Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory joint disease. The cellular effectors include both innate and adaptive immune cells. In addition, fibroblast-like synoviocytes adopt an aggressive and invasive phenotype, which contributes to joint damage, and increased osteoclast activity mediates excessive bone resorption. Current treatment strategies mainly aim to suppress autoimmune inflammation using disease-modifying antirheumatic drugs (DMARDs) and biologics. Although the success of immune modulation and cytokine inhibition is considerable, approximately 30% of patients in trials do not respond satisfactorily to treatments [1,2]. Even when clinical remission is achieved, cartilage and bone damage may be established or continue to progress. A challenging goal is to induce remission via permanent immune tolerance, protect against structural damage, and repair existing damage.
Mesenchymal stromal/stem cells (MSCs) have immunomodulatory and tissue-repair properties, and their use for the management of RA is being explored. The original definition of human MSCs is based on in-vitro properties of isolated and culture-expanded plastic-adherent cells, namely, trilineage differentiation to osteoblasts, chondrocytes, and adipocytes, and expression of CD73, CD90, and CD105, but not haematopoietic or endothelial markers . MSCs have been isolated from several connective tissues, including bone marrow , synovium [5,6], periosteum [7,8], adipose tissue , and umbilical cord  (Fig. 1).
MSCs can regulate inflammation via an array of mechanisms, involving both the adaptive and innate immune response. These include inhibition of T-cell proliferation and function, induction of CD4+CD25+FoxP3+ regulatory T cells (Tregs), suppression of B-cell proliferation, differentiation, and immunoglobulin production, suppression of dendritic cell maturation, promotion of macrophage polarization towards an anti-inflammatory phenotype, and suppression of natural killer cells (for review, see ). Immunomodulation by MSCs is mediated via both direct cell–cell contact and secretion of soluble factors such as prostaglandin E2, indoleamine 2,3-dioxygenase (IDO), nitric oxide, and interleukin-10 (IL-10), released in response to stimulation by interferon (IFN)-γ from activated immune cells . All these mechanisms could contribute to resolution of inflammation in RA.
This review will examine MSCs as a possible therapy for RA by critically assessing recent literature on the mechanisms by which MSCs modulate the immune system and promote repair.
INSIGHTS INTO MESENCHYMAL STROMAL/STEM CELL IMMUNOMODULATORY MECHANISMS IN RHEUMATOID ARTHRITIS
Preclinical studies have shown beneficial effects of MSC therapy in models of RA-like inflammatory arthritis . One of the first studies to demonstrate protective effects of intraperitoneally injected mouse MSCs against joint destruction in collagen-induced arthritis (CIA) failed to detect administered MSCs in the joints, suggesting that prevention of joint damage resulted predominantly from a dampening down of the immune system .
Modulation of T-cell function, including suppression of T-cell proliferation and activation of Tregs, has been implicated [13–15], and recent studies have provided additional insights into the immunomodulatory effects of MSCs in inflammatory arthritis. Lopez-Santalla et al.[16▪] showed that intravenous administration of human adipose-MSCs (Ad-MSCs) in CIA mice decreased granulocyte-macrophage colony-stimulating factor-expressing CD4+ T cells, key effector cells in RA pathophysiology , in blood and spleen. Regulatory T cells, including classical Tregs and IL10+IL17–CD4+ Tr1 cells, were decreased in spleen and increased in draining lymph nodes, suggestive of their mobilization towards inflamed tissues. In addition, an increased proportion of Th17 cells expressed the anti-inflammatory cytokine IL-10 [16▪], suggesting that the previously reported induction of a regulatory phenotype in Th17 cells by MSCs [18,19] also occurs in vivo in the context of CIA. Indeed, this was confirmed in a study by Luz-Crawford et al.[20▪▪] that further showed this to be dependent on glucocorticoid-induced leucine zipper, which inhibits the proinflammatory transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ϰB) and activator protein 1 (AP-1), in MSCs. Downregulation of NF-ϰB signalling may also occur via decreased expression of microRNA (miR)-548e and a resulting derepression of IκB translation [21▪]. Intraperitoneal injection of MSCs in conjunction with a miR-548e-encoding adeno-associated virus prevented the beneficial effects of MSC transplantation on CIA, whereas intraperitoneal injection of antisense-miR-548e alone showed improved arthritis outcome, although the main cell type targeted was not clear from the evidence provided [21▪]. Follicular helper T (Tfh) cells, which provide proliferative signals to B cells in secondary lymphoid tissues , have also been implicated in the immunosuppressive effects of MSCs. Umbilical cord-mesenchymal stromal/stem cells (UC–MSCs) inhibited Tfh cell differentiation in vitro, and intravenous administration of human UC-MSCs in mice after onset of CIA decreased the number of Tfh cells in the spleen, and suppressed their capacity to support B lymphocyte differentiation in an ex vivo coculture assay [23▪▪]. Inhibitory effects of MSCs on B cells were recently shown to be dependent on interactions between MSCs and T cells [24▪], and effects on Tfh cells could thus mediate the indirect suppressive effects of MSCs on B cells.
Strategies to augment the immunomodulatory potency of MSCs have been explored to enhance therapeutic efficacy. For example, coadministration of MSCs and Tr1 cells was more effective in reducing inflammation, pannus formation, and cartilage erosion in the CIA model compared with single cell therapy, possibly through increased IDO expression in MSCs induced by IFN-β and IL-10 produced by the Tr1 cells [25▪]. Another strategy involved engineering of MSCs with microparticles loaded with the glucocorticoid budesonide. Such MSCs exhibited enhanced IDO activity compared with budesonide-preconditioned and naive MSCs, resulting in improved in-vitro immunosuppression .
Protective effects of MSCs against excessive osteoclast-mediated bone resorption, resulting in local and systemic bone loss, are likely mediated via suppression of inflammatory cytokines that promote osteoclastogenesis , and independently, via boosting of Tregs [28,29]. Direct inhibitory effects of MSCs on osteoclastogenesis via production of the receptor activator of nuclear factor kappa-B ligand decoy receptor osteoprotegerin , or through CD200/CD200R-dependent inhibitory interactions with osteoclast precursors , have also been suggested. In addition, a recent study reported that prevention of local and systemic bone loss by administration of syngeneic Ad-MSCs to CIA mice was associated with a decrease in CD11b+c-fms+ osteoclast precursors in bone marrow [32▪], though the mechanisms remain to be elucidated.
Of note, several studies have failed to demonstrate an improvement in experimental CIA with MSC treatment, with some even reporting a worse outcome . In a comprehensive study, Schurgers et al. did not detect any benefit from MSC therapy in CIA, using both intravenous and intraperitoneal routes to administer either syngeneic or allogeneic MSCs. In contrast, injection of Tregs before or after disease onset let to a dramatic improvement of arthritis . Contradictory results may arise from variables including source of MSCs, tissue of origin, MSC culture conditions, timing of treatment, number of cells injected, route of injection, and treatment regime . Although MSCs have low immunogenicity and display low levels of MHC I and absence of MHC II and costimulatory molecules, culture expansion and differentiation of MSCs into mature cell types can increase the expression of MHC class I and II molecules , and allogeneic MSCs may elicit both a humoural and cellular response in vivo[35–37]. Hence, these cells may not be completely immune privileged. Donor-variability is also likely a confounding factor, and many studies fail to demonstrate whether findings are reproducible using MSCs from different human donors.
THE INFLUENCE OF TISSUE SOURCE ON MESENCHYMAL STROMAL/STEM CELL POTENCY
MSCs from several tissues possess immunomodulatory properties, adding to the MSC armamentarium, but also raising critical questions regarding their equivalence vs. diversity in potency and clinical effectiveness. The potency of MSCs appears to be dependent on, among other factors, the ontogenetic pathways through embryonic tissue formation and the adult tissues in which MSCs reside postnatally. For instance, human MSCs from synovium display greater chondrogenic potency in vitro when compared with MSCs from bone marrow, periosteum, and adipose tissue , whereas they are inferior to periosteal MSCs in bone-forming potency in vivo. Similarly, tissue source seems to affect the immunosuppressive effects of MSCs. For example, Ad-MSCs were found to have a greater immunosuppressive capacity on T cells and monocytes in comparison to bone marrow MSCs .
In addition to the plethora of ‘finite’ adult MSCs, MSCs could be derived from embryonic stem cells, recognized as a potential ‘infinite’ and more easily standardizable source of MSCs. It was recently shown that intraperitoneal administration of MSCs derived from human embryonic stem cells can ameliorate CIA when administered after disease onset. Injected MSCs were found to home to draining lymph nodes and to upregulate IDO expression by the host [41▪].
IDENTIFICATION OF MESENCHYMAL STROMAL/STEM CELL SUBSETS IN VIVO
Recent advances have been made in our understanding of the identity and functions of MSCs in vivo in their native tissues, mainly in bone marrow. Subpopulations of MSCs in mouse bone marrow are marked by Pdgfrα and Sca1 , leptin receptor [43,44], Nestin , or Gremlin-1 [46▪▪], with varying degrees of overlap. MSCs have also been identified in mouse synovium . It is becoming clear that different MSC subsets variably contribute to the formation of mesenchymal tissues during development and growth, adult tissue turnover, and following injury. In human bone marrow, MSCs are marked by low-affinity nerve growth factor receptor (LNGFR) (CD271) [48,49] and CD146 [50,51], with the latter shown to be a perivascular subset of LNGFR-expressing cells . Pdgfrα and CD51 mark a subset of CD146+ MSCs that are Nestin+ in both adult mouse and foetal human bone marrow , although Li et al. reported MSCs in adult human bone marrow to be enriched within the Pdgfrαlow/neg fraction of LNGFR+ cells.
Discovery of specific markers will allow isolation of defined MSC populations using standardized protocols, which will aid consistency in research and translation to clinic. In this regard, an important question is whether MSC subpopulations show varying immunomodulatory potency. A recent study [55▪] reported that intra-articular injection of CD146+ UC-MSCs but not CD146- cells ameliorated CIA in mice. However, sorting for CD146 expression in this study was performed on culture-expanded cells. Tormin et al. showed that CD146 expression by freshly sorted CD146neg/lowLNGFR+ MSCs from bone marrow was rapidly upregulated in culture under normoxia to levels comparable with CD146+LNGFR+ cells. The relationship between the CD146+ sorted cells in the study by Wu et al.[55▪] and the cells marked by CD146 expression in vivo is therefore not clear.
An in-depth analysis of MSC lineages and subtypes in vivo will aid investigations aimed at addressing whether MSCs have a specific function to regulate immune homeostasis in their native tissues, and whether immunomodulation is a generic function of MSCs or specific to a distinct MSC subset. In a recent study [56▪], clonal analysis of immortalized human bone marrow-mesenchymal stromal/stem cell (BM-MSCs) revealed the existence of clones lacking multipotency that were positive for CD317 and were enriched for immunomodulatory transcriptional networks. Lineage tracing in mice allowed the identification of a rare nondifferentiating BM-MSC subtype, distinct from perivascular MSCs, which was also found at 1–3% frequency in human BM-MSC fractions [56▪]. An intriguing scenario in RA pathogenesis is that stromal cells become unable to control the aberrant immune system and instead contribute to the perpetuation of joint inflammation in liaison with the immune system .
MESENCHYMAL STROMAL/STEM CELLS AND REPAIR
The repair potential of MSCs has been extensively studied preclinically and trialled in patients with joint surface defects and/or osteoarthritis with promising results (for review, see ). In a recent proof-of-concept phase I/II clinical trial, the intra-articular injection of autologous Ad-MSCs into the osteoarthritic knee improved function and pain without causing adverse events, and reduced cartilage defects as determined by MRI, with histological evidence of hyaline cartilage repair . Instead, the use of MSCs in RA has primarily focused on immune modulation, and the prevailing view is that MSCs prevent joint damage mainly via their immunosuppressive and anti-inflammatory activity. Evidence that the injected MSCs would contribute directly to joint tissue repair is scant. Bioluminescence imaging to trace luciferase-transfected MSCs after intra-articular injection in mice with proteoglycan-induced arthritis showed that MSCs were retained for several weeks in the injected joint , raising the possibility that injected MSCs could directly or indirectly modulate the local stromal compartment to promote intrinsic tissue repair. The recent identification of MSC populations in vivo and development of lineage tracing models will help address this knowledge gap.
An exciting prospect is the use of MSC-derived extracellular vesicles, which have been shown to play roles in mediating tissue regeneration and immunomodulation [61▪,62]. Intriguingly, the beneficial properties of extracellular vesicles may not be reliant on stem cells only. A recent study demonstrated that neutrophil-derived extracellular vesicles delivered into the knee joints of mice with serum-transfer arthritis displayed anti-inflammatory properties, prevented cartilage degradation, and favoured cartilage anabolism by penetrating the avascular cartilage extracellular matrix to deliver bioactive molecules to the chondrocytes [63▪▪]. Extracellular vesicles, directly or loaded with therapeutics, could thus be harnessed as a therapeutic strategy in RA.
CLINICAL EVALUATION OF MESENCHYMAL STROMAL/STEM CELL THERAPY IN RHEUMATOID ARTHRITIS
Intravenous infusion of allogeneic BM-MSCs or UC-MSCs into four patients with established RA, resistant to DMARDs and at least one anti-tumor necrosis factor alpha agent, was safe and resulted in partial and transient clinical improvement . Intravenous injection of UC-MSCs in addition to DMARDs in 136 patients with active RA who had inadequate responses to traditional medication induced a significant clinical improvement when compared with the control group of 36 patients who received DMARDs and medium without MSCs. The therapeutic effects were maintained for 3–6 months, and correlated with an increased percentage of Tregs in peripheral blood . In a recent multicentre, dose-escalation, randomized, single-blind (double-blind for efficacy), placebo-controlled, phase Ib/IIa clinical trial [66▪▪], intravenous infusions of allogeneic Ad-MSCs in 46 patients with active refractory RA (with failure to at least two biologics) were in general well tolerated without evidence of toxicity over 3 months. There was a trend for clinical benefit, which was not persistent after 3 months, suggesting that cell therapy in RA would require repeated administration. However, in some patients, sensitization against allogeneic cells was detected [66▪▪], calling for caution in multiple cell infusions.
In summary, preliminary data in human trials indicate that allogeneic MSCs could be effective in RA but larger, multicentre clinical studies are needed for sound evidence. So far, the use of MSCs in clinical studies has been restricted to patients with severe RA refractory to standard therapies. MSC treatment could be more effective if given at early stages of RA in order to ‘reset’ the immune system by inducing regulatory networks. The selection criteria of RA patients for clinical studies will be crucial.
Advances have been made in understanding the mechanisms of the protective effects of MSC therapy in RA (Fig. 2). The putative ability of MSCs to rewire an autoimmune process into a more naive, tolerant state is an exciting concept. The study of the joint microenvironment and its interactions with the delivered cell populations will be crucial to maximize MSC therapeutic potential. The expanding knowledge of the mechanisms of MSC therapeutic effects will contribute to our understanding of the molecular taxonomy of RA, will inform patient stratification, and will unravel additional targets for pharmacological interventions in our journey to precision rheumatology.
The authors thank all members of the Arthritis & Regenerative Medicine Laboratory.
Financial support and sponsorship
The authors are grateful for support to their research from Arthritis Research UK (grants 19271, 19429, 19667, 20050, and 20775) and the Medical Research Council (grant no. MR/L020211/1).
Conflicts of interest
The authors have no conflicts of interest to disclose.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
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