Conditioned Medium from Early-Outgrowth Bone Marrow Cells Is Retinal Protective in Experimental Model of Diabetes

Autor(es)

Duarte, Diego A. ^[1] ; Papadimitriou, Alexandros ^[1] ; Gilbert, Richard E. ^[2] ; Thai, Kerri ^[2] ; Zhang, Yanling ^[2] ; Rosales, Mariana A. B. ^[1] ; Lopes de Faria, Jose B. ^[1] ; Lopes de Faria, Jacqueline M. ^[1]

Afiliação do(s) autor(es)

^[1] State Univ Campinas UNICAMP, Fac Med Sci, Renal Pathophysiol Lab, Invest Diabet Complicat, Campinas, SP - Brazil

^[2] Univ Toronto, St Michaels Hosp, Keenan Res Ctr, Li KaShing Knowledge Inst, Toronto, ON - Canada

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 11, n. 2 FEB 2 2016.
• Citações Web of Science: 7

Resumo

Bone marrow-derived cells were demonstrated to improve organ function, but the lack of cell retention within injured organs suggests that the protective effects are due to factors released by the cells. Herein, we tested cell therapy using early outgrowth cells (EOCs) or their conditioned media (CM) to protect the retina of diabetic animal models (type 1 and type 2) and assessed the mechanisms by in vitro study. Control and diabetic (db/db) mice (8 weeks of age) were randomized to receive a unique intravenous injection of 5x10(5)EOCs or 0.25 ml thrice weekly tail-vein injections of 10x concentrated CM and Wystar Kyoto rats rendered diabetic were randomized to receive 0.50 ml thrice weekly tail-vein injections of 10x concentrated CM. Four weeks later, the animals were euthanized and the eyes were enucleated. Rat retinal Muller cells (rMCs) were exposed for 24 h to high glucose (HG), combined or not with EOC-conditioned medium (EOC-CM) from db/m EOC cultures. Diabetic animals showed increase in diabetic retinopathy (DR) and oxidative damage markers; the treatment with EOCs or CM infusions significantly reduced this damage and re-established the retinal function. In rMCs exposed to diabetic milieu conditions (HG), the presence of EOC-CM reduced reactive oxygen species production by modulating the NADPH-oxidase 4 system, thus upregulating SIRT1 activity and deacetylating Lys-310-p65-NF.B, decreasing GFAP and VEGF expressions. The antioxidant capacity of EOC-CM led to the prevention of carbonylation and nitrosylation posttranslational modifications on the SIRT1 molecule, preserving its activity. The pivotal role of SIRT1 on the mode of action of EOCs or their CM was also demonstrated on diabetic retina. These findings suggest that EOCs are effective as a form of systemic delivery for preventing the early molecular markers of DR and its conditioned medium is equally protective revealing a novel possibility for cell-free therapy for the treatment of DR. (AU)

• Processo FAPESP: 13/04331-1 - Possível proteção da retina de camundongos diabéticos tipo 2 com o tratamento com células da medula (Early Outgrowth Cells, EOCs): possível participação da via SIRT-1 nas células de Müller
• Beneficiário: Jacqueline Mendonça Lopes de Faria
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 08/57560-0 - Efeitos do chá verde (Camellia sinensis), do cacau e de um doador de óxido nítrico na nefropatia e retinopatia diabética: papel da redução do estresse oxidativo e da inflamação e do aumento do óxido nítrico
• Beneficiário: Jose Butori Lopes de Faria
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 10/11514-7 - O chá-verde (Camellia sinensis) apresenta efeito neuroprotetor na patogênese da retinopatia diabética? Estudo in vitro em cultura de células de Muller de ratos dos possíveis mecanismos moleculares neuroprotetores da Camellia sinensis
• Beneficiário: Jacqueline Mendonça Lopes de Faria
• Modalidade de apoio: Auxílio à Pesquisa - Regular