Identification of vascular inductive signals in liver regeneration

Summary

Principal Investigator: Shahin Rafii
Abstract: DESCRIPTION (provided by applicant): Liver transplantation is the mainstay of treatment for patients with end-stage liver disease. However, the paucity in genetically matched donors and technical hurdles associated with expanding hepatocytes has limited the number patients that could have otherwise been treated effectively with liver or hepatocyte transplantation. Therefore, identification of the molecular and cellular pathways that allow expansion and engraftment of hepatocytes and augment liver regeneration will have significant therapeutic impact. We have found that after 70% partial hepatectomy (PH), activation of liver sinusoidal endothelial cells (LSECs) by production of paracrine factors, defined as angiocrine factors, induce liver regeneration. We have defined phenotypic and operational definition of LSECs and have shown that LSECs compose of a specialized vascular network that are in direct cellular contact with hepatocytes, supporting liver regeneration (Ding et al, Nature 2010). After PH, activation of LSECs initiates and sustains the regeneration of remaining lobes of the liver. The activation of the VEGF-A tyrosine kinase receptor (VEGFR2) and Id1 pathway in LSECs upregulated the angiocrine expression of Wnt2 and hepatocyte growth factor (HGF) stimulating hepatic proliferation. However, the mechanism by which PH induces LSECs to produce hepatocyte-active angiocrine factors is unknown. We show that after PH subsets of the hematopoietic cells, (i.e. platelets), are recruited to liver sinusoids and activate LSECs by depositing VEGF-A and SDF-1. In addition to VEGFR2, chemokine receptor for SDF-1, CXCR7, is upregulated specifically on LSECs. Based on these data, we hypothesize that after PH, hematopoietic cells, specifically activated platelets, are recruited to liver LSECs and by deploying VEGF-A and SDF-1 stimulate VEGFR2+CXCR7+ LSECs to produce hepatocyte-active angiocrine factors that initiate and maintain liver regeneration. We will employ liver regeneration and angiogenic models developed in our laboratory to examine these hypotheses by executing the following experiments: Aim 1. Determine the mechanism by which activation of CXCR7 in VEGFR2+ LSECs support angiocrine-mediated hepatocyte regeneration. Aim 2. Define the role of recruited hematopoietic cells, specifically platelets in mediating LSEC activation driving liver regeneration. Aim 3. Determine the role of reciprocal interaction between platelets and Akt-activated LSECs in angiocrine factor induction and accelerating hepatocyte proliferation. Our approach to improve expansion of hepatocytes by unraveling the mechanism by which LSECs support liver regeneration will pave the way for identification of angiocrine factors that support long-term proliferation of functional hepatocytes and engraftment into the liver. In addition, our proposed experiments will allow for development of strategies in which by proper activation of LSECs, will set the stage for accelerating liver regeneration in the clinical setting.
Funding Period: 2012-05-01 - 2017-04-30
more information: NIH RePORT

Top Publications

  1. pmc Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression
    Michael Ginsberg
    Howard Hughes Medical Institute, Ansary Stem Cell Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, 10065, USA
    Cell 151:559-75. 2012
  2. pmc Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration
    Daniel J Nolan
    Department of Genetic Medicine, Howard Hughes Medical Institute, Weill Cornell Medical College, New York, NY 10065, USA
    Dev Cell 26:204-19. 2013
  3. ncbi Akt suppression of TGFβ signaling contributes to the maintenance of vascular identity in embryonic stem cell-derived endothelial cells
    Edo Israely
    Department of Genetic Medicine, Ansary Stem Cell Institute, Howard Hughes Medical Institute, Weill Cornell Medical College, New York, New York, USA
    Stem Cells 32:177-90. 2014
  4. pmc Endothelial Jagged-1 is necessary for homeostatic and regenerative hematopoiesis
    Michael G Poulos
    Department of Genetic Medicine, Ansary Stem Cell Instiute, Weill Cornell Medical College, New York, NY 10021, USA Department of Surgery, Weill Cornell Medical College, New York, NY 10021, USA
    Cell Rep 4:1022-34. 2013
  5. pmc Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis
    Bi Sen Ding
    1 Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA 2
    Nature 505:97-102. 2014
  6. pmc Histone variant H3.3 is an essential maternal factor for oocyte reprogramming
    Duancheng Wen
    Department of Genetic Medicine, Ansary Stem Cell Institute, Howard Hughes Medical Institute, Ronald O Perelman and Claudia Cohen Center for Reproductive Medicine
    Proc Natl Acad Sci U S A 111:7325-30. 2014

Detail Information

Publications6

  1. pmc Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression
    Michael Ginsberg
    Howard Hughes Medical Institute, Ansary Stem Cell Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, 10065, USA
    Cell 151:559-75. 2012
    ..Banking of HLA-typed rAC-VECs establishes a vascular inventory for treatment of diverse disorders...
  2. pmc Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration
    Daniel J Nolan
    Department of Genetic Medicine, Howard Hughes Medical Institute, Weill Cornell Medical College, New York, NY 10065, USA
    Dev Cell 26:204-19. 2013
    ..These factors could be exploited therapeutically to engineer tissue-specific ECs for regeneration. ..
  3. ncbi Akt suppression of TGFβ signaling contributes to the maintenance of vascular identity in embryonic stem cell-derived endothelial cells
    Edo Israely
    Department of Genetic Medicine, Ansary Stem Cell Institute, Howard Hughes Medical Institute, Weill Cornell Medical College, New York, New York, USA
    Stem Cells 32:177-90. 2014
    ....
  4. pmc Endothelial Jagged-1 is necessary for homeostatic and regenerative hematopoiesis
    Michael G Poulos
    Department of Genetic Medicine, Ansary Stem Cell Instiute, Weill Cornell Medical College, New York, NY 10021, USA Department of Surgery, Weill Cornell Medical College, New York, NY 10021, USA
    Cell Rep 4:1022-34. 2013
    ..Taken together, these data demonstrate that the instructive function of endothelial-specific Jagged-1 is required to support the self-renewal and regenerative capacity of HSCs in the adult BM vascular niche...
  5. pmc Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis
    Bi Sen Ding
    1 Ansary Stem Cell Institute, Howard Hughes Medical Institute, Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA 2
    Nature 505:97-102. 2014
    ..These results provide a therapeutic roadmap to achieve hepatic regeneration without provoking fibrosis. ..
  6. pmc Histone variant H3.3 is an essential maternal factor for oocyte reprogramming
    Duancheng Wen
    Department of Genetic Medicine, Ansary Stem Cell Institute, Howard Hughes Medical Institute, Ronald O Perelman and Claudia Cohen Center for Reproductive Medicine
    Proc Natl Acad Sci U S A 111:7325-30. 2014
    ..3 protein. Our study shows that H3.3 is a crucial maternal factor for oocyte reprogramming and provides a practical model to directly dissect the oocyte for its reprogramming capacity. ..

Research Grants30

  1. Role of Bile Acids in the Initiation of Liver Regeneration
    Willscott E Naugler; Fiscal Year: 2013
    ....
  2. Novel Approaches to Understanding the Nutrient Regulation of Fetal Somatic Growth
    Philip A Gruppuso; Fiscal Year: 2013
    ....
  3. Role of microRNA-122 in hepatocarcinogenesis using conditional knock out mice
    Kalpana Ghoshal; Fiscal Year: 2013
    ..Thus, establishing role of miR-122 mimetic in an animal model (in preclinical trial) would be a major milestone in the treatment of this deadly disease in the near future. ..
  4. Role of Wnt/Beta-Catenin Signaling in Liver Development
    SATDARSHAN SINGH MONGA; Fiscal Year: 2013
    ..The molecular basis of these findings will be elucidated. Thus, this proposal will be a comprehensive analysis of canonical &noncanonical Wnt signaling in hepatic biology. ..