Bone Marrow Stem Cells Contribute to Alcohol Liver Fibrosis in Humans

Abstract

Bone marrow-derived stem cell (BMSC) contribution to liver repair varies considerably and recent evidence suggests these cells may contribute to liver fibrosis. We investigated the mobilization and hepatic recruitment of bone marrow (BM) stem cells in patients with alcohol liver injury and their contribution to parenchymal/non-parenchymal liver cell lineages. Liver biopsies from alcoholic hepatitis (AH) patients and male patients, who received a female liver transplant and developed AH, were analyzed for BM stem cell content by fluorescence in situ hybridization and immunostaining. Y chromosome analysis was performed, along with co-staining for hepatocyte, biliary, myofibroblast, and Ki-67 markers. Blood CD34(+) levels were quantified in AH patients by flow cytometry. AH patients had increased CD34(+) cell counts in liver tissue (1.834% +/- 0.605%; P < 0.05) and in blood (0.195% +/- 0.063%; P < 0.05) as compared with matched controls (0.299% + 0.208% and 0.067% +/- 0.01%). A proportion of hepatic myofibroblasts were BM-derived (7.9%-26.8%) as deemed by the co-localization of Y chromosome/alpha-smooth muscle actin (alpha-SMA) staining. In the cross-sex liver grafts with AH, 5.025% of the myofibroblasts were co-staining for CD34, suggesting that a population of CD34(+) cells were contributing to the hepatic myofibroblast population. There was no evidence of BM contribution to hepatocyte or biliary cell differentiation, nor evidence of increased hepatocyte regeneration. Alcohol liver injury mobilizes CD34(+) stem cells into the circulation and recruits them into the liver. These BMSCs contribute to the hepatic myofibroblast population but not to parenchymal lineages and do not promote hepatocyte repair.

Regeneration of extrahepatic bile ducts by tissue engineering with a bioabsorbable polymer

“…Re-epithelialization may result not from continuous division, proliferation, and differentiation of cells in the hepatic or duodenal part of the graft, but from the differentiation of stem/progenitor cells into biliary epithelial cells that uniformly adhere to the scaffold. Bone marrow cells are reported to migrate to an injured liver via peripheral circulation and to differentiate into hepatocytes at the injured site [20][21][22]. Speculating that the same process may take place in our model, we are currently investigating whether juvenile cells such as bone marrow cells adhere to the scaffold and differentiate into a regenerated bile duct.…”

Liver Regenerative Medicine: Advances and Challenges

“…Beneficial results were achieved in most clinical trials, with prolonged (up to 1 year) improvement of liver function after treatment with HSCs [Terai et al, 2006;Lyra et al, 2007;Levicar et al, 2008;Lorenzini et al, 2008;Pai et al, 2008]. However, in certain circumstances, an unfavorable ability of HSCs to preferentially differentiate to myofibroblast-like cells (not to hepatocytes) was observed in a murine model of liver injury [di Bonzo et al, 2008] and in the liver of cirrhotic patients [Dalakas et al, 2010] thus contributing to hepatic fibrosis. Therefore, the profibrogenic potential of human MSC transplants should not be underevaluated in further clinical trials.…”

Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism

“…Importantly, fibrosis is associated with the generation of tissue-associated myofibroblasts in the liver, which are thought to be highly related to cancer-associated fibroblasts, and represent a fibrotic component of human breast cancers. [14][15][16][17][18][19][20] Here, we show that ethanol treatment induces the generation of ROS species in human fibroblasts, which has certain metabolic consequences that are known to drive tumor growth and metastasis. This resulting oxidative stress promotes autophagy, mitochondrial dysfunction and ketone production in cancerassociated fibroblasts.…”