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.

Available for download on Wednesday, July 01, 2020

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