title: CD39 modulates hematopoietic stem cell recruitment and promotes liver regeneration in mice and humans after partial hepatectomy.
abstract: OBJECTIVE
  To study molecular mechanisms involved in hematopoietic stem cell (HSC) mobilization after liver resection and determine impacts on liver regeneration.
  
  
  BACKGROUND
  Extracellular 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.
  
  
  METHODS
  Partial 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.
  
  
  RESULTS
  Subsets 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Department of Medicine, Liver Center and Transplantation Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Moritz
authors.initials: M
authors.lastname: Schmelzle
authors.affiliation: Department of Surgery, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Duhme
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Junger
authors.affiliation: Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.|Department of Medicine, Liver Center and Transplantation Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Salhanick
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medicine, Liver Center and Transplantation Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Flow Cytometry Core Facility, Harvard Stem Cell Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Toxavidis
authors.affiliation: Department of Medicine, Liver Center and Transplantation Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.affiliation: Department of Medicine, Liver Center and Transplantation Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Lihui
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Medicine, Liver Center and Transplantation Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Shu
authors.initials: S
authors.lastname: Bian
authors.affiliation: Department of Radiology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Fürst
authors.affiliation: Department of Medicine, Liver Center and Transplantation Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.|Department of Anesthesiology, Peri-operative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Martina
authors.initials: M
authors.lastname: Nowak
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Karp
authors.affiliation: Department of Surgery, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Wolfram T
authors.initials: WT
authors.lastname: Knoefel
authors.affiliation: Department of Surgery, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Jan Schulte Am
authors.initials: JSA
authors.lastname: Esch
authors.affiliation: Department of Medicine, Liver Center and Transplantation Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
mesh_terms: D000251:Adenosine Triphosphatases / Q000502:physiology; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D001081:Apyrase / Q000378:metabolism / Q000502:physiology*; D001854:Bone Marrow Cells / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology; D004224:Diterpenes; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D006498:Hepatectomy; D006801:Humans; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D043705:Receptor, Adenosine A2A / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D015703:Antigens, CD; D004224:Diterpenes; D043705:Receptor, Adenosine A2A; D042461:Vascular Endothelial Growth Factor A; C121573:elisabatin A; D000251:Adenosine Triphosphatases; D001081:Apyrase; C067869:CD39 antigen