Mesenchymal stromal cells (MSCs) are multipotent cells found in connective tissues that can differentiate into bone, cartilage, and adipose tissue. Interestingly, they can regulate immune responses in a paracrine way and allogeneic MSCs do not elicit immune response. These properties have encouraged a number of clinical trials in a broad range of regenerative therapies. Although these trials were first focused on their differentiation properties, in the last years, the immunosuppressive features have gained most of the attention. In this review, we will summarize the up-to-date knowledge about the immunosuppressive mechanisms of MSCs in vivo and in vitro and the most promising approaches in clinical investigation.
Mesenchymal stromal cells (MSCs) are found in a variety of tissues, although bone marrow represents the most common source for research and clinical purposes. These cells are multipotent progenitors that have the capacity to differentiate into multiple lineages such as bone, cartilage, and adipocytes [
MSCs have been shown to regulate the activity in a range of effector cells involved in both innate and adaptive immunities. The crosstalk between MSCs and the cells of the immune system leads to an increased production of several soluble immunomodulatory factors. Despite identification of many of these factors, the mechanism behind MSCs immunomodulation is not fully understood. However, the inflammatory environment and in particular the immune cells involved in each phase of the immune response are likely to be the critical determinants of the regulatory process. The immunosuppressive ability of MSCs is not constitutive but rather is induced by crosstalk with cells of the immune system [
The ability of MSCs to modulate several processes of the immune system in vitro has been intensively studied in the last years. MSCs have a broad range of target immune effector cells and are able to inhibit key functions of innate and adaptive immune cells during inflammatory responses. The exact mechanisms by which MSCs are able to regulate immune functions are still not fully understood. However, while the requirement of cell-to-cell contact is not clear, a number of soluble factors involved in the process have been identified.
The most studied soluble molecules and cytokines secreted by MSCs and involved in immunosuppression are indoleamine 2,3-dioxygenase (IDO), prostaglandin E2 (PGE2), transforming growth factor-beta (TGF-
MSC-mediated inhibition of T cell proliferation has been largely described. In vitro, MSCs can inhibit T cell proliferation regardless of the signaling pathway stimulated in the lymphocytes (i.e., alloantigen-, mitogen-, or anti-CD3/anti-CD28-mediated stimulation) [
The mechanisms by which MSCs are able to mediate immunosuppression of T cells are diverse and complex, and several secreted effector molecules have been linked to this process. Among them, IDO, PGE2, TGF-
IDO is the first and rate-limiting enzyme in tryptophan metabolism catalyzing the breakdown of tryptophan to N-formylkynurenine. It is known that both tryptophan starvation and the presence of N-formylkynurenine induce proliferative arrest of T cells [
PGE2 is synthesized from fatty acids by cyclooxygenases 1 and 2 (COX-1, COX-2), and its immunosuppressive effects on T cells have been largely studied. PGE2 reduces interleukin-2 (IL-2) and interferon-gamma (IFN-
The role of TGF-
To which extent HGF, constrictively expressed in MSC [
Finally, HLA-G5, a nonclassical HLA class I molecule, has first been shown in the maternal tolerance to the fetus by mediating inhibition of NK cell cytotoxicity. Since then, its role in immunoregulation has been described in various types of pathological conditions such as viral infections, tumors, autoimmune diseases, and solid organ transplantation [
The relationship between MSCs and NK cells is ambiguous, and the mechanisms by which MSCs regulate inflammatory functions of NK cells are not well understood. On the one hand, freshly isolated NK cells fail to attack MSCs, while in contrast in vitro preactivated NK cells acquire this ability [
The effect of human MSCs on B cells mainly depends on several factors linked to B cell biology, the state of differentiation, and the kind and strength of stimulus given to the cells. Furthermore, results depend on dissection of viability, proliferation, and differentiation of B cells and show strong dependence on methodological differences. While some studies show that MSCs inhibit B cell proliferation, others claim that this effect is not statistically significant, or even that MSCs stimulate B cell proliferation [
The role of MSCs in immunoregulation of monocytes is considered to affect both different maturation steps and their function as antigen-presenting cells (APCs). First, MSCs impair the differentiation and maturation towards effector dendritic cells (DCs). They can induce a reduction in the expression of CD1a, CD40, CD80, CD86, and MHC-II in monocytes along macrophage differentiation and impair the induction of CD40, CD83, and CD86 during the following maturation [
The two main effects of MSCs on neutrophils are an increase of their lifespan and inflammatory activity. Consistent results show a reduction of the spontaneous apoptosis rate in both resting and activated neutrophils mediated by MSCs secreting IL-6. Apoptosis in neutrophils is positively linked to production of reactive oxygen species (ROS). Hence, as MSCs have been shown to inhibit ROS production, they lead to decrease inflammatory activity and reduced onset of respiratory burst of neutrophils [
To date, more than 290 clinical trials involving infusion or transplantation of MSCs have been registered at clinicaltrials.gov, the largest part of which depend on the immunomodulatory properties of MSCs. Most of these trials have not been completed yet, but data collected up to now support the biosafety of MSC transplantation in humans. So far, none of them has reported significant pathological incidences related to transplanted cells. Even if generally they have shown clinical benefits below the expected and immunoregulatory mechanisms are not fully understood, there is a general agreement that therapies based on immunomodulatory features of MSCs aiming to treat a number of immunological disorders that currently have no effective treatments are promising.
Experiments aiming to restore damaged tissues relied first on the ability of MSCs to give rise to mesodermal lineages and eventually also on their immunomodulatory and trophic effects. Despite the success of preclinical studies with MSCs in tissue repair [
Crohn’s disease and ulcerative colitis are inflammatory bowel diseases in which progression impaired immune function plays a key role. Phase I studies have been performed by systemic injection of MSCs in patients that did not respond to conventional treatments; their outcome varies from discrete improvements in Crohn’s disease activity index (CDAI) [
Crohn’s disease often results in the formation of perianal fistulae, which can also result from other inflammatory diseases, such as cryptoglandular disease. A phase I trial involved the local transplantation of autologous MSCs from lipoaspirates in five patients to test the feasibility and safety of the system. 75% of treated fistulae were effectively healed, with no adverse effects reported [
Multiple sclerosis (MS) is a neurodegenerative inflammatory disease in which antibodies are produced against myelin sheaths of the brain and spinal cord neurons, leading to a wide variety of neurological disorders. Despite the efficiency of MSC treatment in rodent models of experimental encephalomyelitis (Table
Pathology | Animal species | Target organ | Mechanism of action | WD | Ref. |
---|---|---|---|---|---|
Lupus erythematosus | Mouse | Bone marrow | Regeneration of hematopoietic niche | Sys | [ |
Rejection of HSC transplantation | Sheep | Hematopoietic compartment | Improve transplantation efficiency, increase hematopoiesis | Sys | [ |
Rejection of cutaneous grafts | Monkey | Skin | Inhibition of T cells | Sys | [ |
Ictus | Rat | Central nervous system | Secretion of neurotrophic factors | Sys | [ |
Acute renal failure | Rat | Kidneys | Secretion of trophic factors. Inhibition of proinflammatory cytokines | Sys | [ |
Diabetes | Mouse | Pancreas and renal glomeruli | Inhibition of macrophage infiltration | Sys | [ |
Diabetes | Mouse | Pancreas | Inhibition of |
Sys | [ |
Rejection of transplanted islets | Mouse | Kidney capsule | Inhibition of |
Loc | [ |
Rheumatoid arthritis | Mouse | Joints | Inhibition of secretion of proinflammatory cytokines and inhibition of T cells | Sys | [ |
Retinal degeneration | Rat | Eyes | Induction and secretion of trophic factors | Loc | [ |
Acute lung injury | Mouse | Lungs | Inhibition of secretion of proinflammatory cytokines | Sys | [ |
Acute lung injury | Mouse | Lungs | Inhibition of secretion of proinflammatory cytokines. |
Loc | [ |
Hepatic failure | Mouse | Liver | Inhibition of inflammatory infiltrate | CM | [ |
Experimental autoimmune encephalomyelitis | Rat | Central nervous system | Inhibition of myelin-specific T cells | Sys | [ |
Myocardial infarction | Rat | Heart | Secretion of trophic factor SFRP2 | Loc | [ |
Ulcerative colitis | Mouse | Gut | Suppression of inflammatory infiltrates and cytokines. Increase of regulatory T cell activity | Sys | [ |
It is widely believed that immune response plays also a crucial role in the development of amyotrophic lateral sclerosis (ALS). ALS is an incurable neurodegenerative disease that progresses rapidly impairing motor neuron function. MSC-based cell therapy has emerged as a promising approach to treat these neurological diseases, due to, on the one hand, their ability to support tissue regeneration and local stem cell stimulation through trophic effects and, on the other hand, their immunomodulatory properties. A third feature of MSCs has been proposed. It is very controversial, which claims that MSCs might have transdifferentiating capacity towards neural lineages [
A phase I clinical trial was performed in ten ALS patients by injecting MSCs in cerebrospinal fluid. Patients showed no symptoms of adverse effects, although the effectiveness of the treatment could not be assessed [
Diabetes is also a promising target for MSC-based therapies, due to its local, autoimmune nature and its high prevalence and severity. MSCs’ ability to suppress autoimmunity against islets, help damaged islet regeneration, and enhance survival of engrafted islets in mouse diabetes models (Table
Graft-versus-host disease (GVHD) is, at least in theory, one of the most suitable candidates for MSC-based applications. In its acute form, this systemic immune reaction prompted by grafted immune cells can be very severe and is often refractory to classical immunosuppressive treatments. The treatment of GVHD by MSC transplantation has successfully overcome phase I and II clinical trials. A pioneer compassionate study involving only one patient showed a complete response after 1 year [
Although GVHD clinical trials have pioneered the use of MSC-mediated immunosuppression to avoid rejection of allografts, increasing numbers of MSC-based clinical trials are being initiated aiming to improve transplanted solid organ tolerance. Experiments in mice have shown that MSCs can increase immune tolerance for allografts (Table
Despite the very optimistic results obtained in mouse models, MSC-based preliminary clinical trials have not fully met the expectations. The lack of obvious outcomes in clinical trials may be the result of specific human MSCs features and MSC-niche interactions and must be further addressed by analyzing these factors in human contexts. Indeed, there is renewed interest in studying these specific interaction processes in order to boost the therapeutic effect of MSCs. Examples of this effort are genetic manipulation of MSCs or in vitro priming of MSCs cultures, which is discussed below.
The ability of MSCs to modulate the activity of surrounding cells is not constitutive but rather requires activation by signals from a proinflammatory environment [
Although the precise signaling pathway involved in the priming by IFN-
IL-1
The fact that these proinflammatory cytokines and signaling pathways can also activate MSC-mediated immunosuppression may seem paradoxical. When the inflammatory reaction overshoots, the same signals that are normally involved in inflammation prime the MSCs and activate their immunomodulatory properties as a negative feedback safety loop. In this regard, the overload of proinflammatory cytokines is precisely the necessary step that activates immunosuppression in MSCs in order to avoid a nondesired immunosuppression due to resident stromal cells. Moreover, in the absence of IFN-
Cell-based therapy employing MSCs has evolved as an interesting approach in the treatment of a wide range of autoimmune disorders as well as graft rejection, and a large number of clinical trials are currently ongoing. Although there are promising results the outcome has not fully met the expectations from preceding experiments in mouse models. This could be due to the differences observed between mechanisms of human and murine MSC immunoregulations. Furthermore, it is known that the immunomodulatory response changes depend on the given inflammatory environment. Increased knowledge about the complex crosstalk between MSCs and the immune system in humans could help to find clues about how to improve the therapeutic effect of MSCs. In the last years, cell priming has become an emerging research area in the field of MSCs immunomodulation. The encouraging results obtained aiming to enhance the immunoregulatory properties of MSCs render primed and genetically modified MSCs interesting alternatives worth being considered in future clinical trials. Additionally, analysis of data from clinical trials will be needed to optimize treatment dose, timing and frequency of administration.
The authors declare that there is no conflict of interests.