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oai:dspace.mit.edu:1721.1/1391632022-01-15T03:50:36Zcom_1721.1_7582com_1721.1_7581col_1721.1_131022

Edelman, Elazer R. Wilcox, Elise C. Harvard-MIT Program in Health Sciences and Technology 2022-01-14T14:53:56Z 2022-01-14T14:53:56Z 2021-06 2021-06-15T14:03:57.760Z https://hdl.handle.net/1721.1/139163 Endothelial cells (ECs) sense and adapt to their environment, allowing them to shift between a range of functional phenotypes. When connected in a monolayer they create the endothelium, a barrier and a platform from which ECs can individually respond to flow, and circulating cells and factors apically, cell density circumferentially, and substratum composition, stiffness, and texture basolaterally. Plasticity allows ECs to promote vascular homeostasis, and to interact with and modulate the immune system. Changes in endothelial state enable immune cells to migrate into the tissue to repair tissue damage and fight infection. However, the ECs also modulate the function of immune cells through the expression of adhesion molecules, chemokines, major histocompatibility complex (MHC), and an array of co-stimulatory and inhibitor molecules. These interactions allow ECs to act as antigen presenting cells (APCs) and influence the outcome of immune recognition. Thus, the study of ECs elucidates how microenvironment, vascular cell biology, and immune response are not only connected but interdependent. This work explored how cell-substratum interactions influence EC phenotype and function and how these differences affect allorecognition in a model of cell transplantation. Investigation of EC state was carried out using RNA sequencing and flow cytometry while assessment of the allogeneic response included measurements of immune cell cytotoxic ability, T cell proliferation, cytokine release, serum antibodies, and histological staining. We found that differences in substratum led to divergent EC phenotypes which in turn influenced immune response to transplanted cells, both due to the physical barrier of matrix-adhesion and differences in gene expression. Ph.D. Massachusetts Institute of Technology In Copyright - Educational Use Permitted Copyright retained by author(s) https://rightsstatements.org/page/InC-EDU/1.0/ Substratum Interactions Modulate the Interplay between Endothelial Cell Phenotype, Function, and Immune Recognition Thesis application/pdf Doctoral Doctor of Philosophy Publication unknown unknown <Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="46b7d5bc-a528-4aab-a937-65ecfbecd72e"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Title>Substratum Interactions Modulate the Interplay between Endothelial Cell Phenotype, Function, and Immune Recognition</Title> <PublishedIn> <Publication> </Publication> </PublishedIn> <PublicationDate>2021-06</PublicationDate> <Authors> <Author> <DisplayName>Wilcox, Elise C.</DisplayName> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <DisplayName>Massachusetts Institute of Technology</DisplayName> <OrgUnit /> </Publisher> </Publishers> <License>https://rightsstatements.org/page/InC-EDU/1.0/</License> <Abstract>Endothelial cells (ECs) sense and adapt to their environment, allowing them to shift between a range of functional phenotypes. When connected in a monolayer they create the endothelium, a barrier and a platform from which ECs can individually respond to flow, and circulating cells and factors apically, cell density circumferentially, and substratum composition, stiffness, and texture basolaterally. Plasticity allows ECs to promote vascular homeostasis, and to interact with and modulate the immune system. Changes in endothelial state enable immune cells to migrate into the tissue to repair tissue damage and fight infection. However, the ECs also modulate the function of immune cells through the expression of adhesion molecules, chemokines, major histocompatibility complex (MHC), and an array of co-stimulatory and inhibitor molecules. These interactions allow ECs to act as antigen presenting cells (APCs) and influence the outcome of immune recognition. Thus, the study of ECs elucidates how microenvironment, vascular cell biology, and immune response are not only connected but interdependent. This work explored how cell-substratum interactions influence EC phenotype and function and how these differences affect allorecognition in a model of cell transplantation. Investigation of EC state was carried out using RNA sequencing and flow cytometry while assessment of the allogeneic response included measurements of immune cell cytotoxic ability, T cell proliferation, cytokine release, serum antibodies, and histological staining. We found that differences in substratum led to divergent EC phenotypes which in turn influenced immune response to transplanted cells, both due to the physical barrier of matrix-adhesion and differences in gene expression.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication>