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Preconditioning in an Inflammatory Milieu Augments the Immunotherapeutic Function of Mesenchymal Stromal Cells

1
United States Army Institute of Surgical Research, San Antonio, TX 78234, USA
2
Oak Ridge Institute for Science and Education, Oak Ridge, TN 37830, USA
3
University of Texas at San Antonio, San Antonio, TX 78249, USA
*
Author to whom correspondence should be addressed.
Cells 2019, 8(5), 462; https://doi.org/10.3390/cells8050462
Received: 5 March 2019 / Revised: 9 May 2019 / Accepted: 13 May 2019 / Published: 15 May 2019
(This article belongs to the Special Issue Immunomodulation by Mesenchymal Stem Cells)
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Abstract

Multipotent mesenchymal stromal cells (MSCs) have emerged as potent therapeutic agents for multiple indications. However, recent evidence indicates that MSC function is compromised in the physiological post-injury milieu. In this study, bone marrow (BM)- and adipose-derived (AD)-MSCs were preconditioned in hypoxia with or without inflammatory mediators to potentiate their immunotherapeutic function in preparation for in vivo delivery. Human MSCs were cultured for 48 hours in either normoxia (21% O2) or hypoxia (2% O2) with or without the addition of Cytomix, thus creating 4 groups: 1) normoxia (21%); 2) Cytomix-normoxia (+21%); 3) hypoxia (2%); and 4) Cytomix-hypoxia (+2%). The 4 MSC groups were subjected to comprehensive evaluation of their characteristics and function. Preconditioning did not alter common MSC surface markers; nonetheless, Cytomix treatment triggered an increase in tissue factor (TF) expression. Moreover, the BM-MSCs and AD-MSCs from the +2% group were not able to differentiate to chondrocytes and osteoblasts, respectively. Following Cytomix preconditioning, the metabolism of MSCs was significantly increased while viability was decreased in AD-MSCs, but not in BM-MSCs. MSCs from both tissues showed a significant upregulation of key anti-inflammatory genes, increased secretion of IL-1 receptor antagonist (RA), and enhanced suppression of T-cell proliferation following the Cytomix treatment. Similarly, following a lipopolysaccharide challenge, the Cytomix-treated MSCs suppressed TNF-α secretion, while promoting the production of IL-10 and IL-1RA. These preconditioning approaches facilitate the production of MSCs with robust anti-inflammatory properties. AD-MSCs preconditioned with Cytomix under normoxia appear to be the most promising therapeutic candidates; however, safety concerns, such as thrombogenic disposition of cells due to TF expression, should be carefully considered prior to clinical translation.
Keywords: adipose tissue; bone marrow; mesenchymal stromal cells (MSCs); hypoxia; Cytomix; immunomodulation; anti-inflammatory adipose tissue; bone marrow; mesenchymal stromal cells (MSCs); hypoxia; Cytomix; immunomodulation; anti-inflammatory
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Rodriguez, L.A., II; Mohammadipoor, A.; Alvarado, L.; Kamucheka, R.M.; Asher, A.M.; Cancio, L.C.; Antebi, B. Preconditioning in an Inflammatory Milieu Augments the Immunotherapeutic Function of Mesenchymal Stromal Cells. Cells 2019, 8, 462.

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