Immunology and Cell Biology (2013) 91, 3–4 & 2013 Australasian Society for Immunology Inc. All rights reserved 0818-9641/13 www.nature.com/icb
EDITORIAL
A look at the interface between mesenchymal stromal cells and the immune system Immunology and Cell Biology (2013) 91, 3–4; doi:10.1038/icb.2012.68
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ecent interest in mesenchymal stromal cells (MSCs) results from the convergence of two disparate observations concerning their behaviour. First, it has been known for some time that the process of blood cell formation, or hematopoiesis, is fundamentally dependent upon signals obtained either directly or indirectly from MSCs. Indeed, it has been shown that MSCs form an integral part of the hematopoietic stem cell (HSC) niche. Using so-called Whitlock-Witte cultures, adherent bone marrow cells were isolated and used to study the effects of MSCs on early stages of hematopoiesis, particularly B lymphopoiesis.1 The adherent cells growing in such cultures could be maintained in vitro for long term, and from such cultures, a few continuously growing, cloned MSC cell lines were developed. Some time ago, work from Kincade2 highlighted phenotypic and molecular heterogeneity of mouse MSC lines supportive of hematopoiesis. Therapeutically, it has been suggested that coinjection of MSCs along with HSCs could enhance hematopoietic recovery following bone marrow transplantation. The second observation was that initiated by Friedenstein et al.3 who described the growth of plastic-adherent, fibroblast-like cells in cultures of bone marrow. Importantly, Pittenger et al.4 then showed that such cells grown in bulk cultures could be induced to differentiate to three other mesenchymal lineages, namely, fat (adipocytes), cartilage (chondrocytes) and bone (osteoblasts). It is worth pointing out that such assays of potential lineage are relatively crude. These observations, however, were interpreted as indicating that in such cultures, there were precursor or ‘stem’ cells capable of trilineage differentiation. Indeed, Morikawa et al.5 showed that single mouse MSCs possessed trilineage potential. The possibility that MSCs could form tissues particularly affected by degenerative joint diseases, namely, cartilage and bone, resulted in considerable interest in using MSCs for regenerative medical purposes. For clinical situations, transplantation of cells would most likely be carried out with MSCs from another, allogeneic, individual. Immunologists became particularly interested in MSCs following the observations that MSCs were not only weakly immunogenic but also had immunosuppressive activity on both the adaptive and natural immune system. Thus, MSCs were viewed as the perfect cell source for tissue repair; they had potent regenerative ability, yet, were nonimmunogenic. This has sparked a huge amount of interest in MSCs. This special feature of Immunology and Cell Biology presents a series of review articles, written by groups actively involved in investigation of the immunobiology of MSCs. Topics covered focus largely, but not exclusively, on the interactions of MSCs with cells of the immune system.
For bone marrow transplantation, conditioning regimes are used in order to deplete the hematopoietic system of endogenous HSCs and hematopoietic progenitors and to prepare the bone marrow for donor stem cell engraftment. Conditioning can involve use of irradiation and chemotherapy, and it is assumed that mesenchymal elements required to support hematopoiesis survive this treatment. Indeed, in bone marrow transplant recipients, evidence indicates that mesenchymal stromal elements remain largely of host origin. The first article by Sugrue et al.6 reviews this aspect of MSC biology and deals with the ability of MSCs to activate the DNA-damage response (DDR) following irradiation. The authors comprehensively review current knowledge of MSC radiobiology, including the emerging importance of the DDR in mediating MSC radioresistance, and discuss the potential clinical impact of the radioresistance of these stem cells. They also compare the DDR of MSCs with that of other stem cells. This is particularly relevant as some tissue-specific and tumor stem cells show an enhanced DDR and are able to survive doses of irradiation lethal to their differentiated progeny. For the specific immune system, lymphocytes develop potentially expressing a repertoire of antigen-recognition receptors of any specificity, but this initial repertoire is normally purged of most cells capable of recognizing self-molecules. However, the existence of autoimmune diseases clearly indicates that removal of potentially autoreactive lymphocytes is not perfect. Thus, in the T-cell compartment, fine tuning and control of autoreactive escapees are mediated by so-called regulatory T cells or TRegs. How the TReg compartment is itself controlled is an area of active investigation. The article by Burr et al.7 focuses on the interactions between MSCs and TRegs. Three possible mechanisms of MSC/TReg interaction are discussed, namely, via direct cell contact, via soluble mediators or indirectly via effects of MSCs on antigen-presenting cell. The authors then go on to discuss the impact of these findings on the therapeutic uses of MSCs in the control of autoimmune diseases. The ability of MSCs to switch off immune responses has led to the idea that they can be used therapeutically to modulate immune responses in vivo, in particular, to control the orchestrated reaction of the activated innate immune system, namely inflammation. To control inflammation, MSCs should be endowed with an ability to migrate to and remain at sites of inflammation. This topic is addressed in the comprehensive article by English8 that also deals with macrophage reprogramming by MSCs, production of soluble immunomodulatory molecules, alterations in the balance between the different T-helper cell subpopulations, and dendritic cell and TReg cell interactions.
Editorial 4
To continue with innate immunity, interactions between human MSCs and natural killer (NK) cells are the focus of the review by Spaggiari and Moretta.9 This group has published extensively on the cellular and molecular interactions between MSCs and NK cells. MSCs have been shown to inhibit the proliferation and function of NK cells and to hinder the generation of dendritic cells and macrophages. In this article, the authors review their own and other literatures on this topic, including the interactions between MSCs and monocytes, an often neglected and difficult to study subpopulation of blood cells. Monocytes are immature myeloid cells produced by the bone marrow, and transiting via the blood to differentiate into tissue-specific macrophages. Monocytes are endowed with an ability to rapidly differentiate, and interactions with MSCs may well have a profound influence on their fate, especially, toward that of pro-inflammatory macrophages. The group of Verfaille was the first to describe a novel population of bone marrow-derived cells, which they called multipotent adult progenitor cells (MAPCs). MAPCs obtained from both rat and mouse appeared to represent mesenchymal cells at an earlier stage of development than conventional MSCs. MAPCs could proliferate without senescence and could, at the single cell level, differentiate into cells of the three embryonic germ layers. When injected into the blastocyst, a single mouse MAPC could contribute to most somatic tissues. The broader expansion capacity in vitro as well as their more extensive differentiation capacity makes MAPCs attractive candidates for therapeutic applications. Their growth in vitro is crucially dependent on the use of hypoxia and low serum concentration. The article by Jacobs et al.10 compares and contrasts the effects of MAPCs with MSCs on the adaptive as well as innate immune system, with a focus on their lack of immunogenicity and immunomodulatory activities. The therapeutic potentials and status of clinical trials using MAPCs are briefly discussed. Both MAPCs and MSCs are often referred to as cells of low immunogenicity, which presumably means that in an allogeneic setting, they are not rejected by alloreactive T cells, do not prime a secondary allograft response and do not induce alloantibodies. However, the comprehensive review by Griffin et al.11 takes a closer look at the evidence behind these claims. They investigate evidence for the lack of immunogenicity in vivo of normal allogeneic MSCs as well as those that had been previously rendered more immunogenic. By analyzing the literature, they note large variations in study design and results. However, some degree of allo-sensitization, including the generation of alloantibodies, was discernible in many of these studies. Consequently, the authors propose that the concept of MSCs lacking immunogenicity should be reconsidered.
Immunology and Cell Biology
From an immunological perspective, progress in the field of MSC biology is hampered by our inability to efficiently grow mouse MSCs at the clonal level, particularly from C57Bl/6 mice. MSCs are relatively easy to grow from human bone marrow but difficult to grow from the mouse. Routine use of hypoxic conditions would probably greatly improve culture efficiency. Our inability to grow mouse MSCs at the clonal level poses difficulties for investigating their heterogeneity and biological activities. For immunologists, MSCs also pose a paradox in that on the one hand, they are cells supportive of early stages of hematopoiesis and lymphopoiesis, yet on the other, have suppressive properties on mature lymphocytes. How they achieve this dual role is a mystery. Compared with our extensive knowledge of hematopoiesis gleaned over the last 60 odd years, our knowledge of MSC biology remains fairly rudimentary. Hopefully, by applying technologies useful for the dissection of hematopoiesis, such as transgenic reporter mice for lineage tracing, significant inroads into MSC biology will soon be forthcoming. Rhodri Ceredig Department of Physiology, School of Medicine, Nursing and Health Sciences, Regenerative Medicine Institute, National Centre of Biomedical Engineering Science, National University of Ireland, Galway, Ireland E-mail:
[email protected]
1 Whitlock CA, Witte ON. Long-term culture of B lymphocytes and their precursors from murine bone marrow. Proc Natl Acad Sci USA 1982; 79: 3608–3612. 2 Kincade PW. Molecular interactions between stromal cells and B lymphocyte precursors. Sem Immunol 1991; 3: 379–390. 3 Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 1970; 3: 393–403. 4 Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147. 5 Morikawa S, Mabuchi Y, Kubota Y, Nagai Y, Niibe K, Hiratsu E et al. Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J Exp Med 2009; 206: 2483–2496. 6 Sugrue T, Lowndes NF, Ceredig R. Mesenchymal stromal cells: radio-resistant members of the bone marrow. Immunol Cell Biol 2013; 91: 5–11. 7 Burr SP, Dazzi F, Garden OA. Mesenchymal stromal cells and regulatory T cells: the Yin and Yang of peripheral tolerance? Immunol Cell Biol 2013; 91: 12–18. 8 English K. Mechanisms of mesenchymal stromal cell immunomodulation. Immunol Cell Biol 2013; 91: 19–26. 9 Spaggiari GM, Moretta L. Cellular and molecular interactions of mesenchymal stem cells in innate immunity. Immunol Cell Biol 2013; 91: 27–31. 10 Jacobs SA, Roobrouck VD, Verfaillie CM, Van Gool SW. Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells. Immunol Cell Biol 2013; 91: 32–39. 11 Griffin MD, Ryan AE, Alagesan S, Lohan P, Treacy O, Ritter T. Anti-donor immune responses elicited by allogeneic mesenchymal stem cells: what have we learned so far? Immunol Cell Biol 2013; 91: 40–51.
