ReviewThe effect of three-dimensional matrix-embedding of endothelial cells on the humoral and cellular immune response
Introduction
The artery is an intensely sensitive organ, and its trilaminar architecture is an essential determining component of its ability to maintain vascular homeostasis. The intact blood vessel is thromboresistant, balances vascular tone with patent flow and initiates cascades of repair without impinging on the lumen. The vascular endothelium, covering nearly 700 m2 in the average person, is the luminal lining of the blood vessels in the body and detects minute changes in the local environment [1]. The endothelium not only serves as a simple physical barrier between circulating (immune) cells, metabolites and the underlying tissue but actively regulates vasomotor tone, thrombogenicity, proliferation and interaction with immune cells of adaptive and innate lineage. In the usual quiescent state, turnover rates of endothelial cells are on the order of months to years, but these cells are easily damaged by mechanical, oxidative, metabolic, and immunologic stressors [1]. Over a century ago, Virchow recognized endothelial dysfunction as one of the triad of elements essential for loss of vascular homeostasis and thrombotic occlusion. Each phase of the vascular response to injury: thrombosis, inflammation, cellular proliferation, and vascular remodeling, is influenced if not controlled by the endothelium [2]. Environmental exposure classically contributed to endothelial injury. More recently therapeutic techniques such as balloon angioplasty, endovascular stent implantation, and vascular surgery all significantly impair the integrity of the endothelium as an intact monolayer [2], [3]. Endothelial dysfunction with endothelial cell immune activation, increased leakiness, apoptosis and angiogenesis has been demonstrated for a wide variety of diseases, including rheumatoid arthritis, psoriasis, multiple sclerosis, gut inflammation, chronic lung disease, diabetes, and atherosclerosis [4], [5], [6], [7], [8].
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Endothelial cells and immune response
Inflammatory changes of the endothelium favor local recruitment of leukocytes, and transendothelial migration of monocytes and T cells into the subintimal space, which is a fundamental step in the response to tissue-invading microbes and antigens. When this phase is overexuberant significant damage can occur. Indeed, leukocyte infiltration is a crucial initiating step in the development of atheroma within the vessel wall. Endothelial immune behavior is tightly regulated. Recruitment and
Three-dimensional matrix-embedding of endothelial cells
It is increasingly evident that organ tissues yield significant control over local immune reactions and cell behavior [19]. As such three-dimensional cell culture systems offer a milieu to study endothelial biosecretory, migratory, and proliferative functionality that is perhaps more physiological and robust than the conventional two-dimensional state of plated cultures [20], [21], [22], [23], [24]. The three-dimensional state offers the opportunity to consider external mechanical and cell
Influence of matrix composition on endothelial cell phenotype
Matrix environment influences pivotal endothelial cell functions: receptors for the extracellular matrix, in particular the integrins, act not only to provide anchorage for endothelial cells, but also provide information about the local microenvironment that facilitates their decision to proliferate, migrate or die [33] and mediate endothelial permeability [34]. Integrins actively affect intracellular signaling, e.g., via focal adhesion kinase, and signaling via different integrins modulates
Immune phenotype of three-dimensional matrix-embedded endothelial cells
As previously demonstrated in other cell systems intracellular cytokine signaling pathways are modulated by the surrounding tissue architecture. We therefore analyzed endothelial expression of adhesion, costimulatory and MHC molecules upon TNF-α and IFN-γ stimulation. Endothelial cells were either placed within collagen-based scaffolds (three-dimensional), grown to confluence on two-dimensional polystyrene tissue culture plates or tissue plates coated with collagen. Whereas the matrix
Interaction with immune cells
Progressive infiltration of engrafted tissues by host mononuclear cells is characteristic of acute rejection. Surprisingly, we could not detect a significant humoral or cellular rejection after implantation of matrix-embedded allo- and even xenogeneic endothelial cells in immunocompetent hosts [32]. In marked contrast to endothelial cells injected as saline suspensions, matrix-embedded endothelial cells did not evoke formation of endothelial-specific antibodies (Fig. 3) or host immune cell
Discussion
Our results corroborate others’ results that composition and spatial formation of extracellular matrix components affect cellular behavior. Yet, to the best of our knowledge our group is the first to demonstrate effects of matrix–endothelial cell connectivity for endothelial cell immunogenicity. Immune responses against cellular and non-cellular components of tissue engineered devices are becoming increasingly appreciated as potential limitations to successful therapeutic approaches. As the
Acknowledgements
Research described in this article was supported by Philip Morris USA Inc. and by Philip Morris International. Heiko Methe was supported by a grant from the Deutsche Herzstiftung, Frankfurt, Germany. Shmuel Hess was supported by the NIH Post-Doctoral Ruth L. Kirschstein Research Service Award, Elazer R. Edelman by a grant from the USA National Institutes of Health (GM 49039).
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