Immune dysfunctionality of replicative senescent mesenchymal stromal cells is corrected by IFNγ priming.

• Type of Material: Article
• Authors: Raghavan Chinnadurai, Emory University; Devi Rajan, Emory University; Spencer Ng, Emory University; Kenneth McCullough, Emory University; Dalia Arafat, Georgia Institute of Technology; Edmund Waller, Emory University; Larry Anderson, Emory University; Greg Gibson, Georgia Institute of Technology; Jacques Galipeau, Emory University
• Language: English
• Date: 2017-04-17
• Publisher: American Society of Hematology
• Publication Version: Final Published Version
• Copyright Statement: © 2017 by The American Society of Hematology
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2017006205
• Title of Journal or Parent Work: Blood Advances
• ISSN: 2473-9529
• Volume: 1
• Issue: 11
• Start Page: 628
• End Page: 643
• Grant/Funding Information: The study was supported by a grant from ACTSI/ImmunoEngineering Pilot Award.; Research reported in this publication was supported in part by developmental funds from the Winship Cancer Institute of Emory University (R.C.).; This work was directly supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases award R01DK109508.
• Research Categories: Health Sciences, Oncology; Biology, General

Abstract

Industrial-scale expansion of mesenchymal stromal cells (MSCs) is often used in clinical trials, and the effect of replicative senescence on MSC functionality is of mechanistic interest. Senescent MSCs exhibit cell-cycle arrest, cellular hypertrophy, and express the senescent marker β-galactosidase. Although both fit and senescent MSCs display intact lung-homing properties in vivo, senescent MSCs acquire a significant defect in inhibiting T-cell proliferation and cytokine secretion in vitro. IFNγ does not upregulate HLA-DR on senescent MSCs, whereas its silencing did not reverse fit MSCs' immunosuppressive properties. Secretome analysis of MSC and activated peripheral blood mononuclear cell coculture demonstrate that senescent MSCs are significantly defective in up (vascular endothelial growth factor [VEGF], granulocyte colony-stimulating factor [GCSF], CXCL10, CCL2) or down (IL-1ra, IFNγ, IL-2r, CCL4, tumor necrosis factor-α, IL-5) regulating cytokines/chemokines. Unlike indoleamine 2,3 dioxygenase (IDO), silencing of CXCL9, CXCL10, CXCL11, GCSF, CCL2, and exogenous addition of VEGF, fibroblast growth factor-basic do not modulate MSCs' immunosuppressive properties. Kynurenine levels were downregulated in senescent MSC cocultures compared with fit MSC counterparts, and exogenous addition of kynurenine inhibits T-cell proliferation in the presence of senescent MSCs. IFNγ prelicensing activated several immunomodulatory genes including IDO in fit and senescent MSCs at comparable levels and significantly enhanced senescent MSCs' immunosuppressive effect on T-cell proliferation. Our results define immune functional defects acquired by senescent MSCs, which are reversible by IFNγ prelicensing.