Extracellular Vesicles isolated from Mesenchymal Stromal Cells Modulate CD4(+) T Lymphocytes Toward a Regulatory Profile

Author(s):Show less -

da Cunha, Flavia Franco ^[1] ; Andrade-Oliveira, Vinicius ^[2] ; de Almeida, Danilo Candido ^[1] ; da Silva, Tamiris Borges ^[1] ; de Souza Breda, Cristiane Naffah ^[2] ; Cruz, Mario Costa ^[2] ; Faquim-Mauro, Eliana L. ^[3] ; Cenedeze, Marcos Antonio ^[1] ; Hiyane, Meire Ioshie ^[2] ; Pacheco-Silva, Alvaro ^{[1, 4]} ; Cavinato, Regiane Aparecida ^[1] ; Torrecilhas, Ana Claudia ^[5] ; Saraiva Camara, Niels Olsen ^{[1, 2]}

Affiliation

^[1] Univ Fed Sao Paulo, Dept Nefrol, Rua Pedro Toledo 669, BR-04039032 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Imunol, Ave Prof Lineu Prestes 1730, ICB IV, BR-05508000 Sao Paulo - Brazil

^[3] Inst Butantan, Lab Imunopatol, Ave Vital Brasil 1500, BR-05503900 Sao Paulo - Brazil

^[4] Hosp Israelita Albert Einstein, Ave Albert Einstein, BR-62705652 Sao Paulo - Brazil

^[5] Univ Fed Sao Paulo, Dept Ciencias Farmaceut, Rua Sao Nicolau 210, BR-09913030 Sao Paulo - Brazil

• Document type: Journal article
• Source: CELLS; v. 9, n. 4 APR 2020.
• Web of Science Citations: 0

Abstract

Mesenchymal stromal cells (MSCs) can generate immunological tolerance due to their regulatory activity in many immune cells. Extracellular vesicles (EVs) release is a pivotal mechanism by which MSCs exert their actions. In this study, we evaluate whether mesenchymal stromal cell extracellular vesicles (MSC-EVs) can modulate T cell response. MSCs were expanded and EVs were obtained by differential ultracentrifugation of the supernatant. The incorporation of MSC-EVs by T cells was detected by confocal microscopy. Expression of surface markers was detected by flow cytometry or CytoFLEX and cytokines were detected by RT-PCR, FACS and confocal microscopy and a miRNA PCR array was performed. We demonstrated that MSC-EVs were incorporated by lymphocytes in vitro and decreased T cell proliferation and Th1 differentiation. Interestingly, in Th1 polarization, MSC-EVs increased Foxp3 expression and generated a subpopulation of IFN-gamma(+)/Foxp3(+)T cells with suppressive capacity. A differential expression profile of miRNAs in MSC-EVs-treated Th1 cells was seen, and also a modulation of one of their target genes, TGFbR2. MSC-EVs altered the metabolism of Th1-differentiated T cells, suggesting the involvement of the TGF-beta pathway in this metabolic modulation. The addition of MSC-EVs in vivo, in an OVA immunization model, generated cells Foxp3(+). Thus, our findings suggest that MSC-EVs are able to specifically modulate activated T cells at an alternative regulatory profile by miRNAs and metabolism shifting. (AU)

• FAPESP's process: 17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology
• Grantee: Niels Olsen Saraiva Câmara
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 18/08479-7 - Multi-user equipment approved in grant 17/05264-7: analisador de fluxo extracelular Seahorse XFe96
• Grantee: Niels Olsen Saraiva Câmara
• Support type: Multi-user Equipment Program
• FAPESP's process: 14/07390-1 - Mesenchymal stromal cells derived microvesicles as inductors of immune tolerance
• Grantee: Flavia Franco da Cunha
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/13029-5 - Role of miRNAs in regulatory T cell-mediated immunological tolerance
• Grantee: Flavia Franco da Cunha
• Support type: Scholarships abroad - Research Internship - Doctorate