Adenosine inhibits chemotaxis and induces hepatocyte-specific genes in bone marrow mesenchymal stem cells.
Bone marrow-derived mesenchymal stem cells (MSCs) have therapeutic potential in liver injury, but the signals responsible for MSC localization to sites of injury and initiation of differentiation are not known. Adenosine concentration is increased at sites of cellular injury and inflammation, and adenosine is known to signal a variety of cellular changes. We hypothesized that local elevations in the concentration of adenosine at sites of tissue injury regulate MSC homing and differentiation. Here we demonstrate that adenosine does not induce MSC chemotaxis but dramatically inhibits MSC chemotaxis in response to the chemoattractant hepatocyte growth factor (HGF). Inhibition of HGF-induced chemotaxis by adenosine requires the A2a receptor and is mediated via up-regulation of the cyclic adenosine monophosphate (AMP)/protein kinase A pathway. This results in inhibition of cytosolic calcium signaling and down-regulation of HGF-induced Rac1. Because of the important role of Rac1 in the formation of actin stress fibers, we examined the effect of adenosine on stress fiber formation and found that adenosine inhibits HGF-induced stress fiber formation. In addition, we found that adenosine induces the expression of some key endodermal and hepatocyte-specific genes in mouse and human MSCs in vitro.


CONCLUSIONS
We propose that the inhibition of MSC chemotaxis at sites of high adenosine concentration results in localization of MSCs to areas of cellular injury and death in the liver. We speculate that adenosine might initiate the process of differentiation of MSCs into hepatocyte-like cells.
Mohamadnejad
Mehdi
M
Yale University, School of Medicine, Department of Internal Medicine, Section of Digestive Diseases, New Haven, CT, USA.
Sohail
Muhammad A
MA
Watanabe
Azuma
A
Krause
Diane S
DS
Swenson
E Scott
ES
Mehal
Wajahat Z
WZ
D000241:Adenosine / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology* / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology*; D051379:Mice
D000241:Adenosine