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Multipotent mesenchymal stromal cells and the innate immune system

Key Points

  • Multipotent mesenchymal stromal cells (MSCs) are multipotent cells that were initially isolated from the bone marrow. They have been identified in almost all tissues and have a large number of immunomodulatory effects.

  • Based on their immunosuppressive activity, regenerative capacity and immunoprivileged status, MSCs are attractive tools for cellular therapy in inflammatory diseases and are currently being investigated in several clinical studies.

  • MSCs and the components of the innate immune system communicate at several levels, regulating for example the stem cell niche and antimicrobial responses.

  • MSCs residing in the bone marrow are strongly involved in the regulation of haematopoietic stem cell (HSC) homeostasis. Macrophages are an important partner in this process, as they positively regulate the expression of HSC-promoting factors by MSCs.

  • MSCs control the polarization of macrophages. Through the production of cyclooxygenase 2 and the expression of indoleamine 2,3-dioxygenase, MSCs induce interleukin-10-expressing anti-inflammatory M2 macrophages.

  • MSCs attract, activate and increase the lifespan of neutrophils. These beneficial effects can be enhanced by triggering innate immune sensors in MSCs and might support the clearance of pathogens.

  • Two types of MSC have been described, based on their pro-inflammatory (MSC1) and anti-inflammatory (MSC2) phenotypes. Microenvironmental stimuli — such as ligands for Toll-like receptor 3 (TLR3) and TLR4 — are fundamentally involved in this bidirectional polarization.

  • MSCs express several TLRs. Triggering them differentially can affect several biological functions, such as the differentiation, proliferation, migration, antioxidative repertoire and suppressive potency of MSCs.

  • The inflammatory pre-activation of MSCs, for example by interferon-γ, tumour necrosis factor or TLR ligands, is known as 'licensing' and enhances the suppressive activity of MSCs. Deciphering the underlying molecular mechanisms of this effect could help to improve the efficacy of MSC-based cell therapy.

Abstract

Multipotent mesenchymal stromal cells (MSCs) have unique immunoregulatory and regenerative properties that make them an attractive tool for the cellular treatment of autoimmunity and inflammation. Their underlying molecular mechanisms of action together with their clinical benefit — for example, in autoimmunity — are being revealed by an increasing number of clinical trials and preclinical studies of MSCs. However, autoimmunity and therapy-related alloimmunity are not only triggered and sustained by responses of the adaptive immune system; there is growing evidence that components of the innate immune system also have a key role. It is therefore important to study the crosstalk between MSCs and innate immunity, which ranges from the bone marrow niche to injured tissue.

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Figure 1: MSCs have a key role in the HSC niche of the bone marrow and show reciprocal regulation with local monocytes and macrophages.
Figure 2: MSCs and phagocytes closely interact during inflammatory responses.
Figure 3: MSCs inhibit the generation of TH17 cells and promote the reprogramming of differentiated RORγt+ TH17 cells into suppressive FOXP3+ TReg cells.

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Acknowledgements

The authors thank R. Jitschin for critically reviewing and discussing the manuscript. K.L.B. is supported by grants from the Cancer Society of Stockholm, the Children's Cancer Foundation, the Karolinska Institutet, Stockholm City Council, the Swedish Cancer Society, the Swedish Research Council, the Swedish Society of Medicine, the Tobias Foundation and VINNOVA. D.M. is supported by grants from the Interdisciplinary Center for Clinical Research at the University Hospital of the Erlangen and the German Research Foundation.

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Glossary

Mesenchymal

Embryonic tissues of mesodermal origin, consisting of loosely packed, unspecialized cells set in a gelatinous ground substance. Connective tissue, bone, cartilage and the circulatory and lymphatic systems all develop from mesenchymal cells.

Colony-forming-unit fibroblasts

(CFU-fibroblasts). Freshly isolated single MSCs initiate colonies through clonal expansion. Their ability to form colonies still remains a key assay in the assessment of MSC function.

Graft-versus-host disease

(GVHD). Following allogeneic bone marrow transplantation, donor-derived T cells can be activated by residual host-derived antigen-presenting cells. The resulting T cell reactivity can escalate into the life-threatening condition known as GVHD, which mainly targets the skin, liver and intestines.

Crohn's disease

A chronic inflammatory disease of the gastrointestinal tract that is a type of inflammatory bowel disease. Autoimmune processes are thought to be involved in the pathogenesis of the disease.

Multiple sclerosis

An inflammatory disease of the central nervous system. It leads to demyelination and axonal and neuronal degeneration, causing a broad range of neurological symptoms.

Nestin

An intermediate filament that is usually found in neuronal (progenitor) cells. Its expression is associated with cell division, proliferation and morphological changes and might be characteristic of an immature type of MSC.

Sympathetic nerve fibres

Part of the functional division of the autonomic nervous system that innervates the heart, lungs, gastrointestinal tract and sweat glands.

Mesenchymal spheres

Cells with stem cell features (such as MSCs derived from diverse tissues) form spheres in vitro under non-adherent conditions.

HSC-promoting factors

Growth factors, cytokines and other soluble or membrane-bound factors that determine the fate of haematopoietic stem cells (HSCs). They control key functions such as self-renewal, survival, quiescence, motility and adhesion. MSCs express several of these factors, including jagged 1, stem cell factor, CXCL12, angiopoietin 1, vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and N-cadherin.

Adrenergic signalling

Adrenergic nerves release the hormones and neurotransmitters adrenaline and noradrenaline. These molecules are agonists for the G-protein-coupled adrenergic receptors, activation of which leads to downstream alterations in second messengers (cyclic AMP or Ca2+) that widely promote an ergotropic state. Adrenergic receptors are found presynaptically and postsynaptically on the target organs and cells (including immune cells) of the sympathetic nervous system, which contributes to the regulation of vegetative functions.

Haploidentical stem cell transplantation

Allogeneic stem cell transplantation with mismatches at all three histocompatibility loci (HLA-A, HLA-B and HLA-DRB1) is an alternative for patients without HLA-matched donors. However, crossing the major histocompatibility barrier can have substantial immunological consequences, namely graft-versus-host disease, graft rejection and delayed immune reconstitution.

Wnt

A conserved family of paracrine signalling molecules. They regulate several developmental processes, such as proliferation and differentiation. Wnt signalling is, among other mechanisms, a key pathway for promoting epithelial cell proliferation in the intestine.

Regulatory T cells

(TReg cells). A T cell subpopulation with T cell-suppressive capacities mediated by both cell–cell contact and soluble factors (such as TGFβ and IL-10). FOXP3 is the master transcription factor for TReg cells, and the population is essential for immunological homeostasis and the prevention of autoimmunity.

M1 macrophages

Macrophages that have been activated by Toll-like receptor ligands (such as LPS) and interferon-γ and that express, among other molecules, inducible nitric oxide synthase and produce nitric oxide.

M2 macrophages

Macrophages that have been stimulated by interleukin-4 (IL-4) or IL-13 and that express arginase 1, the mannose receptor CD206 and the IL-4 receptor α-chain.

Indoleamine 2,3-dioxygenase

(IDO). An intracellular enzyme that catalyses the oxidative catabolism of L-tryptophan to N-formylkynurenine (KYN). Insufficient availability of the essential amino acid tryptophan and the presence of KYN promote immune tolerance by inducing T cell apoptosis and anergy and the generation of M2 macrophages (among other effects). Remarkably, tryptophan depletion also impedes microbial growth, thereby contributing to antimicrobial defence. MSCs express IDO.

Cyclooxygenase 2

(COX2). An enzyme that initiates the conversion of arachidonic acid into prostaglandin E2 (PGE2). Its expression is inducible (in particular by inflammatory stimuli). MSCs produce and release PGE2, which is involved in several immunomodulatory effects, including the inhibition of dendritic cell maturation and the induction of IL-10+ macrophages.

Zymosan

A polysaccharide isolated from yeast cell walls that is a ligand for Toll-like receptor 2. In macrophages, it elicits a pro-inflammatory response.

TNF-stimulated gene 6

(TSG6). A multifunctional protein that is associated with inflammation and whose expression is upregulated in many cell types in response to various pro-inflammatory mediators. TSG6 has anti-inflammatory effects and could be part of a negative-feedback loop that downregulates inflammatory responses.

Neutrophil extracellular traps

Webs of chromatin fibres that trap and kill microorganisms. Chromatin from the nuclei of neutrophils is extruded to form these extracellular nets, which also contain proteases from the azurophil granules of neutrophils.

Respiratory burst

The process by which molecular oxygen is reduced by the NADPH oxidase system to produce reactive oxygen species. This process accompanies the exposure of neutrophils to microorganisms and/or pro-inflammatory mediators.

Oxidative stress

Cells continuously produce reactive oxygen species (ROS) such as hydrogen peroxide or superoxide anions. Under physiological conditions, mitochondria are the main source, and cellular antioxidants ensure that the redox equilibrium is maintained. During inflammatory responses (and also in cancer), excessive production of ROS leads to a metabolic condition known as oxidative stress, which can lead to apoptosis and necrosis.

Experimental autoimmune encephalomyelitis

(EAE). An experimental animal model of the human autoimmune disease multiple sclerosis. It is induced by immunization with myelin components such as myelin-oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP). Inflammation of the central nervous system leads to demyelination and paralysis.

Complement system

Three independent pathways can initiate the complement cascade. The classical pathway is activated by antigen–antibody immune complexes. The alternative pathway is triggered by direct hydrolysis of complement component C3, and activation of the lectin pathway results from the binding of lectin to mannose residues on the surface of pathogens.

Reactive oxygen species

(ROS). The metabolism of oxygen, and in particular its reduction through the mitochondrial electron-transport chain, generates by-products such as superoxide (O2), hydrogen peroxide (H2O2) and hydroxyl radicals (OH). These three species and the unstable intermediates that are formed by lipid peroxidation are referred to as ROS. ROS can damage important intracellular targets such as DNA, carbohydrates and proteins.

Carboxypeptidase N

An enzyme that regulates biologically active peptides (including the complement anaphylatoxin C3a) by removing carboxy-terminal arginine or lysine residues.

Pattern-recognition receptors

(PRRs). PRRs detect microbial non-self molecules and endogenous danger signals and initiate immune responses. Several types of PRR, which reside either on the cell surface or in the cytoplasm, have been described. These include Toll-like receptors, scavenger receptors, mannose receptors and NOD-like receptors.

Inflammatory MSC licensing

Pro-inflammatory mediators such as IFNγ and TNF activate ('license') MSCs to be immunosuppressive or to boost their suppressive potency. As these pro-inflammatory cytokines are mainly derived from immune effector cells such as T cells, which in turn are inhibited by MSCs, inflammatory licensing is thought to be part of a negative-feedback loop.

Inflammasome

A cytosolic multiprotein complex that activates the inflammatory cascade. When triggered, it activates the protease caspase 1, which cleaves pro-IL-1β and pro-IL-18 into their active pro-inflammatory cytokine forms.

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Le Blanc, K., Mougiakakos, D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 12, 383–396 (2012). https://doi.org/10.1038/nri3209

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