No abstract

Bone marrow (BM) hematopoietic stem cells (HSCs) have been shown to facilitate regeneration in multiple nonhematopoietic tissues by either generating epithelial cells or altering the inflammatory response. Depending on injury type, the predominant mechanism of epithelial lineage regeneration occurs by spontaneous cell fusion or transdifferentiation. Irrespective of the mechanism, mobilization from the BM is a prerequisite. Mechanisms by which HSCs mobilize into damaged organs are currently under scrutiny. Murine and human studies have shown that the chemokine SDF-1 and its receptor CXCR4 participate in the mobilization of HSCs from BM and in the migration of HSCs to injured liver. SDF-1 is a potent HSC chemoattractant and is produced by the liver. Production is increased during liver injury leading to increased HSC migration to the liver, a finding diminished by neutralizing anti-CXCR4 antibodies. Additional factors have been implicated in the control of hepatic migration of HSCs such as IL-8, hepatocyte growth factor, and MMP-9. Matriceal remodeling is an essential component in HSC engraftment, and MMP-9 expression is increased in liver injury. This review focuses on the complex interaction of chemokines, adhesion molecules, and extracellular matrix factors required for successful migration and engraftment of HSCs into the liver.

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.

Medline 1966-2005, EMBASE/Excerpta Medica 1980-2005, The Cochrane Library (2005 Issue 2) and contact with authors of published reports.