Tissue-specific endothelial cell heterogeneity contributes to unequal inflammatory responses

Scientific Reports, vol. 11, pp. 1949

Abstract

Endothelial cells (EC) coordinate vascular homeostasis and inflammation. In organ transplantation, EC are a direct alloimmune target. We posited that tissue specific heterogeneity of vascular EC may partly underlie the disparate organ-specific alloimmune risk. We examined the vascular endothelial response to inflammation across six primary endothelial beds from four major transplanted organs: the heart, lung, kidney and liver. First, we reanalyzed a public dataset of cardiac allograft rejection and found that endothelial inflammatory response genes were elevated in human cardiac allograft biopsies undergoing rejection compared with stable grafts. Next, the inducible inflammatory phenotypes of EC from heart, lung, kidney, and liver were characterized in vitro, focused on expression of adhesion molecules and chemokines, and recruitment of allogeneic peripheral blood mononuclear immune cells. Large vessel cardiac EC most highly upregulated VCAM-1, particularly compared with hepatic EC, supported greater leukocyte adhesion and had distinct chemokine profiles after stimulation with cytokines and complement. Differentially expressed gene candidates that are known regulators of cytokine signaling and inflammatory programming were verified in publicly available datasets of organ-specific endothelial transcriptomes. In summary, differential baseline expression of immune regulating genes may contribute to differential vascular inflammatory responses depending on organ.

Authors 7

1. Hasitha Gunawardana

   University of California, Los Angeles

   Affiliation as printed

   Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, 1000 Veteran Avenue, Room 1-520, Los Angeles, CA, 90095, USA

2. Tahmineh Romero

   University of California, Los Angeles

   Affiliation as printed

   Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

3. Ning Yao

   University of California, Los Angeles

   Affiliation as printed

   Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

4. Sebastiaan Heidt Aachen Department of Immunohaematology and Blood Transfusion

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

5. Arend Mulder Aachen Department of Immunohaematology and Blood Transfusion

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

6. David A. Elashoff

   University of California, Los Angeles

   Affiliation as printed

   Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

7. Nicole M. Valenzuela corresponding

   University of California, Los Angeles

   Affiliation as printed

   Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, 1000 Veteran Avenue, Room 1-520, Los Angeles, CA, 90095, USA. npyburn@mednet.ucla.edu

   Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, 1000 Veteran Avenue, Room 1-520, Los Angeles, CA, 90095, USA