Enhancement of Pig Embryonic Implants in Factor VIII KO Mice A Novel Role for the Coagulation Cascade in Organ Size Control 英文参考文献.docVIP

EnhancementofPigEmbryonicImplantsinFactorVIIIKO Mice:ANovelRolefortheCoagulationCascadeinOrgan SizeControl AnnaAronovich1,DalitTchorsh1,EliasShezen1,ChavaRosen1,YaelKlionsky1,SivanCohen1,OrnaTal1, UriMartinowitz2,HelenaKatchman1,SmadarEventov-Friedman1,NinetteAmariglio3 ,Jasmine Jacob-Hirsch3,GideonRechavi3,YairReisner1* 1Department of Immunology, Weizmann Institute of Science, Rehovot, Israel, 2The Israel National Hemophilia Center, Sheba Medical Center, Tel Hashomer, Israel, 3CancerResearchCenter,ShebaMedicalCenter,TelHashomer,Israel Abstract Very little is known about the mechanisms that contribute to organ size differences between species. In the present study,weusedamousemodelofembryonic pigtissue implantation todefinetheroleofhostFactorVIIIincontrolling the final size attained by the implant. We show here that pig embryonic spleen, pancreas, and liver all grow to an increased size in mice that are deficient in the Factor VIII clotting cascade. Similar results were obtained using the transplantation model after treatment with the low molecular weight heparin derivative Clexane which markedly enhanced transplant size. Likewise, enhanced size was found upon treatment with the direct thrombin inhibitor Dabigatran, suggesting that organ size regulation might be mediated by thrombin, downstream of Factor VIII. Considering that thrombin was shown to mediate various functions unrelated to blood clotting, either directly by cleavage ofprotease-activated receptors (PARs) orindirectly bycleaving osteopontin (OPN) onstroma cells, theroleof PAR1 andPAR4 antagonists aswell astreatment with cleaved form ofOPN(tcOPN) were tested. While theformer was notfoundtohaveanimpactonovergrowthofembryonicpigspleenimplants,markedreductionofsizewasnotedupon treatment with the (tcOPN). Collectively, our surprising set of observations suggests that factors of the coagulation cascade have anovel role in organ size control. Citation:AronovichA,TchorshD,ShezenE,RosenC,KlionskyY,etal.(20