(HEPATOLOGY 2010.) Mesenchymal stem cells (MSCs) are a diverse population of cells that can be isolated from multiple tissues, including bone marrow, fat, and others. NSC 683864 Bone marrow MSCs are stromal cells that support hematopoiesis during embryogenesis and in adult life. Their mesodermal origin is reflected by their ability to differentiate into fat, cartilage, and bone in vitro.2 In addition to their ability to differentiate into mesodermal tissues,

MSC can differentiate into other cell types, including hepatocyte-like cells.3 The ability of MSCs to differentiate into multiple cell types, and the relative ease by which they can be expanded in culture makes them attractive candidates for therapy in a variety of conditions. In this context they have been tested in animal models of acute liver injury.4–6 The initial step required is localization to the site of tissue injury. After localization, MSCs have been proposed to have a range of functional effects. In the liver,

for example, there is evidence for MSCs differentiating into hepatocyte-like cells, as well as inducing stimulation of endogenous hepatocyte proliferation.4 In keeping with their highly plastic phenotype, MSCs also may differentiate into the matrix, depositing hepatic myofibroblasts, but this is controversial.7, 8 There is a requirement for signals that will localize MSCs to the area within the liver with hepatocyte death, and also signals that will initiate MSC differentiation. Adenosine is produced both extracellularly and intracellularly by dephosphorylation of adenosine PLEKHM2 triphosphates, diphosphates, and monophosphates, and by degradation Crenolanib datasheet of nucleic acids through the uric acid pathway during cellular injury.9, 10 These sources of adenosine result in elevated levels at sites of tissue ischemia, cellular apoptosis, and inflammation, with concentrations increasing more than 100-fold from the 30-300-nM range present in health.11, 12 Elevated levels of adenosine are known to induce a variety of adaptive changes in response to tissue injury via four receptor subtypes: A1, A2a, A2b, and

A3. These include matrix remodeling, immune regulation, and angiogenesis.13 The role of adenosine in localization of stem cells to sites of tissue injury is not known. Our goal was to study whether adenosine induces MSC chemotaxis, to determine whether adenosine regulates the response of MSC to established chemoattractants, and to investigate whether adenosine has any role in differentiation of MSCs. Here we demonstrate that adenosine alone does not affect MSC chemotaxis, but it significantly inhibits hepatocyte growth factor (HGF)–induced chemotaxis. We further identify an important role for down-regulation of Rac1 in the inhibitory effect of adenosine on MSC chemotaxis. In addition to providing a chemotactic stop signal to MSC, adenosine also stimulates transcription of genes potentially associated with MSC differentiation.