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American Liver Foundation
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American Liver Foundation Postdoctoral Research Fellowship Award
Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts
“Platelet activation triggered by CD39L1/NTPDase2 facilitates stem cell-mediated liver regeneration”
Hematopoietic bone marrow stem cells (BMSCs) are considered to promote liver regeneration and augment revascularization. Given the requirement of ectonucleotidases for mobilization of BM-derived cells and vascular reconstitution during liver regeneration, Dr. Schmelzle has recently examined whether mobilization of CD133+/CD45+ BMSCs from the BM and cellular functions locally in the liver are dictated by purinergic ectoenzymes. He could show that CD133+/CD45+ BMSCs express CD39 and CD39L1, as well as P1 and P2 receptors at the transcriptional level. A subset of CD133+/CD45+ BMSCs, which appears preferentially mobilized after liver injury, highly expresses CD39. Chemotaxis of these cells towards VEGF is triggered by CD39 and regulated by nucleoside binding to CD133+/CD45+ BMSC-associated A2A receptors. He could furthermore show that CD133+/CD45+ BMSCs boost liver regeneration. Mechanisms underlying the process of homing and sequestration of CD133+/CD45+ BMSCs after liver injury and their differentiation, however, remain unclear.
There is evidence to suggest that homing of BMSCs can be modulated by activated platelets. The nucleotide ADP is a key agonist of platelets. CD39L1 is expressed by both CD133+/CD45+ BMSCs and portal myofibroblasts; the latter are located in a putative liver stem cell niche. Whereas CD39 scavenges platelet nucleotide mediators to generate AMP, CD39L1 hydrolyzes extracellular ATP to ADP. Dr. Schmelzle proposes that local production of ADP by CD39L1 activates platelets to boost CD133+/CD45+ BMSC homing. He will test this hypothesis in a model of partial hepatectomy using infusions of CD133+/CD45+ BMSCs and altering platelet levels in mutant mice null for these ectonucleotidases. Effects of extracellular nucleotides and derivatives on parameters of liver regeneration will be determined. Dr. Schmelzle’s data may indicate new therapeutic options to boost regenerative responses after extended resections of the liver and in other settings of hepatic failure.
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