Interplay between Mesenchymal Stem Cells and Lymphocytes

Abstract

In addition to their potential for replacing damaged and diseased tissues by differentiating into tissue-specific cells, mesenchymal stem cells (MSCs) have been found to interact closely with immune cells, such as lymphocytes. In this review, we will discuss current research regarding the immunomodulatory properties of MSCs and the effects of lymphocytes on MSCs. We will suggest how these findings could be translated to potential clinical treatment. MSCs can regulate immune response by inducing activated T-cell apoptosis through the FAS ligand (FASL)/FAS-mediated death pathway via cell-cell contact, leading to up-regulation of regulatory T-cells (Tregs), which ultimately results in immune tolerance. Conversely, lymphocytes can impair survival and osteogenic differentiation of implanted MSCs by secreting the pro-inflammatory cytokines IFN-γ and TNF-α and/or through the FASL/FAS-mediated death pathway, thereby negatively affecting MSC-mediated tissue regeneration. One novel strategy to improve MSC-based tissue engineering involves the reduction of IFN-γ and TNF-α concentration by systemic infusion of Tregs or local application of aspirin. Further understanding of the mechanisms underlying the interplay between lymphocytes and MSCs may be helpful in the development of promising approaches to improve cell-based regenerative medicine and immune therapies.

Introduction

Mesenchymal stem cells (MSCs) are a population of plastic-adherent stromal cells with self-renewal and multipotent differentiation capabilities (Friedenstein et al., 1970; Caplan, 1991; Shi and Gronthos, 2003). MSCs reside in a wide spectrum of post-natal tissue types (da Silva Meirelles et al., 2006; Bi et al., 2007), and they have been successfully isolated from several orofacial tissues (Gronthos et al., 2000; Miura et al., 2003; Seo et al., 2004; Morsczeck et al., 2005; Sonoyama et al., 2006; Zhang et al., 2009; Yamaza et al., 2011). In addition to their potential for replacing damaged and diseased tissue by differentiating into tissue-specific cells, MSCs have been shown to interact with hematopoietic stem cells (HSCs) by controlling or directly providing a stem cell niche for HSCs (Sacchetti et al., 2007; Mendez-Ferrer et al., 2010). MSC ablation has been proven to disrupt hematopoiesis (Raaijmakers et al., 2010). Lymphocytes, originating from HSCs, are a type of white blood cell in the vertebrate immune system. It has recently been shown that MSCs are capable of interacting with lymphocytes. In this review, we discuss current studies on the immunomodulatory properties of MSCs and the effects of lymphocytes on MSCs.

MSCs Target Lymphocytes

Lymphocytes constitute a vital part of the immune system and can be divided into large and small lymphocytes. Large lymphocytes are mainly natural killer cells (NK cells), which are important innate immune cells in the defense against viruses and tumors by cytolysis and secretion of cytokines. Small lymphocytes consist of T-cells and B-cells, which are capable of generating specific immune responses to pathogens, constituting major components of the adaptive immune system. T-cells include CD8⁺ cytotoxic T-lymphocytes (CTLs) that induce death of target cells or CD4⁺ helper T-cells (Ths) that regulate other immune cells (Uccelli et al., 2008). Both autologous and allogenic bone marrow MSCs have been found to suppress T-cell proliferation by secreting mediators, including transforming growth factor β1 (TGFβ1) and hepatocyte growth factor (HGF) (Di Nicola et al., 2002). Since then, the immunomodulatory properties of MSCs have attracted extensive attention. It appears that MSCs derived from bone marrow, the orofacial region, and other areas of the body are able to target all subsets of lymphocytes (Fig. 1) (Ren et al., 2008; Zhao et al., 2010).

Figure 1.

Immunomodulatory properties of mesenchymal stem cells (MSCs). (A) MSCs can target several subsets of lymphocytes, including CD4⁺ helper T-lymphocytes (Ths), CD8⁺ cytotoxic T-lymphocytes (CTLs), gammadelta T-cells, natural killer (NK) cells, B-lymphocytes, and regulatory T-lymphocytes (Tregs). These effects may be mediated by several soluble factors secreted by MSCs, including, for example, prostaglandin E₂ (PGE₂), transforming growth factor-β1 (TGF β1), nitric oxide (NO), indoleamine 2,3-dioxygenase (IDO), or hepatocyte growth factor (HGF). (B) Infused MSCs can induce T-cell apoptosis through FAS/FASL-mediated multiple paracrine interactions and cell-cell contacts, as well as promoting the generation of Tregs, which ultimately leads to immune tolerance. This process consists of the following stages: (1) MSCs use FAS to control monocyte chemotactic protein 1 (MCP-1) secretion, and MCP-1 recruits activated T-cells; (2) MSCs use FASL to induce activated T-cell apoptosis; (3) apoptotic T-cells subsequently trigger macrophages to produce high levels of TGFβ; and (4) the high level of TGFβ up-regulates Tregs to induce immune tolerance.

CD4⁺ T-helper cells (Ths) play an important role in the adaptive immune system by activating and directing other immune cells through cytokines or a combination of cell/cell interactions (e.g., CD40 and CD40L). It has been shown that MSCs efficiently suppress proliferation of CD4⁺ Ths by arresting T-cells in the G0/G1 phase (Di Nicola et al., 2002; Glennie et al., 2005; Krampera et al., 2006). Moreover, MSCs are able to reduce Th1-cell-produced interferon γ (IFN-γ) and Th17-cell-produced interleukin-17 (IL17), whereas they enhance Th2 cells to secrete IL-4 (Aggarwal and Pittenger, 2005; Sun et al., 2009). CD8⁺ CTLs mediate major histocompatibility complex (MHC)-restricted killing of allogenic or virus-infected cells, and they are vital for the graft-vs.-leukemia effect. MSCs have been demonstrated to inhibit CTL formation, thereby down-regulating CTL-mediated cytotoxicity (Rasmusson et al., 2003).

Regulatory T-cells (Tregs) are a functionally distinct CD4⁺ T-cell population in the peripheral blood. They express the transcription factor forkhead box P3 (FOXP3) to regulate their own development and function to actively suppress autoimmune response (Fontenot et al., 2003). MSCs have been reported to directly or indirectly promote the proliferation of Tregs and enhance their regulatory capacity (Aggarwal and Pittenger, 2005; Maccario et al., 2005; Di Ianni et al., 2008; Selmani et al., 2008). Gammadelta T-cells play an important role in the immunosurveillance of cancer and have been shown to be implicated in acute graft-vs.-host disease (GVHD). MSCs effectively suppress in vitro expansion of gammadelta T-cells without affecting their cytotoxicity (Petrini et al., 2009). MSCs are also potent suppressors of TCRVgamma9Vdelta2(+) gammadelta lymphocyte proliferation, cytokine production, and cytolytic responses in vitro, as mediated by the cyclooxygenase-2 (COX-2)-dependent production of prostaglandin E₂ (PGE₂) (Martinet et al., 2009). Natural killer (NK) cells are important effector cells of innate immunity and play a key role in antitumor and antiviral effects by their cytotoxic potential and secretion of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and IFN-γ. However, they also contribute to several pathophysiological autoimmune conditions by their cytotoxic activity (Malhotra and Shanker, 2011). MSCs can inhibit the proliferation, cytokine production, and cytotoxic activity of both resting and pre-activated NK cells (Sotiropoulou et al., 2006; Spaggiari et al., 2006).

B-lymphocytes produce antibodies and closely interact with T-cells, thereby contributing to several autoimmune diseases, such as multiple sclerosis. The effects of MSCs on B-cells remain controversial. Most studies have demonstrated that MSCs inhibit B-cell proliferation, differentiation, and antibody secretion in in vitro co-culture assays and in vivo multiple sclerosis models (Augello et al., 2005; Corcione et al., 2006; Gerdoni et al., 2007; Asari et al., 2009). However, other in vitro studies showed that MSCs support B-cell proliferation and stimulate antibody secretion in B-cells (Rasmusson et al., 2007; Traggiai et al., 2008). It is possible that MSC-mediated regulation of B-cells may depend on the developmental stage of B-cells and the local microenvironment.

The immunoregulatory properties of MSCs provide a foundation for the clinical use of MSCs to treat a variety of immune diseases (Table). Since Bartholomew et al. first demonstrated that systemic infusion of allogenic MSCs can prolong skin-graft survival in monkeys by inhibiting T-cells in vivo (Bartholomew et al., 2002), MSC-based immunotherapy has shown successful outcomes in several pre-clinical disease models, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and systemic sclerosis (SS). In terms of using the systemic infusion of MSCs for patient treatment, Le Blanc et al. first reported that allogenic MSC infusion may provide appropriate therapy for a severe treatment-resistant acute GVHD patient (Le Blanc et al., 2004). Our group and collaborators demonstrated that allogenic MSCs can effectively ameliorate disease activity, improve serologic markers, and reverse renal dysfunction in patients with SLE, through up-regulating Tregs and down-regulating Th17 cells, leading to an immune tolerance (Sun et al., 2009). However, another group showed that autologous MSC infusion failed to ameliorate disease activity in SLE patients (Carrion et al., 2010). These discrepant results may be attributed, at least in part, to the impairment of bone marrow MSCs as observed in SLE patients and SLE-like MRL/lpr mice (Sun et al., 2009). Therefore, it is critical to use healthy MSCs for cell-based immune therapies. MSCs have also shown efficacy and safety in several clinical trials for myocardial infarction, acute lung injury, chronic obstructive pulmonary disease (COPD), diabetes, and Crohn’s disease, a painful inflammatory disease in the bowels and gastrointestinal tract (Boumaza et al., 2009; Hare et al., 2009; Ciccocioppo et al., 2011; Matthay et al., 2010; Mannon, 2011; Mabed and Shahin, 2012). Recently, Osiris Therapeutics, Inc. (Columbia, MD, USA) has received market authorization in Canada to market the first undifferentiated stem cell product, Prochymal^®, an intravenously administered formulation of MSCs derived from human bone marrow of healthy adults, for the management of acute GVHD in children who are unresponsive to steroids (Prasad et al., 2011; Pollack, 2012). The emergence of such MSC products provides a promising opportunity for the management of autoimmune diseases by taking advantage of the immunomodulatory properties of MSCs.

Table.

Systemic Infusion of Mesenchymal stem cells (MSCs) for Clinical and Pre-clinical Therapies

Species	Disease	Major Organs Affected	Immunological Mechanisms	References
Human	Graft vs. host disease (GVHD)	Gut and liver	Inhibition of donor T-cell reactivity to the normal tissues of the recipient	Le Blanc et al., 2004; Prasad et al., 2011
Human and mouse	Systemic lupus erythematosus (SLE)	Bone and kidney	Osteoblastic niche reconstruction; inhibition of Th17 and promotion of Tregs	Sun et al., 2009; Yamaza et al., 2010
Human and mouse	Systemic sclerosis (SS)	Skin	Induction of T-cell apoptosis and up-regulation of Tregs through coupling of FAS/ FAS ligand (FASL)	Akiyama et al., 2012
Human	Crohn’s disease	Bowels and gastrointestinal tract	Mucosal T-cell apoptosis in the bowels and gastrointestinal tract	Ciccocioppo et al., 2011; Mannon, 2011
Human and mouse	Chronic obstructive pulmonary disease (COPD), acute lung injury, lung fibrosis	Lung	Inhibition of pro-inflammatory cytokine production	Ortiz et al., 2007; Matthay et al., 2010; Pollack, 2012
Human, rat, and mouse	Diabetes	Pancreas and renal glomeruli	Alteration of T-cell cytokine pattern and preservation of Tregs; inhibition of macrophage infiltration	Lee et al., 2006; Boumaza et al., 2009; Mabed and Shahin, 2012
Human, swine, and mouse	Myocardial infarction	Heart	IL-10-mediated switch from infiltration of pro-inflammatory to anti-inflammatory macrophages; SDF-1/CXCR4-induced engraftment	Freyman et al., 2006; Hare et al., 2009; Dayan et al., 2011; Dong et al., 2012
Monkey	Graft rejection	Skin	Inhibition of T-cells	Bartholomew et al., 2002
Rat	Acute renal failure	Kidney	Inhibition of pro-inflammatory cytokine production	Togel et al., 2005
Mouse	Colitis	Colon and small intestine	Induction of T-cell apoptosis and up-regulation of Tregs through coupling of FAS/FASL, or secretion of immunosuppressive factors	Zhang et al., 2009; Akiyama et al., 2012
Mouse	Encephalomyelitis (EAE) model of multiple sclerosis	Nerve system	Inhibition of myelin-specific T-cells	Zappia et al., 2005
Mouse	Rheumatoid arthritis	Joint	Inhibition of pro-inflammatory cytokine-producing T-cells and induction of Tregs	Augello et al., 2007
Mouse	Acute pancreatitis	Pancreas	Reducing infiltration of CD3+ T-cells and up-regulation of Tregs	Jung et al., 2011

The promising results of treating immune-related diseases by MSC infusion have led to exploration of the underlying mechanisms. It has been shown that MSCs target lymphocytes through several soluble factors, such as PGE₂, TGF-β, nitric oxide (NO), indoleamine 2,3-dioxygenase (IDO), HGF, and human leukocyte antigen G (HLA-G) (Meisel et al., 2004; Sotiropoulou et al., 2006; Sato et al., 2007; Ren et al., 2008, 2009; Selmani et al., 2008; English et al., 2009). Although these studies provided fundamental knowledge for MSC-based immunoregulation, the diverse and conflicting results indicate that the immunomodulatory effects of MSCs are, most likely, a dynamic process, which may be involved in multiple factors. Very recently, our group revealed a new signaling cascade that may contribute to understanding the interplay between infused MSCs and recipient immune cells in MSC-mediated immune therapies. We found that MSCs produce FAS ligand (FASL) to induce activated T-cell apoptosis via cell-cell contact. Additionally, MSCs use FAS, a death receptor known as tumor necrosis factor receptor superfamily member 6, to control secretion of monocyte chemotactic protein 1 (MCP-1), which attracts T-cell migration to ensure cell-cell contact between MSCs and activated T-cells (Akiyama et al., 2012). In a diseased mouse model, including systemic sclerosis (SS) and dextran-sulfate-sodium-induced experimental colitis, apoptotic T-cells, caused by systemic MSC infusion, triggered macrophages to produce high levels of TGFβ, leading to an up-regulation of CD4⁺CD25⁺Foxp3⁺ Tregs. Eventually, up-regulation of Tregs results in an immune tolerance and ameliorates disease phenotype in the animal models (Akiyama et al., 2012). The systemically infused MSCs may also lead to their lodging in the ischemic brain or myocardium, and stromal-cell-derived factor-1 (SDF-1) may play an important role in guiding MSCs to the sites of injury (Li et al., 2005; Dong et al., 2012). Moreover, bone marrow MSCs express C-X-C chemokine receptor type 4 (CXCR-4), the specific receptor of SDF-1, suggesting that the interaction of SDF-1 with CXCR4 may mediate the trafficking of these stem cells to the impaired site (Kortesidis et al., 2005).

The large study-to-study variations in the effects and underlying mechanisms of MSC-lymphocyte interaction may be attributed to the following: (1) variations in MSC properties and status which are due to batch-to-batch variations in MSCs, culture conditions, and human MSC cell division number, etc. (Song et al., 2008; Lee et al., 2012); and (2) variations in in vivo environments derived from different individuals and immune-related diseases (Ren et al., 2008). Rather than only through a single molecule, it is most likely that MSCs exert immunoregulatory effects through a multi-staged biological process involving the use of receptor FAS to control MCP-1 secretion for recruiting activated T-cells and ligand FASL to induce T-cell apoptosis (Akiyama et al., 2012). A full understanding of the mechanisms is the key to solving this problem, and may allow for the use of non-cell-based therapies that replicate the key factors secreted by MSCs.

Importantly, orofacial tissue-derived MSCs have also been demonstrated to have immunoregulatory properties. MSCs from human exfoliated deciduous teeth (SHED) can inhibit secretion of IL-17 in vitro, and they are capable of effectively reversing SLE-associated disorders in MRL/lpr mice by elevating the ratio of Tregs to Th17 cells (Yamaza et al., 2010). Swine MSCs from apical papilla (SCAP) can suppress T-cell proliferation in vitro through an apoptosis-independent mechanism (Ding et al., 2010a). Human MSCs from periodontal ligament (PDLSCs) also possess immunosuppressive properties when co-cultured with activated peripheral blood mononuclear cells (PBMNCs) (Wada et al., 2009). Accumulated evidence shows that gingiva-derived MSCs are a unique and promising cell source for immune therapies (Zhang et al., 2009).

Lymphocytes Affect MSC Survival and Differentiation

Apart from the promising applications in immune therapies, exogenously added MSCs have long been thought capable of generating new bone and associated tissues to replace damaged tissues. The use of culture-expanded MSCs in conjunction with scaffolds has been widely reported for tissue engineering in pre-clinical models and clinical trials. Seed cells, bio-scaffold, and growth factors have long been considered as key factors for tissue engineering, and the majority of studies in this field focus on the development of better bio-scaffolds, especially biocompatible nanomaterials, as well as improvement in the tissue-specific differentiation capabilities of seed cells by exogenous application of growth factors. Despite the marked progress in MSC-based tissue engineering, the main challenge remains the formation of large quantities of high-quality tissue or even complex organs that meet the functional requirements. Recently, it was reported that cells from the recipient microenvironment may participate in cell-based tissue regeneration. Although MSCs are generally considered to be less immunogenic because they constitutively express low levels of MHC class I and are negative for MHC class II (Le Blanc et al., 2003), the survival of implanted MSCs may be affected by the recipient immune system. It has been proved that cytokine-activated NK cells can efficiently lyse both autologous and allogenic MSCs in vitro (Spaggiari et al., 2006; Sotiropoulou et al., 2006). Moreover, T-cells activated by CD3 and CD28 T-cells can induce bone marrow MSC apoptosis through the FAS/FASL pathway (Yamaza et al., 2008). Similarly, activated T-lymphocytes impair orofacial bone/bone-marrow-derived MSCs (OMSCs), suggesting that OMSCs are capable of interacting with systemic immunity (Yamaza et al., 2011). In addition, T-cells induce bone marrow MSC and osteoblast apoptosis through the CD40/CD40L pathway, as observed in some bone-disease-related animal models, such as osteoporosis (Li et al., 2011). Conversely, immune components have been proven to regulate the differentiation of MSCs. For example, it has been shown that pro-inflammatory cytokine TNF-α inhibits MSC adipogenesis and osteoblastogenesis (Suzawa et al., 2003; Lu et al., 2011). These studies suggested that the crosstalk between implanted MSCs and recipient immune cells may play a key role in determining the success of MSC-based tissue regeneration.

Most recently, our group found that host lymphocytes secrete IFN-γ and TNF-α to block MSC-based bone regeneration (Liu et al., 2011). When treating bone marrow MSCs with IFN-γ alone or a combination of IFN-γ and TNF-α in vitro, we found that IFN-γ alone blocks osteogenic differentiation by inducing up-regulation of SMAD family member 6 (SMAD6), thereby inhibiting Runt-related transcription factor 2 (RUNX2), a key transcription factor associated with osteoblast differentiation. In contrast, TNF-α induces MSC apoptosis in a dose-dependent manner. More interestingly, the combination of IFN-γ and TNF-α can accelerate MSC apoptosis through internalization of FAS, with reduction of the anti-apoptotic factors nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB), X-linked inhibitor of apoptosis protein (XIAP), and FLICE-like inhibitory protein (FLIP). By grafting bone marrow MSCs subcutaneously in a mouse model, using hydroxyapatite tricalcium phosphate (HA-TCP) particles as a carrier, we confirmed that recipient T-cells inhibit MSC-based bone regeneration using the same mechanism observed in vitro. Based on this finding, we further applied systemic infusion of Tregs, or local administration of aspirin, to reduce IFN-γ and TNF-α concentration, and found that both methods can markedly alleviate IFN-γ/TNF-α-induced MSC apoptosis, thereby improving MSC-mediated subcutaneous bone formation (Liu et al., 2011). Furthermore, we showed that local aspirin treatment and systemic Treg infusion are able to significantly improve MSC-mediated calvarial bone repair via inhibition of IFN-γ and TNF-α levels (Liu et al., 2011). Therefore, treatment with aspirin or Tregs may provide promising approaches for improving MSC-based tissue engineering (Fig. 2).

Figure 2.

Recipient T-lymphocytes govern Mesenchymal stem cell (MSC)-based bone regeneration via IFN-γ and TNF-α. Recipient T-cells secrete IFN-γ to inhibit osteogenic differentiation of implanted MSCs by inducing Smad6/Runx2 signaling and TNF-α to trigger apoptotic pathway via activation of caspase 8 and caspase 3. However, a combination of IFN-γ and TNF-α treatment initiates FAS internalization and accelerates caspase 8/3 apoptotic process. As a novel strategy to improve MSC-mediated bone regeneration, local administration of aspirin or systemic infusion of Tregs can reduce the levels of IFN-γ and TNF-α, thereby protecting implanted MSCs from recipient T-cell attack.

MSC Immunomodulatory Properties Contribute to Oral Disease Therapy and Regenerative Dentistry

Immunomodulatory properties of MSCs may play an important role in treating immune-related oral diseases. Among the many immune-related diseases in the orofacial region, bisphosphonate- related osteonecrosis of the jaw (BRONJ) is a critical side-effect of bisphosphonate therapy for metastatic cancer or osteoporosis patients, especially in those who undergo high-dose bisphosphonate and immunosuppressant drug administration. To date, appropriate therapy has not yet been established for the treatment of BRONJ, largely due to a lack of understanding of its patho-physiological mechanisms. We have developed a mouse model of BRONJ-like disease by the administration of zoledronate and dexamethasone, an immunosuppressant drug, and found that such BRONJ-like disease in mice is caused by suppression of Tregs and activation of Th17 cells (Kikuiri et al., 2010). Interestingly, systemic infusion of MSCs is able to prevent and cure BRONJ-like disease, possibly via induction of peripheral tolerance, shown as an inhibition of Th17 cells and elevation of Tregs, thereby supporting the rationale for the use of MSCs as an immunomodulatory approach for BRONJ treatment (Kikuiri et al., 2010). Additionally, local transplantation of bone marrow MSCs with platelet-rich plasma was reported to alleviate BRONJ lesion of a patient undergoing alendronate and pamidronate treatment for osteoporosis, with a complete healing observed in a 30-month follow-up (Cella et al., 2011).

The crosstalk between the locally implanted MSCs and recipient cells also presents implications for cell-based regenerative dentistry, which has attracted extensive attention in the past decade. In a swine model of periodontal defects, autologous and allogenic PDLSC-mediated treatment has been demonstrated to result in a regeneration of PDL and recovery of alveolar bone height (Liu et al., 2008; Ding et al., 2010b). Furthermore, SHED have been proved to engraft and regenerate bone to repair critical-size craniofacial bone defects generated in mouse and swine models (Seo et al., 2008; Zheng et al., 2009). In terms of tooth regeneration, it has been demonstrated that a combination of SCAP and PDLSCs is able to generate a bio-root with periodontal ligament tissues in a swine model (Sonoyama et al., 2006). Because of their capability of forming dentin-pulp-like complexes, DPSCs, SHED, and SCAP have also been demonstrated to lead to dentin/pulp tissue regeneration (Gronthos et al., 2000; Huang et al., 2008). However, the oral cavity is a challenging environment with active immune responses, which potentially affects periodontal, jaw bone, and tooth regeneration. For example, a wide spectrum of micro-organisms is colonized in periodontal regions, and produces a variety of factors that elicit a host response of inflammatory cell recruitment with secretion of pro-inflammatory mediators (Thomas and Puleo, 2011). Such active immune responses may, in turn, hamper the performance of MSC-based tissue engineering in repairing periodontitis-induced alveolar bone defects. Therefore, it is critical to seek anti-inflammatory treatments, for example, by using aspirin or Tregs, to provide promising approaches for improving MSC-based regeneration in orofacial regions.

Emerging evidence shows that dental MSCs are preferable for regenerative dentistry and treating immune-related oral diseases because of the following: (1) Compared with MSCs derived from bone marrow or other sources, dental MSCs present easier accessibility with minimal trauma. Notably, SHED are the first MSCs derived from human exfoliated tissue, a very accessible tissue resource (Miura et al., 2003). (2) Dental MSCs, including SHED, SCAP, PDLSCs and jaw bone MSCs, show a strong immunomodulatory capacity, possibly because of the high frequency of exposure to the inflammatory environment in the oral cavity (Wada et al., 2009; Ding et al., 2010a; Yamaza et al., 2010, 2011). (3) Because of their neural crest origins, dental MSCs show robust multi-potential differentiation capabilities, benefiting the regeneration of orofacial tissues in orofacial context (Chung et al., 2009; Yamaza et al., 2011). (4) Dental MSCs usually present high proliferation rates to provide sufficient numbers of cells for therapy (Gronthos et al., 2000; Miura et al., 2003).

Conclusions and Outlook

Understanding the role of MSCs and their therapeutic potential has led to great strides over the past decade. MSCs were initially considered as having the potential to differentiate into only tissue-specific cells for regenerative medicine; however, they are now appreciated as an essential cell type that possesses important immunomodulatory properties capable of treating a variety of immune-related diseases. MSCs can regulate the intensity of immune response by inducing T-cell apoptosis through the FAS/FASL-pathway, along with multiple paracrine interactions and cell-cell contacts, as well as promote the generation of Tregs, resulting in immune tolerance. Conversely, lymphocytes can inhibit MSC survival and differentiation by secreting the pro-inflammatory cytokines IFN-γ and TNF-α and/or through cell-cell-contact-induced MSC apoptosis, thereby negatively affecting MSC-based tissue regeneration. In light of such an in-depth understanding of the interplay between lymphocytes and MSCs, novel strategies to improve MSC-based tissue engineering have been proposed to reduce IFN-γ and TNF-α levels by local aspirin treatment or the systemic infusion of Tregs.

Given the complexity of immune profiles in different individuals and various immune-related diseases, the final outcome of the interplay between lymphocytes and MSCs is very likely to be significantly influenced by the in vivo microenvironments. Therefore, it is important to further characterize differences in the immunomodulatory performances of infused MSCs in individuals with different diseases. Conversely, it will be necessary to further understand how the host lymphocytes affect MSCs in various scenarios, such as during tissue injury and immune diseases. Moreover, it will be interesting to clarify whether the locally implanted MSCs can contribute to both tissue repair and immunomodulatory response, thereby preventing potential autoimmune reactions by the host immune system at the site of injury. Through better understanding of the mechanisms underlying the interplay between lymphocytes and MSCs under different physiological and pathological conditions, we will be able to develop promising strategies to improve regenerative medicine and the treatment of immune-mediated diseases.