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 Cd39high 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.

Fragile TIM-4–expressing tissue resident macrophages are migratory and immunoregulatory

“…In contrast to CD169 -APCs, TIM-4 hi CD169 + macrophages expressed low levels of antigen presentation (MHCII) and costimulatory (CD80 and CD86) molecules, but higher levels of antiinflammatory (CD39, CD73, galectin-9, and TGF-β) molecules. Other immune cells with broad immunoregulatory properties, including Tregs (20), hematopoietic stem cells (38), and mesenchymal stem cells (39), express CD39 and CD73. As these cells express multiple immunoregulatory molecules, the principal effector molecule responsible immunoregulation expressed by a given CD39 + CD73…”

Hilar en bloc resection for hilar cholangiocarcinoma in patients with limited liver capacities—preserving parts of liver segment 4

“…Results from non-randomized clinical treatment attempts evaluating the regenerative potential of preoperative left intraportal administration of autologous hematopoietic stem cells in addition to a right portal vein embolization are promising and confirmed by various experimental studies in rodents [21, 22]. …”

Distinct roles of ecto-nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) in liver regeneration and fibrosis

“…We have previously shown that CD39 expression on endothelial and myeloid cells facilitates liver regeneration by modulating VEGF and P2Y receptor signaling in sinusoidal endothelial cells [6] and by increasing hematopoietic stem cell recruitment to the liver [24]. We expected to observe a similar pro-regenerative effect of the portal fibroblast expression of NTPDase2.…”