Murine endometrial-derived mesenchymal stem cells suppress experimental autoimmune encephalomyelitis depending on indoleamine-2,3-dioxygenase expression
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1042/CS20201544 http://hdl.handle.net/11449/207943 |
Resumo: | Cellular therapy with mesenchymal stem cells (MSCs) is a huge challenge for scientists, as little translational relevance has been achieved. However, many studies using MSCs have proved their suppressive and regenerative capacity. Thus, there is still a need for a better understanding of MSCs biology and the establishment of newer protocols, or to test unexplored tissue sources. Here, we demonstrate that murine endometrial-derived MSCs (meMSCs) suppress Experimental Autoimmune Encephalomyelitis (EAE). MSC-treated animals had milder disease, with a significant reduction in Th1 and Th17 lymphocytes in the lymph nodes and in the central nervous system (CNS). This was associated with increased Il27 and Cyp1a1 expression, and presence of IL-10-secreting T CD4+ cells. At EAE peak, animals had reduced CNS infiltrating cells, histopathology and demyelination. qPCR analysis evidenced the down-regulation of several pro-inflammatory genes and up-regulation of indoleamine-2,3-dioxygenase (IDO). Consistently, co-culturing of WT and IDO-/- meMSCs with T CD4+ cells evidenced the necessity of IDO on the suppression of encephalitogenic lymphocytes, and IDO-/- meMSCs were not able to suppress EAE. In addition, WT meMSCs stimulated with IL-17A and IFN-γ increased IDO expression and secretion of kynurenines in vitro, indicating a negative feedback loop. Pathogenic cytokines were increased when CD4+ T cells from AhR-/- mice were co-cultured with WT meMSC. In summary, our research evidences the suppressive activity of the unexplored meMSCs population, and shows the mechanism depends on IDO-kynurenines-Aryl hydrocarbon receptor (AhR) axis. To our knowledge this is the first report evidencing that the therapeutic potential of meMSCs relying on IDO expression. |
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Murine endometrial-derived mesenchymal stem cells suppress experimental autoimmune encephalomyelitis depending on indoleamine-2,3-dioxygenase expressionCellular therapy with mesenchymal stem cells (MSCs) is a huge challenge for scientists, as little translational relevance has been achieved. However, many studies using MSCs have proved their suppressive and regenerative capacity. Thus, there is still a need for a better understanding of MSCs biology and the establishment of newer protocols, or to test unexplored tissue sources. Here, we demonstrate that murine endometrial-derived MSCs (meMSCs) suppress Experimental Autoimmune Encephalomyelitis (EAE). MSC-treated animals had milder disease, with a significant reduction in Th1 and Th17 lymphocytes in the lymph nodes and in the central nervous system (CNS). This was associated with increased Il27 and Cyp1a1 expression, and presence of IL-10-secreting T CD4+ cells. At EAE peak, animals had reduced CNS infiltrating cells, histopathology and demyelination. qPCR analysis evidenced the down-regulation of several pro-inflammatory genes and up-regulation of indoleamine-2,3-dioxygenase (IDO). Consistently, co-culturing of WT and IDO-/- meMSCs with T CD4+ cells evidenced the necessity of IDO on the suppression of encephalitogenic lymphocytes, and IDO-/- meMSCs were not able to suppress EAE. In addition, WT meMSCs stimulated with IL-17A and IFN-γ increased IDO expression and secretion of kynurenines in vitro, indicating a negative feedback loop. Pathogenic cytokines were increased when CD4+ T cells from AhR-/- mice were co-cultured with WT meMSC. In summary, our research evidences the suppressive activity of the unexplored meMSCs population, and shows the mechanism depends on IDO-kynurenines-Aryl hydrocarbon receptor (AhR) axis. To our knowledge this is the first report evidencing that the therapeutic potential of meMSCs relying on IDO expression.Neuroimmune Interactions Laboratory Department of Immunology University of São Paulo (USP)Immunopathology and Allergy Post Graduate Program School of Medicine University of São Paulo (USP)Institute of Biosciences UNESPClinical Biochemistry Laboratory Clinical Analysis Department University of São Paulo (USP)Department of Immunology Institute of Biomedical Sciences University of São Paulo (USP)Division of Reproductive Medicine Célula MaterDivision of Reproductive Medicine Halpern ClinicDivision of Reproductive Medicine CEERHInstitute of Biosciences UNESPUniversidade de São Paulo (USP)Universidade Estadual Paulista (Unesp)Célula MaterHalpern ClinicCEERHPolonio, Carolina Manganelide Freitas, Carla Longode Oliveira, Marília GarciaRossato, CristianoBrandão, Wesley NogueiraZanluqui, Nágela Ghabdande Oliveira, Lilian GomesNishiyama Mimura, Luiza Ayumi [UNESP]Barros Silva, Maysa BragaGarcia Calich, Vera LúciaNisenbaum, Marcelo GilHalpern, SilvioEvangelista, LucilaMaluf, MariangelaPerin, PauloCzeresnia, Carlos EduardoSchatzmann Peron, Jean Pierre2021-06-25T11:03:38Z2021-06-25T11:03:38Z2021-05-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1065-1082http://dx.doi.org/10.1042/CS20201544Clinical Science, v. 135, n. 9, p. 1065-1082, 2021.1470-87360143-5221http://hdl.handle.net/11449/20794310.1042/CS202015442-s2.0-85105452174Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengClinical Scienceinfo:eu-repo/semantics/openAccess2021-10-23T17:52:00Zoai:repositorio.unesp.br:11449/207943Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T17:56:04.291301Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Murine endometrial-derived mesenchymal stem cells suppress experimental autoimmune encephalomyelitis depending on indoleamine-2,3-dioxygenase expression |
title |
Murine endometrial-derived mesenchymal stem cells suppress experimental autoimmune encephalomyelitis depending on indoleamine-2,3-dioxygenase expression |
spellingShingle |
Murine endometrial-derived mesenchymal stem cells suppress experimental autoimmune encephalomyelitis depending on indoleamine-2,3-dioxygenase expression Polonio, Carolina Manganeli |
title_short |
Murine endometrial-derived mesenchymal stem cells suppress experimental autoimmune encephalomyelitis depending on indoleamine-2,3-dioxygenase expression |
title_full |
Murine endometrial-derived mesenchymal stem cells suppress experimental autoimmune encephalomyelitis depending on indoleamine-2,3-dioxygenase expression |
title_fullStr |
Murine endometrial-derived mesenchymal stem cells suppress experimental autoimmune encephalomyelitis depending on indoleamine-2,3-dioxygenase expression |
title_full_unstemmed |
Murine endometrial-derived mesenchymal stem cells suppress experimental autoimmune encephalomyelitis depending on indoleamine-2,3-dioxygenase expression |
title_sort |
Murine endometrial-derived mesenchymal stem cells suppress experimental autoimmune encephalomyelitis depending on indoleamine-2,3-dioxygenase expression |
author |
Polonio, Carolina Manganeli |
author_facet |
Polonio, Carolina Manganeli de Freitas, Carla Longo de Oliveira, Marília Garcia Rossato, Cristiano Brandão, Wesley Nogueira Zanluqui, Nágela Ghabdan de Oliveira, Lilian Gomes Nishiyama Mimura, Luiza Ayumi [UNESP] Barros Silva, Maysa Braga Garcia Calich, Vera Lúcia Nisenbaum, Marcelo Gil Halpern, Silvio Evangelista, Lucila Maluf, Mariangela Perin, Paulo Czeresnia, Carlos Eduardo Schatzmann Peron, Jean Pierre |
author_role |
author |
author2 |
de Freitas, Carla Longo de Oliveira, Marília Garcia Rossato, Cristiano Brandão, Wesley Nogueira Zanluqui, Nágela Ghabdan de Oliveira, Lilian Gomes Nishiyama Mimura, Luiza Ayumi [UNESP] Barros Silva, Maysa Braga Garcia Calich, Vera Lúcia Nisenbaum, Marcelo Gil Halpern, Silvio Evangelista, Lucila Maluf, Mariangela Perin, Paulo Czeresnia, Carlos Eduardo Schatzmann Peron, Jean Pierre |
author2_role |
author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade de São Paulo (USP) Universidade Estadual Paulista (Unesp) Célula Mater Halpern Clinic CEERH |
dc.contributor.author.fl_str_mv |
Polonio, Carolina Manganeli de Freitas, Carla Longo de Oliveira, Marília Garcia Rossato, Cristiano Brandão, Wesley Nogueira Zanluqui, Nágela Ghabdan de Oliveira, Lilian Gomes Nishiyama Mimura, Luiza Ayumi [UNESP] Barros Silva, Maysa Braga Garcia Calich, Vera Lúcia Nisenbaum, Marcelo Gil Halpern, Silvio Evangelista, Lucila Maluf, Mariangela Perin, Paulo Czeresnia, Carlos Eduardo Schatzmann Peron, Jean Pierre |
description |
Cellular therapy with mesenchymal stem cells (MSCs) is a huge challenge for scientists, as little translational relevance has been achieved. However, many studies using MSCs have proved their suppressive and regenerative capacity. Thus, there is still a need for a better understanding of MSCs biology and the establishment of newer protocols, or to test unexplored tissue sources. Here, we demonstrate that murine endometrial-derived MSCs (meMSCs) suppress Experimental Autoimmune Encephalomyelitis (EAE). MSC-treated animals had milder disease, with a significant reduction in Th1 and Th17 lymphocytes in the lymph nodes and in the central nervous system (CNS). This was associated with increased Il27 and Cyp1a1 expression, and presence of IL-10-secreting T CD4+ cells. At EAE peak, animals had reduced CNS infiltrating cells, histopathology and demyelination. qPCR analysis evidenced the down-regulation of several pro-inflammatory genes and up-regulation of indoleamine-2,3-dioxygenase (IDO). Consistently, co-culturing of WT and IDO-/- meMSCs with T CD4+ cells evidenced the necessity of IDO on the suppression of encephalitogenic lymphocytes, and IDO-/- meMSCs were not able to suppress EAE. In addition, WT meMSCs stimulated with IL-17A and IFN-γ increased IDO expression and secretion of kynurenines in vitro, indicating a negative feedback loop. Pathogenic cytokines were increased when CD4+ T cells from AhR-/- mice were co-cultured with WT meMSC. In summary, our research evidences the suppressive activity of the unexplored meMSCs population, and shows the mechanism depends on IDO-kynurenines-Aryl hydrocarbon receptor (AhR) axis. To our knowledge this is the first report evidencing that the therapeutic potential of meMSCs relying on IDO expression. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-06-25T11:03:38Z 2021-06-25T11:03:38Z 2021-05-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1042/CS20201544 Clinical Science, v. 135, n. 9, p. 1065-1082, 2021. 1470-8736 0143-5221 http://hdl.handle.net/11449/207943 10.1042/CS20201544 2-s2.0-85105452174 |
url |
http://dx.doi.org/10.1042/CS20201544 http://hdl.handle.net/11449/207943 |
identifier_str_mv |
Clinical Science, v. 135, n. 9, p. 1065-1082, 2021. 1470-8736 0143-5221 10.1042/CS20201544 2-s2.0-85105452174 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Clinical Science |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
1065-1082 |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
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1808128876903137280 |