In mammals,the livers regenerate after chemical injury or resection of hepatic lobe by hepatectomy.How liver regeneration is initiated after mass loss remains to be defined.Here we report that following liver injury,a...In mammals,the livers regenerate after chemical injury or resection of hepatic lobe by hepatectomy.How liver regeneration is initiated after mass loss remains to be defined.Here we report that following liver injury,activated platelets deploy SDF-1 and VEGF-A to stimulate CXCR7+liver sinusoidal endothelial cell(LSEC)and VEGFR1^(+)myeloid cell,orchestrating hepatic regeneration.After carbon tetrachloride injection or hepatectomy,platelets and CD11b+VEGFR1^(+)myeloid cells were recruited to LSECs,and liver regeneration in both models was impaired in thrombopoietin-deficient(Thpo^(−/−))mice repressing production of circulating platelets.This impeded regeneration phenotype was recapitulated in mice with either conditional ablation of Cxcr7 in LSEC(Cxcr7iΔ/iΔ)or Vegfr1 in myeloid cell(Vegfr1^(lysM/lysM)).Both Vegfr1lysM/lysM and Cxcr7i^(Δ/iΔ)mice exhibited suppressed expression of hepatocyte growth factor and Wnt2,two crucial trophogenic angiocrine factors instigating hepatocyte propagation.Of note,administration of recombinant thrombopoietin restored the prohibited liver regeneration in the tested genetic models.As such,our data suggest that platelets and myeloid cells jointly activate the vascular niche to produce pro-regenerative endothelial paracrine/angiocrine factors.Modulating this‘hematopoietic–vascular niche’might help to develop regenerative therapy strategy for hepatic disorders.展开更多
基金supported by the Ansary Stem Cell Institute,the starr foundation TRI-Institution stem cell core projecthe Empire State Stem Cell Board and New York State Department of Health grants(C026878,C028117,C029156,C030160)+3 种基金by grants from the National Institute of Health(NIH)R01(HL119872,HL128158)ZC was supported by Druckenmiller Fellowship from the New York Stem Cell Foundation and U54 CA163167 from NIHThis work was also supported by a National Scientist Development Grant from the American Heart Association(12SDG1213004)R01HL130826 from NIH.SR is supported by the Ansary Stem Cell Institute and grant from the NIH R01(DK095039).
文摘In mammals,the livers regenerate after chemical injury or resection of hepatic lobe by hepatectomy.How liver regeneration is initiated after mass loss remains to be defined.Here we report that following liver injury,activated platelets deploy SDF-1 and VEGF-A to stimulate CXCR7+liver sinusoidal endothelial cell(LSEC)and VEGFR1^(+)myeloid cell,orchestrating hepatic regeneration.After carbon tetrachloride injection or hepatectomy,platelets and CD11b+VEGFR1^(+)myeloid cells were recruited to LSECs,and liver regeneration in both models was impaired in thrombopoietin-deficient(Thpo^(−/−))mice repressing production of circulating platelets.This impeded regeneration phenotype was recapitulated in mice with either conditional ablation of Cxcr7 in LSEC(Cxcr7iΔ/iΔ)or Vegfr1 in myeloid cell(Vegfr1^(lysM/lysM)).Both Vegfr1lysM/lysM and Cxcr7i^(Δ/iΔ)mice exhibited suppressed expression of hepatocyte growth factor and Wnt2,two crucial trophogenic angiocrine factors instigating hepatocyte propagation.Of note,administration of recombinant thrombopoietin restored the prohibited liver regeneration in the tested genetic models.As such,our data suggest that platelets and myeloid cells jointly activate the vascular niche to produce pro-regenerative endothelial paracrine/angiocrine factors.Modulating this‘hematopoietic–vascular niche’might help to develop regenerative therapy strategy for hepatic disorders.
