Critical Review of Clinical Trials of Bone Marrow Stem Cells in Liver Disease  Diarmaid Dominic Houlihan, Philip Noel Newsome  Gastroenterology  Volume 135, Issue 2, Pages 438-450 (August 2008) DOI: 10.1053/j.gastro.2008.05.040 Copyright © 2008 AGA Institute Terms and Conditions

Figure 1 Bone marrow–derived stem cell subpopulations and their potential role in liver injury. Multipotent adult progenitor cells (mapcs) and MSCs are plastic adherent cell populations. MAPCs may contribute to liver regeneration after transdifferentiation to endothelial cells and subsequent neovascularization of injured tissue. MSCs have a potential therapeutic effect modulating the fibrotic process by minimizing collagen deposition, in addition to their capacity to differentiate into hepatocytes. HSCs and endothelial progenitor cells (epcs) are characterized by expression of a typical pattern of cell surface markers using flow cytometric analysis. HSCs aid hepatic regeneration through a variety of mechanisms including cellular fusion, transdifferentiation, and matrix remodeling. EPCs may revascularize the injured liver. Furthermore, expression of growth factors including hepatocyte growth factor, transforming growth factor-α, epidermal growth factor, and vascular endothelial growth factor promote liver regeneration and hepatocyte proliferation. Gastroenterology 2008 135, 438-450DOI: (10.1053/j.gastro.2008.05.040) Copyright © 2008 AGA Institute Terms and Conditions

Figure 2 Release and migration of HSCs from bone marrow to the injured liver. Stem cell recruitment to the injured liver may be divided into 4 different steps. First, after liver injury a variety of proteolytic enzymes (matrix metalloproteinases [mmps]), cytokines (interleukin-8, hepatocyte growth factor [hgf]), and chemokines (stromal cell–derived factor-1 [sdf-1]) are released into the peripheral circulation. Second, the proteolytic enzymes (MMP-9 in particular) degrade SDF-1 locally within the bone marrow and cleave the adhesion molecules tethering the stem cells, thereby facilitating their mobilization. Third, the resultant SDF-1 concentration gradient between bone marrow and the injured liver facilitates stem cell migration to the liver. This process is augmented by high concentrations of hepatic growth factor (hgfs). Finally, the interaction of SDF-1 and its receptor CXCR4 facilitates migration and uptake of HSCs into the injured liver, where they exert their therapeutic effect. Gastroenterology 2008 135, 438-450DOI: (10.1053/j.gastro.2008.05.040) Copyright © 2008 AGA Institute Terms and Conditions