Universität zu Köln

Philipp, Denise, Suhr, Laura, Wahlers, Thorsten, Choi, Yeong-Hoon and Paunel-Goerguelue, Adnana (2018). Preconditioning of bone marrow-derived mesenchymal stem cells highly strengthens their potential to promote IL-6-dependent M2b polarization. Stem Cell Res. Ther., 9. LONDON: BMC. ISSN 1757-6512

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Abstract

BackgroundDuring the last decade, mesenchymal stem cells (MSCs) have gained much attention in the field of regenerative medicine due to their capacity to differentiate into different cell types and to promote immunosuppressive effects. However, the underlying mechanism of MSC-mediated immunoregulation is not fully understood so far. Macrophages are distinguished in classical activated, pro-inflammatory M1 and alternatively activated M2 cells, which possess different functions and transcriptional profiles with respect to inflammatory responses. As polarization is not fixed, macrophage functional plasticity might be modulated by the microenvironment allowing them to rapidly react to danger signals and maintaining tissue homeostasis.MethodsMurine MSCs were preconditioned with IL-1 ss and IFN-? to enhance their immunosuppressive capacity regarding macrophage polarization under M1- and M2a-polarizing conditions. Macrophage polarization was analyzed by real-time PCR, flow cytometry, and cytokine detection in culture supernatants. The role of MSC-derived nitric oxide (NO), prostaglandin E2 (PGE2), and IL-6 in this process has been evaluated using siRNA transfection and IL-6 receptor-deficient macrophages, respectively.ResultsPreconditioned, but not unprimed, MSCs secreted high levels of NO, IL-6, and PGE2. Co-culture with macrophages (M0) in the presence of M1 inducers (LPS+IFN-?) led to significant reduction of CD86 and iNOS protein in macrophages and diminished TNF- secretion. Additionally, CD86 and iNOS protein expression as well as NO and IL-10 secretion were markedly increased under M2a-polarizing culture conditions (IL-4). MSC-dependent macrophage polarization did not depend on direct cell-cell contact. Co-culturing in the presence of LPS and IFN-? resulted in the upregulation of M2a, M2b, and M2c marker genes, whereas in the presence of IL-4 only M2b markers were significantly increased. In turn, IL-10-producing regulatory M2b cells significantly inhibited IFN-? expression in CD4(+) T lymphocytes. Finally, we show that MSC-mediated macrophage polarization strongly depends on IL-6, whereas a minor role for NO and PGE2 was found.ConclusionsPreconditioning of MSCs highly strengthens their capacity to regulate macrophage features and to promote immunosuppression. Repression of M1 polarization during inflammation and M2b polarization under anti-inflammatory conditions strongly depend on functional IL-6 signaling in macrophages. The potential benefit of preconditioned MSCs and IL-6 should be considered for future clinical treatment.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Philipp, Denise UNSPECIFIED UNSPECIFIED UNSPECIFIED Suhr, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Wahlers, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Choi, Yeong-Hoon UNSPECIFIED UNSPECIFIED UNSPECIFIED Paunel-Goerguelue, Adnana UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-168996
DOI:	10.1186/s13287-018-1039-2
Journal or Publication Title:	Stem Cell Res. Ther.
Volume:	9
Date:	2018
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1757-6512
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; MACROPHAGE POLARIZATION; STROMAL CELLS; NITRIC-OXIDE; REGULATORY MACROPHAGES; MYOCARDIAL-INFARCTION; APOPTOTIC CELLS; TISSUE-REPAIR; EXPRESSION; KINASE Multiple languages Cell & Tissue Engineering; Cell Biology; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16899