Date of Award
Spring 5-15-2017
Degree Type
Dissertation
Degree Name
PhD Molecular Bioscience
Department
Biology
Advisor
Jane Ko, Ph.D
Committee Member
Tin-Chun Chu, Ph.D
Committee Member
Roberta L. Moldow, Ph.D
Committee Member
Heping Zhou, Ph.D
Committee Member
Vincent DeBari, Ph.D
Keywords
Liver regeneration, Platelets, VEGFR1 Hematopoietic cells, CXCR7, Angiocrine
Abstract
A critical function for blood vessels is that they secrete paracrine factors necessary for development, homeostasis and repair of the rest of all organs. Among them, the liver is a highly vascular organ, and can undergo regeneration after injury. This liver regeneration process is governed by dynamic interplay between hepatocytes and non-parenchymal cells, liver sinusoidal endothelial cells (LSECs). However, how factors produced from LSECs triggered by injury remains to be defined. Following mouse in vivo liver injury model, activated platelets deploy stromal cell-derived factor 1 and vascular endothelial growth factor A to stimulate CXCR7+ LSECs, orchestrating hepatic regeneration. Upon injection of carbon tetrachloride, platelets and CD11b+VEGFR1+ myeloid cells were recruited to LSECs enabling to replenish liver mass. Liver regeneration was impaired in thrombopoietin-deficient (Thpo-/-) mice repressing platelet production. This impeded regeneration phenotype was recapitulated in mice with either conditional ablation of Cxcr7 in LSEC (Cxcr7iΔ/iΔ) or Vegfr1 in myeloid cell (Vegfr1lysM/lysM). These mice exhibited suppressed expression of hepatocyte growth factor and Wnt2, two crucial hepatocyte propagation factors. Administration of recombinant thrombopoietin restored the prohibited liver regeneration in the tested genetic models. These results suggest that platelets and myeloid cells activate the vascular niche to produce pro-regenerative endothelial paracrine factors. Modulating this “hematopoietic-vascular niche” might help to develop regenerative therapy strategy for hepatic disorders.
Recommended Citation
Shido, Koji, "Platelets Prime Hematopoietic-Vascular Niche to Drive Angiocrine-Mediated Liver Regeneration" (2017). Seton Hall University Dissertations and Theses (ETDs). 2252.
https://scholarship.shu.edu/dissertations/2252
