Platelets prime hematopoietic and vascular niche to drive angiocrine-mediated liver regeneration.

Overview

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 (CCl₄) injection or hepatectomy, platelets and CD11b⁺VEGFR1⁺ myeloid cells were recruited LSEC, and liver regeneration in both models was impaired in thrombopoietin-deficient (Thpo^-/-) mice lacking circulating platelets. This impeded regeneration phenotype was recapitulated in mice with either conditional ablation of Cxcr7 in LSEC (Cxcr7^iΔ/iΔ) or Vegfr1 in myeloid cell (Vegfr1^lysM/lysM). Both Vegfr1^lysM/lysM and Cxcr7^iΔ/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.