Mesenchymal Stem Cells and Induced Bone Marrow-Derived Macrophages Synergistically Improve Liver Fibrosis in Mice

Abstract

We describe a novel therapeutic approach for cirrhosis using mesenchymal stem cells (MSCs) and colony‐stimulating factor‐1‐induced bone marrow‐derived macrophages (id‐BMMs) and analyze the mechanisms underlying fibrosis improvement and regeneration. Mouse MSCs and id‐BMMs were cultured from mouse bone marrow and their interactions analyzed in vitro. MSCs, id‐BMMs, and a combination therapy using MSCs and id‐BMMs were administered to mice with CCl4‐induced cirrhosis. Fibrosis regression, liver regeneration, and liver‐migrating host cells were evaluated. Administered cell behavior was also tracked by intravital imaging. In coculture, MSCs induced switching of id‐BMMs toward the M2 phenotype with high phagocytic activity. In vivo, the combination therapy reduced liver fibrosis (associated with increased matrix metalloproteinases expression), increased hepatocyte proliferation (associated with increased hepatocyte growth factor, vascular endothelial growth factor, and oncostatin M in the liver), and reduced blood levels of liver enzymes, more effectively than MSCs or id‐BMMs monotherapy. Intravital imaging showed that after combination cell administration, a large number of id‐BMMs, which phagocytosed hepatocyte debris and were retained in the liver for more than 7 days, along with a few MSCs, the majority of which were trapped in the lung, migrated to the fibrotic area in the liver. Host macrophages and neutrophils infiltrated after combination therapy and contributed to liver fibrosis regression and promoted regeneration along with administered cells. Indirect effector MSCs and direct effector id‐BMMs synergistically improved cirrhosis along with host cells in mice. These studies pave the way for new treatments for cirrhosis. Stem Cells Translational Medicine 2019;8:271&284

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

“…Nonetheless, their exact contribution to liver disease development is still controversial. On one hand, studies indicate their ability to differentiate into pro-fibrogenic myofibroblasts [70], on the other hand several studies demonstrated that injection of MSCs improves liver fibrosis/cirrhosis in mice and could be used as a novel therapeutic approach [71,72]. More studies are therefore needed to clarify the role of these cells.…”

Liver Macrophages: Old Dogmas and New Insights

“…(106) Human autologous bone marrow cell infusion also seems to be beneficial for chronic liver disease treatment. (107) These effects may be attributed to immunomodulatory actions of transplanted cells and their ability to phagocytose cellular debris, (108) arguing once more for the high relevance of the immune system in tissue repair. However, data on the clinical efficacy of macrophage cell therapy in patients are still awaited.…”

Antler stem cells as a novel stem cell source for reducing liver fibrosis

“…However, it is limited by a lack of donor organ availability, immune rejection, surgical complications and high medical cost (Albanis and Friedman 2001). In recent years, stem cell transplantation has emerged as an effective treatment for hepatic diseases (Eom et al 2015;Watanabe et al 2019). Previous studies have shown that mesenchymal stem cells (MSCs) increase hepatocyte regeneration, enhance the liver functionality and reverse hepatic fibrosis (Huang et al 2016;Kisseleva and Brenner 2012;Lan et al 2018).…”