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Are Mesenchymal Stromal Cells Immune Cells? Martin J Hoogduijn

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Are Mesenchymal Stromal Cells Immune Cells? Martin J Hoogduijn Hoogduijn Arthritis Research & Therapy (2015) 17:88 DOI 10.1186/s13075-015-0596-3 REVIEW Open Access Are mesenchymal stromal cells immune cells? Martin J Hoogduijn however, covers various subsets of MSCs with different Abstract phenotypes and different functions [4,5]. Cell isolation Mesenchymal stromal cells (MSCs) are considered to be procedures can, therefore, affect the cellular compos- promising agents for the treatment of immunological ition of MSC cultures. Culture conditions can have a disease. Although originally identified as precursor cells further impact on the phenotype and function of MSCs for mesenchymal lineages, in vitro studies have [6]. This may affect study outcomes. Therefore, some demonstrated that MSCs possess diverse immune care should be taken in comparing the results of studies regulatory capacities. Pre-clinical models have shown using different MSC isolation and culture procedures. beneficial effects of MSCs in multiple immunological In the bone marrow, MSCs have a supportive function diseases and a number of phase 1/2 clinical trials carried for the haematopoietic system and provide a niche for out so far have reported signs of immune modulation haematopoietic progenitor cells to mature. The presence after MSC infusion. These data indicate that MSCs play a of MSCs is not limited, however, to the bone marrow central role in the immune response. This raises the and in other tissues, such as adipose tissue, muscle and academic question whether MSCs are immune cells multiple organs, they provide support for tissue cells by or whether they are tissue precursor cells with producing growth factors and matrix proteins. In immunoregulatory capacity. Correct understanding addition to their differentiation and tissue supportive of the immunological properties and origin of MSCs functions, MSCs have a well-established immune modu- will aid in the appropriate and safe use of the latory function. Several in vitro studies have demon- cells for clinical therapy. In this review the whole strated that MSCs are able to effectively inhibit T spectrum of immunological properties of MSCs is lymphocyte [7,8] and natural killer (NK) lymphocyte [9] discussed with the aim of determining the position proliferation, impair antibody production by B cells [10], of MSCs in the immune system. and inhibit the maturation and function of dendritic cells [11]. Studies in animal models have shown that MSCs can reduce disease progression and/or severity of Introduction various immune diseases such as collagen-induced arth- Mesenchymal stromal cells (MSCs) were originally ritis [12], experimental autoimmune encephalomyelitis identified as precursors for cells of the osteogenic [13], experimental colitis and sepsis [14]. It is believed lineage [1]. They were later discovered to be able to that MSCs mediate their beneficial effects by modulating differentiate also into the chondrogenic, adipogenic the immune system, although the exact mechanisms of and myogenic lineages [2]. Within the scientific com- immunomodulation by MSCs in vivo are not clear. Even munity there is some controversy about the naming though there is abundant evidence that MSCs modulate and precise definition of MSCs. The term 'mesenchy- immune responses by interacting with cells of the im- mal stromal cell' is used in parallel with 'mesenchymal mune system, the question is whether MSCs themselves stem cell' and 'multipotent mesenchymal stromal cell'. should be perceived as true immune cells. Do MSCs ex- MSCs are in fact a heterogeneous population of cells ercise immune functions like immune cells do and what that express CD73, CD90 and CD105 and lack the haem- is their response to pathogens? In this review, the vari- atopoietic lineage markers CD45, CD34, CD11c, CD14, ous immunological roles of MSCs are discussed, culmin- CD19, CD79A and HLA-DR [3]. This immunophenotype, ating in a conclusion on the position of MSCs in the immune system. Correspondence: [email protected] Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands © 2015 Hoogduijn; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hoogduijn Arthritis Research & Therapy (2015) 17:88 Page 2 of 7 Immunological properties of mesenchymal Adaptation to inflammatory conditions stromal cells MSCs can be considered as genuine regulators of the Interaction with immune cells immune system because they adapt their immunoregula- MSCs interact with cells of the immune system via a pleth- tory properties to the local immunological milieu. MSCs ora of mechanisms. They secrete anti-inflammatory factors sense inflammation and in response to pro-inflammatory such as transforming growth factor β (TGF-β), hepatocyte cytokines, in particular interferon-γ and tumour necrosis growth factor (HGF) and prostaglandin-E2 (PGE-2) [7,8], factor (TNF)-α, they change their immunological role. In and they express cell surface molecules with immunosup- the absence of inflammation, MSCs promote the survival pressive properties such as programmed death ligand 1 of T lymphocytes [26] and can even stimulate their pro- (PD-L1) and Fas ligand [15,16], via which they directly tar- liferation, partly via IL-6-dependent mechanisms [27]. get immune cells and inhibit their activation and function. MSCs have recently been identified as producers of IL-7 MSCs furthermore attract immune cells by secreting a [28], which stimulates the differentiation of haematopoi- broad mixture of chemokines. In particular, the neutrophil etic cells into lymphoid cells but also promotes the pro- chemo-attractant interleukin (IL)-8 and the monocyte- liferation of lymphocytes. Once placed under immune attractant CCL2 are secreted in high amounts by MSCs activating conditions, MSCs upregulate the expression of [17]. Chemokine secretion by MSCs may act in a dual way IDO, HGF, PD-L1, TNF-stimulated gene 6 protein and to modulate the immune response. Reactive immune cells PGE2-producing cyclooxygenase 2 [29] as part of im- will be attracted and exert their immunological function, munological negative feedback loops [30]. MSCs adapted but at the same time they may be targeted by MSCs and to inflammatory conditions will inhibit immune cell acti- inhibited in their function. There is evidence that MSCs vation and proliferation [31] and increase their regulatory bind activated immune cells [18], potentially to keep them T cell-inducing capacity [32]. Even though the expression at a close distance to enhance the effect of their immuno- of pro-inflammatory factors such as IL-6, IL-7 and several suppressive actions. The immunoregulatory effects of MSCs chemokines by MSCs is also increased under inflamma- are not only directed directly against efxfector immune cells. tory conditions, the immunosuppressive effects of MSCs MSCs do not themselves produce the anti-inflammatory prevail under these conditions. MSCs thus play a central cytokine IL-10, but they induce other cell types to do this role in maintaining immune homeostasis by interacting [19]. Via the secretion of TGF-β and other factors MSCs with immune cells via cytokines, chemokines, cell surface also promote the induction of regulatory T cells [20], regula- molecules and metabolic pathways. The question is whether tory macrophages [21] and regulatory B cells [22], and in this is sufficient to qualify MSCs as immune cells. Strictly this way pass on their immunosuppressive effects to other speaking, an immune cell protects organisms against patho- cell types that exert different mechanisms of immune sup- gens, cleans up cell debris, and removes diseased cells. The pression. A schematic overview of the interactions between MSC functions described above steer the activities of the MSCs and immune cells is depicted in Figure 1. immune system but do not by themselves represent core immune functions. Do MSCs possess these properties? Metabolic control of the immune system In addition to the well described mechanisms of immune Role of mesenchymal stromal cells in immune modulation via cytokines, chemokines and inhibitory co- defence stimulation molecules, MSCs are actively involved in the Immune cell effector functions metabolic control of the immune system. MSCs can be in- Immune cells fight diseased cells and pathogens by cyto- duced to express the enzyme indoleamine 2,3-dioxygenase toxic activity, antibody production, and phagocytosis. (IDO), which has a potent capacity to inhibit lymphocyte MSCs do not express granzymes or perforins and do not proliferation by metabolising L-tryptophan to L-kynurenine produce antibodies and are not, therefore, capable of cyto- [23]. Reduced levels of L-tryptophan suppress lymphocyte toxic activity or participation in the humoral defence. proliferation and, simultaneously, high levels of L- There is some evidence, however, that MSCs possess kynurenine impose a block on proliferation as well. Fur- phagocytic properties. It was shown that MSCs can phago- thermore, MSCs strongly and constitutively express CD73 cytise apoptotic cells, which as a result enhances their [3], which acts in concordance with CD39 on
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