Wei Wu, Myriam Taverna, Piet Jansen, Christian Latremouille, Francesco Migliavacca, Gabriele Dubini, Antoine Capel, Alain Carpentier, David M Smadja – 2019 Dec 8 – PMID: 31867454 PMCID: PMC6906674 DOI: 10.1016/j.heliyon.2019.e02914
(H) Rossi E, Chassac S, Bieche I, Chocron R, Schnitzler A, Lokajckyk A, Bourdoncle P, Bizier B, Bacha NC, Gendron N, Blandinieres A, Guerin CL, Gaussem P, Smadja DM. Human endothelial colony forming cells express intracellular CD133 that modulates their vasculogenic properties. Cells. Stem Cell Rev. 2019, in press
(H) Bacha NC, Levy M, Guerin CL, Le Bonniec B, Harroche A, Szezepanski I, Renard JM, Gaussem P, Israel-Biet D, Boulanger CM, Smadja DM. Treprostinil treatment decreases circulating platelet microvesicles and their procoagulant activity in pediatric pulmonary hypertension. Pediatr Pulmonol. 2019 Jan;54(1):66-72. PMID: 30485728
(OI) Wierz M, Pierson S, Gargiulo E, Guerin C, Moussay E, Paggetti J. Purification of Leukemia-Derived Exosomes to Study Microenvironment Modulation. Methods Mol Biol. 2019;1884:231-245. PMID: 30465207
(OI) Al Absi A, Wurzer H*, Guerin C*, Hoffmann C, Moreau F, Mao X, Brown-Clay J, Petrolli R, Casellas CP, Dieterle M, Thiery JP, Chouaib S, Berchem G, Janji B, Thomas C. Actin Cytoskeleton Remodeling Drives Breast Cancer Cell Escape from Natural Killer-Mediated Cytotoxicity. Cancer Res. 2018 Oct 1;78(19):5631-5643. PMID: 30104240
(H) Loyer X, Zlatanova I, Devue C, Yin M, Howangyin KY, Klaihmon P, Guerin CL, Kheloufi M, Vilar J, Zannis K, Fleischmann BK, Hwang DW, Park J, Lee H, Menasché P, Silvestre JS, Boulanger CM. Intra-Cardiac Release of Extracellular Vesicles Shapes Inflammation Following Myocardial Infarction. Circ Res. 2018 Jun 22;123(1):100-106. PMID: 29592957
(OI) Wierz M, Pierson S, Guyonnet L, Viry E, Lequeux A, Oudin A, Niclou SP, Ollert M, Berchem G, Janji B, Guérin C, Paggetti J, Moussay E. Dual. PD1/LAG3 immune checkpoint blockade limits tumor development in a murine model of chronic lymphocytic leukemia. Blood. 2018 Apr 5;131(14):1617-1621. PMID: 29439955
(H) Zeboudj L, Maitre M, Guyonnet L, Laurans L, Joffre J, Lemarie J, Bourcier S, Nour-Eldine W, Guerin C, Friard J, Wakkach A, Fabre E, Tedgui A, Mallat Z, Tharaux PL, Ait-Oufella H. Selective EGF-Receptor Inhibition in CD4(+) T Cells Induces Anergy and Limits Atherosclerosis. J Am Coll Cardiol. 2018;71(2):160-172. PMID: 29325640
(H) d’Audigier C, Susen S, Blandinieres A, Mattot V, Saubamea B, Rossi E, Nevo N, Lecourt S, Guerin CL, Dizier B, Gendron N, Caetano B, Gaussem P, Soncin F, Smadja DM. Egfl7 Represses the Vasculogenic Potential of Human Endothelial Progenitor Cells. Stem Cell Rev. 2018 Feb;14(1):82-91. PMID: 28980146
(OI) Mgrditchian T, Arakelian T, Paggetti J, Noman MZ, Viry E, Moussay E, Van Moer K, Kreis S, Guerin C, Buart S, Robert C, Borg C, Vielh P, Chouaib S, Berchem G, Janji B. Targeting autophagy inhibits melanoma growth by enhancing NK cells infiltration in a CCL5-dependent manner. Proc Natl Acad Sci U S A. 2017. Dec. PMID: 29078276
(H) Bacha NC, Blandinieres A, Rossi E, Gendron N, Nevo N, Lecourt S, Guerin CL, Renard JM, Gaussem P, Angles-Cano E, Boulanger CM, Israel-Biet D, Smadja DM. Endothelial Microparticles are Associated to Pathogenesis of Idiopathic Pulmonary Fibrosis. Stem Cell Rev. 2017. PMID: 29101610
(H) Rossi E, Goyard C, Cras A, Dizier B, Bacha N, Lokajczyk A, Guerin CL, Gendron N, Planquette B, Mignon V, Bernabeu C, Sanchez O, Smadja DM. Co-injection of mesenchymal stem cells with endothelial progenitor cells accelerates muscle recovery through an endoglin-dependent mechanism. Thromb Haemost. 2017. June. PMID: 28771278
(H) Guerin CL , Blandinières A, Planquette B, Silvestre JS, Israel-Biet D, Sanchez O, Smadja DM. Very small embryonic-like stem cells are mobilized in human peripheral blood during Hypoxemia COPD exacerbations and Pulmonary Hypertension. Stem Cell Reviews and Reports, 2017 Mar. PMID: 28285391
(H) Guerin CL, Rossi E, Saubamea B, Cras A, Mignon V, Silvestre JS, Smadja DM. Human very small embryonic-like cells support vascular maturation and therapeutic revascularization induced by endothelial progenitor cells. Stem Cell Reviews and Reports, 2017 Mar. PMID: 28303468
(H) Blondiaux E, Pidial L, Autret G, Rahmi G, Balvay D, Audureau E, Wilhelm E, Guerin CL, Bruneval P, Silvestre JS, Menasché P, Clément O. Bone marrow-derived mesenchymal stem cell-loaded fibrin patches act as a reservoir of paracrine factors in chronic myocardial infarction. J Tissue Eng Regen Med. 2017 Feb. PMID: 28156084
(H) Ngkelo A, Richart A, Kirk JA, Bonnin P, Vilar J, Lemitre M, Marck P, Branchereau M, Le Gall S, Renault N, Guerin C, Ranek MJ, Kervadec A, Danelli L, Gautier G, Blank U, Launay P, Camerer E, Bruneval P, Menasche P, Heymes C, Luche E, Casteilla L, Cousin B, Rodewald HR, Kass DA, Silvestre JS. Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction. J Exp Med 2016 213 (7), 1353-1374. PMID: 27353089
(H) Loyer X*, Rautou PE*, Vion AC, Scetbun J, Colnot N, Guérin CL, Romain M, Paul JL, Bedossa P, Boulanger CM, Paradis V, Tedgui A. MicroRNA-21 Contributes to Non Alcoholic Steatohepatitis: Experimental And Clinical Evidences. Gut. 2016 65 (11), 1882-1894. PMID: 26338827
(H) d’Audigier C, Cochain C, Rossi E, Guerin CL, Bieche I, Blandinieres A, Marsac B, Silvestre JS, Gaussem P, Smadja DM. Thrombin receptor PAR-1 activation on endothelial progenitor cells enhances chemotaxis associated gene expression and leukocytes recruitment by a COX-2 dependent mechanism. Angiogenesis. 2015 Jul;18(3):347-59. PMID: 26026674
(H) Guerin CL, Loyer X, Vilar J, Cras A, Mirault T, Gaussem P, Silvestre JS, Smadja DM. Bone-marrow-derived very small embryonic-like stem cells in patients with critical leg ischemia: evidence of vasculogenic potential. Thromb Haemost. 2015. May;113(5):1084-94. PMID: 25608764
(H) Smadja DM, Dorfmüller P, Guerin C, Bieche I, Badoual C, Boscolo E, Kambouchner M, Cazes A, Mercier O, Humbert M, Gaussem P, Bischoff J, Israël-Biet D. Cooperation between human fibrocytes and endothelial colony-forming cells increases angiogenesis via the CXCR4 pathway. Thromb Haemost. 2014 Nov;112(5):1002-13. PMID: 25103869
(H) Richart A, Loyer X, Néri T, Howangyin K, Guérin C, Ngkelo A, Bakker W, Zlatanova I, Rouanet M, Vilar J, Lévy B, Rothenberg M, Mallat Z, Pucéat M, Silvestre JS. MicroRNA-21 coordinates Human Multipotent Cardiovascular Progenitors Therapeutic Potential. Stem Cells 2014 Nov;32(11):2908-22. PMID: 25069679
(H) Amabile N, Cheng S, Renard JM, Larson MG, Ghorbani A, McCabe E, Griffin G, Guerin CL, Vasan RS, Ho JE, Shaw SY, Cohen KS, Tedgui A, Boulanger CM, Wang TJ. Association of circulating endothelial microparticles with cardiometabolic risk factors in the Framingham heart study. Eur Heart J. 2014 Nov 7;35(42):2972-9. PMID: 24742886
(H) Loyer X, Potteaux S, Vion AC, Guérin CL, Boulkroun S, Rautou PE, Ramkhelawon B, Esposito B, Dalloz M, Paul JL, Julia P, Maccario J, Boulanger CM, Mallat Z, Tedgui A. Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice. Circ. Res. 2014 Jan 31;114(3):434-43. PMID: 24255059
(H) Huang J, Filipe A, Rahuel C, Bonnin P, Mesnard L, Guérin C, Wang Y, Le Van Kim C, Colin Y, Tharaux PL. Lutheran/Basal Cell Adhesion Molecule accelerates progression of crescentic glomerulonephritis in mice. Kidney International. 2014 Jan 15. doi: 10.1038/ki.2013.522. PMID: 24429403
(H) d’Audigier C, Gautier B, Yon A, Alili JM, Guerin CL, Evrard SM, Godier A, Haviari S, Reille-Serroussi M, Huguenot F, Dizier B, Inguimbert N, Borgel D, Bièche I, Boisson-Vidal C, Roncal C, Carmeliet P, Vidal M, Gaussem P, Smadja DM. Targeting VEGFR1 on endothelial progenitors modulates their differentiation potential. Angiogenesis. 2014 Jan 14. PMID: 24419917
(H) HoWangYin KY, Loinard C, Bakker W, Guérin CL, José Vilar J, D’Audigier C, Mauge L, Bruneval P, Emmerich J, Lévy B, Pouysségur J, Smadja DM, Silvestre JS. HIF-prolyl hydroxylase 2 inhibition enhances the efficiency of cell-based therapies for the treatment of critical limb ischemia. Stem Cells. 2014 Jan 32(1):231-43. PMID: 24105925
(H) Zouggari Y*, Ait-Oufella H*, Bonnin P, Simon T, Sage AP, Guérin C, Vilar J, Caligiuri G, Tsiantoulas D, Laurans L, Dumeau E, Kotti S, Bruneval P, Charo IF, Binder CJ, Danchin N, Tedgui A, Tedder TF, Silvestre JS, Mallat Z. B lymphocytes trigger MCP3-dependent mobilization of monocytes and promote adverse ventricular remodeling after acute myocardial infarction. Nat Med. 2013 Oct;19(10):1273-80. PMID: 24037091
(H) Smadja DM, Guerin CL, Boscolo E, Bieche I, Mulliken JB, Bischoff J. α6-Integrin plays a major role in the vasculogenic potential of hemangioma stem cells. Stem Cells. 2013 Sep 10. doi: 10.1002/stem.1539. PMID: 24022922
(H) Seguier S, Tartour E, Guerin CL, Couty L, Lemitre M, Lallement L, Folliguet M, El Naderi S, Badoual C, Lafont A, Coulomb B. Inhibition of the differentiation of monocyte-derived dendritic cells by human gingival fibroblasts. PlosOne. 2013 Aug 2;8(8):e70937. PMID: 23936476
(OI) Badoual C, Hans S, Merillon N, Van Ryswick C, Ravel P, Benhamouda N, Levionnois E, Nizard M, Si Mohamed A, N Besnier, Rotem-Yehudar R, Pere H, Tran T, Guerin CL, Chauvat A, Dransart E, Alanio C, Albert S, Barry B, Sandoval F, Quintin-Colonna F, Bruneval P, Fridman WH, Lemoine FM, Oudard S, Johannes L, Olive D, Brasnu D, Tartour E. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV associated head and neck cancer. Cancer Res. 2013 Jan 1;73(1):128-38. PMID: 23135914
(H) Rueda P, Richart A, Récalde A, Gasse P, Vilar J, Guérin C, Lortat-Jacob H, Vieira P, Baleux F, Chretien F, Arenzana-Seisdedos F, Silvestre JS. Homeostatic and tissue reparation defaults in mice carrying selective genetic invalidation of CXCL12/proteoglycan interactions. Circ. 2012 Oct 9;126(15):1882-95. PMID: 23135914
(H) Al Faraj A, Gazeau F, Wilhem C, Devue C, Guerin CL, Pechoux C, Paradis V, Clement O, Boulanger CM, Rautou PE. Endothelial cell-derived microparticles loaded with iron oxide nanoparticles: feasibility of MRI monitoring in mice. Radiology 2012 263(1): p.169-178. PMID: 22332069
(H) Evrard SM, d’Audigier C, Mauge L, Israël-Biet D, Guerin CL, Bieche I, Kovacic JC, Fischer AM, Gaussem P, Smadja DM. Profibrotic cytokine TGF-β1 increases endothelial progenitor cell angiogenic properties. J Thromb Haemost. 2012 Apr 10(4):670-9. PMID: 22284809
(H) Récalde A, Richart A, Guérin C, Cochain C, Zouggari Y, Yin KH, Vilar J, Drouet I, Lévy B, Varoquaux O, Silvestre JS. Sympathetic nervous system regulates bone marrow-derived cells egress through endothelial nitric oxide synthase activation: role in post-ischemic tissue remodeling. Arterioscler Thromb Vasc Biol. 2012 Mar 32(3):643-53. PMID: 22267478
(R) Picot J*, Guerin CL*, Le Van Kim C, Boulanger CM. Flow cytometry: retrospective, fundamentals and recent instrumentation. Cytotechnology. 2012 Jan 64(2):109-130. PMID: 22271369
(H) Smadja DM, d’Audigier C, Guerin CL, Mauge L, Dizier B, Silvestre JS, Cortivo LD, Gaussem P, Emmerich J. Angiogenic potential of BM MSCs derived from patients with critical leg ischemia. Bone Marrow Transplant. 2011 Oct 10. doi: 10.1038/bmt.2011.196. PMID: 21986637
(H) Smadja DM, Mauge L, Sanchez O, Silvestre JS, Guérin C, Godier A, Henno P, Gaussem P, Israël-Biet D. Distinct patterns of circulating endothelial cells in pulmonary hypertension. Eur Respir J. 2010 Dec 36(6):1284-93. PMID: 20413531
(H) Cochain C, Rodero MP, Vilar J, Récalde A, Richart A, Loinard C, Zouggari Y, Guérin C, Duriez M, Combadière B, Poupel L, Lévy BI, Mallat Z, Combadière C, Silvestre JS. Regulation of monocyte subsets systemic levels by distinct chemokine receptors controls postischemic neovascularization. Cardiovasc Res. 2010 Oct 1;88(1):186-95. PMID: 20501509
(OI) Segura E, Guérin C, Hogg N, Amigorena S, Théry C. CD8+ dendritic cells use LFA-1 to capture MHC-peptide complexes from exosomes in vivo. J Immunol. 2007 Aug 1;179(3):1489-96. PMID: 17641014