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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: PLoS One; v. 11, n. 2 FEB 2 2016.
• Web of Science Citations: 7

Abstract

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)

• FAPESP's process: 13/04331-1 - Possible protective effects of Early Outgrow Cells (EOCs) of diabetic retina from db/db mice: the possible role of SIRT-1 in retina Müller cells
• Grantee: Jacqueline Mendonça Lopes de Faria
• Support Opportunities: Regular Research Grants
• FAPESP's process: 08/57560-0 - Effects of green tea (Camellia sinensis), cocoa and nitric oxide donor on diabetic nephropathy and retinopathy: contribution of the reduction of oxidative stress and inflammation and elevation of nitric oxide
• Grantee: Jose Butori Lopes de Faria
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/11514-7 - Does green tea (Camellia sinensis, CS) present neuroprotector effect in the pathogenesis of diabetic retinopathy? In vitro studies in primary rat Muller cell culture to investigate the possible molecular mechanisms involved in neuroprotective effects of CS
• Grantee: Jacqueline Mendonça Lopes de Faria
• Support Opportunities: Regular Research Grants