Enhanced Immunosuppression of T Cells by Sustained Presentation of Bioactive Interferon-gamma Within Three-Dimensional Mesenchymal Stem Cell Constructs

• Type of Material: Article
• Authors: Joshua A. Zimmermann, Georgia Institute of Technology; Marian H. Hettiaratchi, Georgia Institute of Technology; Todd McDevitt, Emory University
• Language: English
• Date: 2017-01-01
• Publisher: WILEY
• Publication Version: Final Published Version
• Copyright Statement: © 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.5966/sctm.2016-0044
• Title of Journal or Parent Work: STEM CELLS TRANSLATIONAL MEDICINE
• Volume: 6
• Issue: 1
• Start Page: 223
• End Page: 237
• Grant/Funding Information: This work was supported by National Institutes of Health Grant R21 AI109499. J.A.Z. was supported by the National Science Foundation Stem Cell Biomanufacturing Integrative Graduate Education and Research Traineeship (DGE 0965945) and National Science Foundation Graduate Research Fellowship Program. Additionally, this publication was supported by NIH/NCRR UCSF‐CTSI Grant UL 1 TR000004.
• Keywords: Cell & Tissue Engineering; STEROID-RESISTANT; Cellular; Science & Technology; STROMAL CELLS; IFN-GAMMA; MACROPHAGES; VERSUS-HOST-DISEASE; INDOLEAMINE 2,3-DIOXYGENASE; LYMPHOCYTE-PROLIFERATION; Spheroids; INDUCTION; Life Sciences & Biomedicine; MYOCARDIAL-INFARCTION; Immunomodulation; Indoleamine 2,3-dioxygenase; Mesenchymal stromal cells; DENDRITIC CELLS; Cell Biology
• Research Categories: Biology, Cell; Health Sciences, Immunology

Abstract

The immunomodulatory activity of mesenchymal stem/stromal cells (MSCs) to suppress innate and adaptive immune responses offers a potent cell therapy for modulating inflammation and promoting tissue regeneration. However, the inflammatory cytokine milieu plays a critical role in stimulating MSC immunomodulatory activity. In particular, interferon-g (IFN-γ)-induced expression of indoleamine 2,3-dioxygenase (IDO) is primarily responsible for MSC suppression of T-cell proliferation and activation. Although pretreatment with IFN-g is commonly used to prime MSCs for immunomodulatory activity prior to transplantation, the transient effects of pretreatment may limit the potential of MSCs to potently modulate immune responses. Therefore, the objective of this study was to investigate whether microparticle-mediated presentation of bioactive IFN-γ within three-dimensional spheroidal MSC aggregates could precisely regulate and induce sustained immunomodulatory activity. Delivery of IFN-γ via heparin-microparticles within MSC aggregates induced sustained IDO expression during 1 week of culture, whereas IDO expression by IFN-g-pretreated MSC spheroids rapidly decreased during 2 days. Furthermore, sustained IDO expression induced by IFN-γ-loaded microparticles resulted in an increased and sustained suppression of T-cell activation and proliferation in MSC cocultures with CD3/CD28-activated peripheral blood mononuclear cells. The increased suppression of T cells by MSC spheroids containing IFN-γ-loaded microparticles was dependent on induction of IDO and supported by affecting monocyte secretion from pro-to anti-inflammatory cytokines. Altogether, microparticle delivery of IFN-γ within MSC spheroids provides a potent means of enhancing and sustaining immunomodulatory activity to control MSC immunomodulation after transplantation and thereby improve the efficacy of MSC-based therapies aimed at treating inflammatory and immune diseases.