• Moritz Schmelzle, Constanze Duhme, Wolfgang Junger, Steven D Salhanick, Yu Chen, Yan Wu, Vasilis Toxavidis, Eva Csizmadia, Lihui Han, Shu Bian, Günter Fürst, Martina Nowak, Seth J Karp, Wolfram T Knoefel, EschJan Schulte AmJSADepartment of Surgery, University Hospital Düsseldorf, Düsseldorf, Germany., and Simon C Robson.
• Department of Medicine, Liver Center and Transplantation Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
• Ann. Surg. 2013 Apr 1; 257 (4): 693701693-701.

ObjectiveTo study molecular mechanisms involved in hematopoietic stem cell (HSC) mobilization after liver resection and determine impacts on liver regeneration.BackgroundExtracellular nucleotide-mediated cell signaling has been shown to boost liver regeneration. Ectonucleotidases of the CD39 family are expressed by bone marrow-derived cells, and purinergic mechanisms might also impact mobilization and functions of HSC after liver injury.MethodsPartial hepatectomy was performed in C57BL/6 wild-type, Cd39 ectonucleotidase-null mice and in chimeric mice after transplantation of wild-type or Cd39-null bone marrow. Bone marrow-derived HSCs were purified by fluorescence-activated cell sorting and administered after hepatectomy. Chemotactic studies were performed to examine effects of purinergic receptor agonists and antagonists in vitro. Mobilization of human HSCs and expression of CD39 were examined and linked to the extent of resection and liver tests.ResultsSubsets of HSCs expressing Cd39 are preferentially mobilized after partial hepatectomy. Chemotactic responses of HSCs are increased by CD39-dependent adenosine triphosphate hydrolysis and adenosine signaling via A2A receptors in vitro. Mobilized Cd39 HSCs boost liver regeneration, potentially limiting interleukin 1β signaling. In clinical studies, mobilized human HSCs also express CD39 at high levels. Mobilization of HSCs correlates directly with the restoration of liver volume and function after partial hepatectomy.ConclusionsWe demonstrate CD39 to be a novel HSC marker that defines a functionally distinct stem cell subset in mice and humans. HSCs are mobilized after liver resection, limit inflammation, and boost regeneration in a CD39-dependent manner. These observations have implications for monitoring and indicate future therapeutic avenues.

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