Murine endometrial-derived mesenchymal stem cells suppress experimental autoimmune encephalomyelitis depending on indoleamine-2,3-dioxygenase expression

Author(s):Show less -

Polonio, Carolina Manganeli ^[1] ; de Freitas, Carla Longo ^[1] ; de Oliveira, Marilia Garcia ^[1] ; Rossato, Cristiano ^[1] ; Brandao, Wesley Nogueira ^[1] ; Zanluqui, Nagela Ghabdan ^{[1, 2]} ; de Oliveira, Lilian Gomes ^[1] ; Nishiyama Mimura, Luiza Ayumi ^[3] ; Barros Silva, Maysa Braga ^[4] ; Garcia Calich, Vera Lucia ^[5] ; Nisenbaum, Marcelo Gil ^[6] ; Halpern, Silvio ^[7] ; Evangelista, Lucila ^[6] ; Maluf, Mariangela ^[8] ; Perin, Paulo ^[8] ; Czeresnia, Carlos Eduardo ^[6] ; Schatzmann Peron, Jean Pierre ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Dept Immunol, Neuroimmune Interact Lab, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Sch Med, Immunopathol & Allergy Post Grad Program, Sao Paulo, SP - Brazil

^[3] UNESP, Inst Biosci, Botucatu, SP - Brazil

^[4] Univ Sao Paulo, Clin Anal Dept, Clin Biochem Lab, Sao Paulo, SP - Brazil

^[5] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, SP - Brazil

^[6] Celula Mater, Div Reprod Med, Sao Paulo, SP - Brazil

^[7] Halpern Clin, Div Reprod Med, Sao Paulo, SP - Brazil

^[8] CEERH, Div Reprod Med, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Clinical Science; v. 135, n. 9, p. 1065-1082, MAY 2021.
• Web of Science Citations: 0

Abstract

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-/- meM-SCs 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-gamma increased IDO expression and secretion of kynurenines in vitro, indicating a negative feedback loop. Pathogenic cytokines were in-creased when CD4(+) T cells from AhR(-/-) mice were co-cultured with WT meMSC. In sum-mary, our research evidences the suppressive activity of the unexplored meMSCs popula-tion, 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. (AU)

• FAPESP's process: 18/10242-5 - The role of ionotropic glutamate receptor NMDA in innate and adaptive immune cells from intestinal mucosa in murine experimental model
• Grantee: Marília Garcia de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/22504-1 - TAM receptors and their ligands Gas6 and Pros1 on the ZIKV Congenital Syndrome in Experimental Models
• Grantee: Jean Pierre Schatzmann Peron
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/11828-0 - Evaluation of the microRNAs role in the immunopathogenesis of microcephaly caused by Zika virus in experimental models
• Grantee: Carolina Manganeli Polonio
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/07371-2 - Characterization of the role of T CD8+ lymphocytes in Zika virus infection
• Grantee: Nagela Ghabdan Zanluqui
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/26170-0 - Neuroimmunology in experimental models of Autoimmune Encephalomyelitis and Congenital Zika Syndrome: physiopathogenesis, susceptibility, cellular therapy, vaccination
• Grantee: Carolina Demarchi Munhoz
• Support Opportunities: Research Projects - Thematic Grants