O transplante de células mononucleares de medula óssea contribui para o remodelamento da matriz extracelular durante a regeneração do fígado em ratos com fibrose hepática induzida por ligadura do ducto biliar

Abstract

Liver fibrosis results from a chronic injury, with the activation of hepatic inflammatory and fibrogenic cells, which lead to an excessive extracellular matrix (MEC) protein accumulation. These alterations result in the death of liver cells, along with disorganization and loss of function of the hepatic parenchyma. Cirrhosis is the advanced stage of fibrosis, and culminates in hepatic failure, a potentially fatal condition whose only effective treatment is liver transplantation, which is limited by organ shortage. Amid the search for alternative therapies aiming hepatic regeneration, bone marrow mononuclear cell (CMMO) transplantation has shown promising and benefic results in animal models and some clinical protocols. Amongst these cells are hematopoietic and mesenchymal stem cells, which present regenerative potential and modulate inflammatory response. This study aimed to add knowledge on the mechanisms by which CMMO may prompt hepatic regeneration. Rats with liver fibrosis induced by bile duct ligation (LDB) were transplanted with CMMO and compared to fibrotic and normal rats without transplantation. Hepatic parameters such as MEC components (total collagen, collagens types I and IV, laminin and matrix metalloproteinases MMPs), cellular components (fibrogenic and Kupffer cells, cholangiocytes) and liver enzymes were analyzed through confocal, fluorescence and light microscopy, western blotting and spectrophotometry. Results showed that CMMO contribute to liver regeneration globally, (a) reducing collagen and laminin accumulation; (b) increasing MMP production, specially by Kupffer cells, that favor MEC remodeling; (c) normalizing cholangiocyte numbers and reducing fibrogenic cells; and (d) normalizing plasma levels of hepatic enzymes. Therefore, we suggest that CMMO may help hepatic regeneration through paracrine mechanisms and by differentiating in Kupffer cells, contributing to the secretion of anti-inflammatory and anti-fibrotic factors within the fibrotic liver.