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. Author manuscript; available in PMC: 2013 Nov 1.
Published in final edited form as: Int J Biochem Cell Biol. 2012 Aug 9;44(11):2044–2050. doi: 10.1016/j.biocel.2012.08.003

The Role of Recipient T Cells in Mesenchymal Stem Cell-Based Tissue Regeneration

Yi Liu 1,2, Songlin Wang 3, Songtao Shi 2
PMCID: PMC3454862  NIHMSID: NIHMS403987  PMID: 22903019

Abstract

Significant progress has been made in stem cell biology, regenerative medicine, and stem cell-based tissue engineering. Such scientific strides highlight the potential of replacing or repairing damaged tissues in congenital abnormalities, diseases, or injuries, as well as constructing functional tissue or organs in vivo. Since mesenchymal stem cells (MSCs) are capable of differentiating into bone-forming cells, they constitute an appropriate cell source to repair damaged bone tissues. In addition, the immunoregulatory property of MSCs provides a foundation for their use in treating a variety of autoimmune diseases. However, the interaction between MSCs and immune cells in cell-based tissue regeneration is largely unknown. In this review, we will discuss the current understanding of MSC-based tissue regeneration, emphasizing the role of the immune microenvironment in bone regeneration.

Introduction

Tissue engineering is commonly defined as “an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function or a whole organ” (Langer et al., 1993). Tissue engineering involves donor cells, synthetic materials (scaffolds), soluble or bound growth factors, and recipient microenvironments. Experimental regenerative medicine is currently investigating virtually every type of tissue and organ within the human body. Pilot studies in a variety of systems, such as urethral, bladder, blood vessel, and tracheal replacement, showed great prospects for cell-based tissue regeneration, either in clinics or laboratories (Bianco et al., 2001; Zandonella 2003; Laflamme et al., 2011; Koike et al., 2004).

Despite the significant demand for repairing severe bone defects caused by congenital malformations, oncologic resection, pathologic degenerative bone destruction, and post-traumatic loss, current therapeutic approaches have often resulted in unsatisfactory clinical outcomes. Therefore, newly developed biotechniques, such as MSC-based bone tissue engineering, should be investigated to overcome current clinical challenges. For MSC-based bone regeneration, the most popular cell source is derived from bone marrow MSCs (BMMSCs). However, the quality and quantity of MSC-mediated bone regeneration may not meet clinical needs, essentially because the mechanisms underlying MSC-mediated tissue regeneration are not fully understood. Furthermore, we still do not understand how donor cells interact with recipient immune cells in vivo, making it difficult to significantly improve MSC-based tissue regeneration. In this review, we will discuss the current knowledge of MSC-based tissue regeneration, emphasizing the crosstalk between MSCs and receipt immune cells, with the aims of 1) highlighting the critical role of the recipient immune system to MSC-based tissue regeneration and 2) providing appropriate approaches to rigorously assess engineered tissue function.

Stem Cell Property of MSCs

MSCs can be derived from a variety of tissues, including amniotic fluid, bone marrow, adipose and dental tissues, etc. (Fig. 1). Each type of tissue-specific MSC possesses advantage and disadvantage biological characteristics as listed in Table 1. BMMSCs were reported to be nonhematopoietic multipotent stem cells and an adherent fibroblast-like population capable of differentiating into osteogenic cells (Friedenstein et al., 1970). MSCs have been confirmed to express CD73, CD90, CD146, CD105, Stro-1, stem cell antigen-1 (Sca-1), octamer-binding transcription factor-4 (Oct-4), pericyte-associated antigen (3G5) and whereas in the absence of CD34, CD45, CD14 or CD11b, CD79a, or CD19 surface molecules (Dominici et al., 2006; Shi et al., 2006). MSCs are also capable of differentiating into both mesenchymal and nonmesenchymal cell types, including, for example, osteoblasts, adipocytes and chondrocytes (Bianco et al., 2001; Friedenstein et al., 1974; Owen et al., 1988; Pittenger et al., 1999; Prockop,1997).

Figure 1.

Figure 1

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Possible sources of mesenchymal stem cells for tissue engineering

Table 1.

Advantages and disadvantages of different MSC sources for tissue engineering.

Source Advantages Disadvantages References
Adipose Rich source, easy isolation and expansion Trauma during harvesting; limited differentiation potentials Locke et al., 2011
Amniotic Fluid Broadly multipotent Limited accessibility De Coppi et al., 2007
Bone marrow As a rich resource; broadly multipotent and well characterized Trauma during harvesting
Dental tissues Easy isolation and expansion; broadly multipotent; ideal for orofacial tissues Some dental stem cells show limited accessibility Zheng et al., 2009
Hair Follicle Easy accessibility, isolation and expansion Limited differentiation potentials Peng et al., 2011
Periosteum Committed osteogenic differentiation Trauma during harvesting; limited differentiation potentials Ferretti et al., 2012
Skeletal muscle Rich source Trauma during harvesting; limited differentiation potentials Chen et al., 2012
Synovium Superiority in cartilage formation Limited accessibility; limited differentiation potentials Jones et al., 2012
Umbilical cord and placenta Highly proliferative, broad differentiation potentials including myogenic Limited accessibility Kadam et al., 2012
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MSCs are generally considered to be poorly immunogenic. Immunological characterization of MSCs revealed that they showed only intermediate expression levels of major histocompatibility complex (MHC) class I and no, or very low, expression of MHC class II antigen and co-stimulatory molecules CD40, CD80 and CD86 (Le Blanc et al., 2003; Zhang et al., 2009; Majumdar et al., 2003). Expression of MHC class I prevented MSCs from behaving like natural killer cells, whereas the absence of co-stimulatory molecules causes a state of anergy in T cells (Ryan et al., 2005; Nauta et al., 2007). Several studies indicated neither differentiated nor undifferentiated MSCs elicit proliferation of allogeneic lymphocytes (Li et al., 2005; Le Blanc, 2003; Djouad et al., 2003). To date, a variety of preclinical and clinical studies have shown that exogenously added autologous and allogenic MSCs could give rise to the generation of new bone and bone-associated tissues to replace damaged and diseased tissues by assisting the regenerative capacities of endogenous cells in the affected areas (García-Gómez et al., 2010; Tasso et al., 2010; Bueno et al., 2009).

Regeneration property of MSCs

There is a great deal of scientific and clinical interest in the potential of using MSC to regeneration the damaged tissues, including bone, skin and cartilage, cardiac, etc (Quarto, et al., 2001; Bianco et al., 2001; Fuster et al., 2001). The most popular cell types include bone marrow-derived MSC, adipose tissue-derived MSCs, peripheral blood MSCs; MSCs from perioplacenta and umbilical cord blood. MSC-based regeneration was associated with following functional properties (Keating et al., 2012; Wu et al., 2007; Battiwalla et al., 2012; Rodríguez et al., 2012): (1) their capacity to differentiate into several cell lineages; (2) their ability to secrete soluble factors which regulate crucial biological functions, such as proliferation and differentiation over a broad spectrum of target cells; and (3) their ability to home to damaged tissues. Based on these properties MSCs are being exploited worldwide for a wide range of potential clinical applications. Until now, MSCs are being used in many clinical trials as therapeutic agents. The major clinical trials for the use of MSC as regenerative medicine purpose are summarized in Table 2 and 3. Although it is indisputable that MSC-based regeneration has offered promising clinical outcome, unstable therapeutic effects and uncleared mechanism limited the advanced application of MSCs in tissue regeneration.

Table 2.

A summary of the major clinical trials for the use of MSC as regenerative medicine and therapy for autoimmune diseases

Disease/Target tissues or organs Methods of MSC administration References
Bone defects/tibia. humerus and ulna Autologous BMMSC+ hydroxyapatite Scaffolds Quarto et al., 2001
Skin defects/cutaneous wounds Autologous BMMSC+ fibrin Falanga et al., 2007
Cartilage defects/trachea Autologous MSC and epithelial cells + acellular trachea matrix Macchiarini et al., 2008
Cardio vascular structures/heart valves Autologous umbilical cord MSC + porous polymer Sodian et al., 2006
Urinary structures/bladder Autologous bladder cells + collagen scaffold Atala et al., 2006
Graft versus host disease (GVHD)/gut and liver Systemic infusion of BMMSC Le Blanc et al., 2004
Systemic lupus erythematosus (SLE)/bone and kidney Systemic infusion of BMMSC or SHED Sun et al., 2009; Yamaza et al., 2010
Systemic sclerosis (SS)/skin Systemic infusion of BMMSC Akiyama et al., 2012
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Table 3.

Current distribution of clinical trials using MSCs (clinicaltrials.gov)

Study Clinical Trials Autologous/Allogeneic Completed Recruiting Other Status
Phase I 139 23/116 32 61 46
Phase II 160 27/133 24 74 62
Phase III 12 2/10 4 5 3
Phase IV 0 0 0 0 0
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Immunomodulatory property of MSCs

It is well known that MSCs have immunosuppressive and immunomodulatory properties in vitro and in vivo. Most in vitro studies showed that MSCs were able to interact with almost all subsets of lymphocytes, including T cells, B cells, natural killer cells, monocyte/macrophages, dendritic cells, and neutrophils (Fig 2) (Krampera et al., 2003; Corcione et al., 2006; Jiang et al., 2005). MSCs could efficiently suppress the proliferation of Th1 and Th17 cells (Di Nicola et al., 2002; Krampera et al., 2006), as well as the production of interferon γ (IFN-γ) by Th1 cells and interleukin-17 (IL17) by Th17 cells, whereas MSCs could enhance IL-4 secretion by Th2 cells (Aggarwal et al., 2005; Zhao et al., 2010). MSCs have been demonstrated to inhibit cytotoxic T lymphocyte (CTL) formation, thereby downregulating CTL-mediated cytotoxicity. MSCs have also been reported to directly or indirectly induce the proliferation of Tregs and promote their immunomodulatory capacity (Aggarwal et al., 2005; Di Ianni et al., 2008). Moreover, MSCs inhibit B cell proliferation, differentiation and antibody secretion in both in vitro coculture system and such animal models as multiple sclerosis mice (Asari et al., 2009; Augello et al., 2005; Corcione et al., 2006; Gerdoni et al., 2007). Additionally, MSCs are capable of inhibiting proliferation, cytokine production, and cytotoxic activity of both resting and preactivated NK cells (Sotiropoulou et al., 2006; Spaggiari et al., 2006; Spaggiari et al., 2008). Although the immunomodulatory mechanism of MSCs remains largely unknown, several soluble factors, or cell contact-dependent mediators, have been proved to play an important role (Aggarwal et al., 2005; Ren et al., 2008; Sheng et al., 2008; Yang et al., 2009; Selmani et al., 2008, Choi, H. et al., 2011; Chiesa et al., 2011; Du Rocher et al., 2012; Giuliani et al., 2011; Jia et al., 2012; Maby-El Hajjami et al., 2009; Nicolaidou et al., 2012; Qu et al., 2012; Sato et al., 2007; Schena et al., 2010; Spaggiari et al., 2009; Tabera et al., 2008) (Fig 2). Recently, our group demonstrates that the transfusion of bone marrow MSCs induces apoptosis in T cell via the Fas/Fas ligand pathway as a novel mechanism for MSC-mediated immune tolerance and immune therapies (Akiyama et al., 2012). Indeed, MSCs express Fas to control their secretion of monocyte chemotactic protein 1 (MCP-1), which attracts T cell migration, facilitating Fas ligand-mediated apoptosis of T cells by MSCs in a cell-cell contact manner. In systemic sclerosis (SS) mouse models and dextran-sulfate-sodium-induced experimental colitis, the apoptotic T cells induced by MSC infusion trigger macrophages to produce TGFβ, leading to a Treg upregulation-associated immune tolerance and eventually ameliorates disease phenotype, respectively (Akiyama et al., 2012). Moreover, a newly identified immunoregulatory property of MSCs provides a foundation for the clinical treatment of a variety of autoimmune diseases, such as acute graft-versus-host disease (GVHD), encephalomyelitis (EAE), multiple sclerosis and systemic lupus (SLE) (Sun et al., 2009; English et al., 2010). The major clinical trials for using MSCs to treat autoimmune diseases are summarized in Table 2 and 3. Interestingly, our group demonstrated that allogenic MSCs effectively ameliorated disease activity in patients with SLE (Sun et al., 2009), whereas another group showed that autologous MSC infusion failed to ameliorate disease activity in SLE patients (Carrion et al., 2010). This may be attributed to diseased-induced impairment of bone marrow MSCs, as observed in SLE patients and SLE-like MRL/lpr mice (Sun et al., 2009). Therefore, health status of the donor from whom MSC are derived may be crucial for cell-based therapies.

Figure 2.

Figure 2

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A summary of the immunomodulatory property of MSCs

Crosstalk between Immune Cells and MSCs

Several studies indicated that priming by inflammatory cytokines is essential for MSC-mediated immunosuppression. That is, no immunosuppression was observed unless MSCs were pretreated with interferon (IFN)-γ, together with TNF-α or IL-1 (Ren et al., 2009; Meisel et al., 2004;Polchert et al., 2008; Mougiakakos et al., 2011; Djouad et al., 2003; Chan et al., 2006). MSCs can participate in antigen presentation if exposed to a narrow window of low levels of IFN-γ through upregulation of MHC-II, whereas high concentrations of IFN-γ and other inflammatory factors, such as TGF-β, suppress MHC-II expression. MHC molecules can be upregulated by IFN-γ treatment (Tang et al., 2008; Romieu-Mourez et al., 2007; Rasmusson et al., 2007). Pretreatment with IFN-γ increased the expression level of MHC class I molecules in MSCs, but failed to restore CTL-mediated killing response (Romieu-Mourez et al., 2007; Zhang et al., 2004), suggesting that MSCs inhibit, but are not the target of, CTL activity. Recent experimental evidence further revealed that stimulated NK cells could efficiently lyse autologous and allogenic MSCs (Crop et al., 2011; Poggi et al., 2006; Chan et al., 2008). Activating NK cell receptors NKp30, NKG2D, and DNAM-1 contributed to NK cell-mediated cytotoxicity against MSCs. IFN-γ-exposed MSCs were less susceptible to NK cell lysis as a consequence of the upregulation of MHC class I molecules at the MSC surface (Chan et al., 2008). Additional studies revealed that IFN-γ-stimulated MSCs present exogenous antigens through MHC class II molecules, resulting in the activation of CD4+ T cells and implying that MSCs may be similar to APCs by possessing antigen presenting function (Stagg et al., 2006; François et al., 2009). MSCs were also able to cross-present exogenous antigens, leading to the induction of CD8+ T-cell proliferation (Liotta et al., 2008). Further studies showed that MSCs express high levels of Toll-like receptors (TLR) 3 and 4. TLR-mediated signaling resulted in the production of proinflammatory mediators, such as IL-1β, IL-6, and IL-8 (Aksu et al., 2008; Spaggiari et al., 2006). In addition, MSCs support the proliferation and stimulation of antibody secretion in B cells (Rasmusson et al., 2007; Traggiai et al., 2008).

Local inflammatory microenvironment affects MSC-based tissue regeneration

It was recently reported that the host immune system, especially T lymphocytes, could affect MSC-mediated bone regeneration (Liu et al., 2011). When bone marrow MSCs were implanted subcutaneously using hydroxyapatite tricalcium phosphate as a carrier, autologous MSCs failed to regenerate bone in C57BL6 mice. However, both human and mouse bone marrow MSCs can form bone and bone-associated hematopoietic marrow components in immunocompromised mice. These data suggest that the recipient immune system may play an inhibitory role in regulating MSC-based tissue regeneration. Further study confirmed that Pan T, CD4+ or CD4+CD25− T cell infusion totally blocked MSC-mediated bone formation and that CD8+ T cells partially blocked MSC-mediated bone formation in immunocompromised mice. However, administration of CD4+CD25+Foxp3+ regulatory T cells (Treg cells) had no inhibitory effect on MSC-mediated bone formation (Liu et al., 2011). It has been reported that interleukin-2 (IL-2)–activated natural killer (NK) cells and CD3/CD28-activated T cells can induce MSC apoptosis through the Fas–Fas ligand (FasL) pathway (Yamaza et al., 2008; Kogianni et al., 2004). In addition, T cells can induce MSC and osteoblast apoptosis through the CD40-CD40L pathway, as observed in some models of bone-related diseases (Hess et al., 1996; Li et al., 2011; Ahuja et al., 2003; Schrum et al., 2003).

Increase in the concentrations of such inflammatory factors as IFN-γ and TNF-α is also negatively correlated with the function of MSCs (Suzawa et al., 2003). A high concentration of IFN-γ inhibits osteogenic differentiation of implanted MSCs by inducing upregulation of smad 6, thereby inhibiting Runt-related transcription factor 2 (Runx2), a key transcription factor associated with osteoblast differentiation. TNF-α is able to induce MSC apoptosis in a dose-dependent manner. However, the combination of IFN-γ and TNF-α significantly accelerates MSC apoptosis through internalization of Fas receptor, which is a death receptor known as tumor necrosis factor receptor superfamily member 6, with reduction of the antiapoptotic 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) (Liu et al., 2011). Therefore, the crosstalk between implanted donor MSCs and recipient immune cells plays a key role in determining the success of MSC-mediated bone regeneration.

MSC-based bone regeneration is regulated by recipient T cells

Since the recipient immune system plays a critical role in MSC-based tissue engineering, it is reasonable to assume that MSC-based tissue regeneration could be improved by modulating recipient T cells. Indeed, reduction of Th1 cytokines IFN-γand TNF-α by systemic infusion of Foxp3+ regulatory T cells, a subpopulation of T cells capable of inducing immune tolerance and ameliorating autoimmune disorders (Aggarwal et al., 2005; Di Ianni et al., 2008; Selmani et al., 2008), markedly improved MSC-based bone regeneration and calvarial defect repair in C57BL/6 mice (Liu et al., 2011). Furthermore, systemically infused MSCs are able to directly or indirectly upregulate Foxp3+ regulatory T cells and home to injury and diseased sites, which may contribute to the tissue repair process (Suzawa et al., 2005; Horwitz et al., 2002; Herrera et al., 2004). The contribution of MSCs to tissue repair is also mediated by secretion of paracrine factors with angiogenic and antiapoptotic properties (Rüster et al., 2006; Kinnaird et al., 2004; Kinnaird et al., 2004). These paracrine factors not only attract endothelial cells and macrophages, but they are also likely to stimulate resident stem/progenitor cells to facilitate the process for tissue repair (Chen et al., 2008; Nakanishi et al., 2008). Therefore, systemic MSC infusion may improve cell-based tissue regeneration through upregulating Tregs, homing to injured sites, and modifying the microenvironment by paracrine factors. Moreover, site-specific pharmacological administration, such as using aspirin, was capable of improving MSC-based bone regeneration and calvarial defect repair via inhibition of the Th1 cytokines IFN-γ and TNF-α (Liu et al., 2011). The therapeutic effects of aspirin in preclinical tests and clinical trials for improving fracture healing may be the focus of future studies.

Conclusions

Recent progress in stem cell biology and tissue engineering suggests that MSC-based tissue regeneration may have an expanded clinical applicability in the future and may represent a viable therapeutic option for those who would benefit from the life-extending benefits of tissue replacement or repair. However, there are still several important issues linked to clinical use of MSCs. Since the health status of the donor from whom MSC are derived varies, it is important to establish effective and reliable protocols to characterize donor MSCs prior to clinical application. Moreover, it will be interesting to clarify the possible role of MSCs in promoting immunosuppression when they are locally implanted, and how these effects can be counterbalanced in order to maintain the homeostasis of the recipients. Properly understanding the characteristics of MSCs and the relationship between host immune system and donor MSCs will provide a foundation for improving the therapeutic effect on MSC-based tissue regeneration.

Acknowledgments

Some studies reported in this manuscript were supported by grants from National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services (R01DE017449 and R01 DE019932 to S.S.)

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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