Author(s):
Felix, Renato Goncalves [UNESP] ; Carvalho Bovolato, Ana Livia [UNESP] ; Cotrim, Ondina Silvia [UNESP] ; Leao, Patricia dos Santos ; Batah, Sabrina Setembre ; Golim, Marjorie de Assis [UNESP] ; Velosa, Ana Paula ; Teodoro, Walcy ; Martins, Vanessa ; Cruz, Fernanda Ferreira ; Deffune, Elenice [UNESP] ; Fabro, Alexandre Todorovic ; Capelozzi, Vera Luiza
Date: 2020
Persistent ID: http://hdl.handle.net/11449/197861
Origin: Oasisbr
Subject(s): Adipose-derived mesenchymal stem cells; Conditioned medium; Collagen fibers; Growth factors; Cytokines; IL-17; Bleomycin; Collagen V; Electron microscopy
Description
Made available in DSpace on 2020-12-11T22:20:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-03-01
National Council for Scientific and Technological Development
Foundation for the Support of Research of the State of Sao Paulo
Laboratories for Medical Research [LIMs], Hospital das Clinicas, University of Sao Paulo
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
The immunogenic collagen V (Col V) and the proinflammatory cytokine interleukin (IL)-17 have been implicated in the pathogenesis of multiple autoimmune diseases. Col V is also up-regulated during adipogencsis and can stimulate adipocyte differentiation in vitro. Conditioned medium (CM) generated from adipose-derived mesenchymal stem cells (MSCs) reduces bleomycin (BLM)-induced lung injury in rats, suggesting a crucial role in situ of immunomodulatory factors secreted by MSCs in these beneficial effects. In the present work, we investigated this hypothesis, analyzing levels of plasma inflammatory mediators and inflammatory and fibrotic mediators in the lung tissue of BLM-injured rats after treatment with MSCs and CM. Pulmonary fibrosis was intratracheally induced by BLM. After 10 days, BLM animals were further randomized into subgroups receiving saline, MSCs, or CM intravenously. On days 14 and 21, the animals were euthanized, and the lungs were examined through protein expression of nitric oxide synthase (NOS), IL-17, transforming growth factor-beta (TGF-beta), vascular endothelial growth factor, endothelin-1, and the immunogenic Col V through histological quantitative evaluation and plasma levels of fibrinogen, Von Willebrand factor, and platelet-derived growth factor (PDGF). Rats that had been injected with MSCs and CM showed a significant increase in weight and significant improvements at 14 and 21 days after intravenous injection at both time points of analysis of plasma fibrinogen, PDGF, and Von Willebrand factor and NOS-2 expression, supporting an early anti-inflammatory action, thus reducing TGF-beta and collagen I fibers. In contrast, intravenous injection of CM was able to significantly increase the deposition of Col V fibers and IL-17 on both day 14 and day 21 as compared with the amount observed in rats from the BLM group and MSC groups. In conclusion, this study reinforces previous observations on the therapeutic properties of MSCs and CM and is the first report to demonstrate the association of its actions with immunomodulatory biomarkers on lung tissue. We concluded that adipose-derived stem cells and adipose-derived stem cells-CM modulate an in situ imbalance between collagen I- and Col V-mediated IL-17 immune response, emerging as a promising therapeutic option for recovering from BLM pulmonary fibrosis.
Sao Paulo State Univ, Botucatu Med Sch, Sao Paulo, Brazil
Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pathol, Sao Paulo, Brazil
Univ Sao Paulo, Fac Med, Rheumatol Div, Sao Paulo, Brazil
Univ Sao Paulo, Fac Med, Dept Pathol, Av Dr Arnaldo 455,Sala 1143, BR-01246903 Sao Paulo, SP, Brazil
Univ Fed Rio de Janeiro, Inst Biophys Carlos Chagas Filho, Lab Pulm Invest, Rio De Janeiro, RJ, Brazil
Sao Paulo State Univ, Botucatu Med Sch, Sao Paulo, Brazil
National Council for Scientific and Technological Development: CNPq-471939/2010-2
National Council for Scientific and Technological Development: 483005/2012-6
Foundation for the Support of Research of the State of Sao Paulo: FAPESP 12/03543-2
Foundation for the Support of Research of the State of Sao Paulo: FAPESP11/09181-2
Foundation for the Support of Research of the State of Sao Paulo: FAPESP 2012/07040-5
Foundation for the Support of Research of the State of Sao Paulo: FAPESP 2013/05886-7
Foundation for the Support of Research of the State of Sao Paulo: FAPESP 2013/14277-4
Foundation for the Support of Research of the State of Sao Paulo: FAPESP 2018/20403-6
