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Abstract

Mesenchymal stem cells (MSCs) have been shown to be effective in the management of graft-versus-host disease (GVHD) due to their immunomodulatory effects. In addition to prevention and treatment of GVHD, many studies have demonstrated that MSCs can promote hematopoietic engraftment, accelerate lymphocyte recovery, reduce the risk of graft failure, and repair tissue damage in patients receiving hematopoietic stem cell transplantation (HSCT). Bone marrow (BM) has been considered as the traditional source of MSCs, and most of the knowledge concerning MSCs comes from BM studies. However, BM-derived MSCs have several limitations for their clinical application. Fetal-type MSCs can be isolated easier and proliferate faster in vitro as well as possessing a lower immunogenicity. Therefore, fetal-type MSCs, such as umbilical cord-derived MSCs, represent an excellent alternative source of MSCs. MSCs play multiple important roles in HSCT. Nevertheless, several issues regarding their clinical application remain to be discussed, including the safety of use in humans, the available sources and the convenience of obtaining MSCs, the quality control of in vitro-cultured MSCs and the appropriate cell passages, the optimum cell dose, and the optimum number of infusions. Furthermore, it is important to evaluate whether the rates of cancer relapse and infections increase when using MSCs for GVHD. There are still many questions regarding the clinical application of MSCs to HSCT that need to be answered, and further studies are warranted.

Keywords

Mesenchymal stem cells (MSCs)Hematopoietic stem cell transplantation (HSCT)Graft-versus-host disease (GVHD)Cell-based therapy

Introduction

Hematopoietic stem cell transplantation (HSCT) is an effective therapeutic modality for a variety of diseases. Nevertheless, a number of transplant-related complications, such as tissue damage from conditioning regimens, graft failure, graft-versus-host disease (GVHD), and infections and hemorrhage during the aplastic phase, may be life threatening. Many studies have demonstrated that cotransplantation of hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) can promote hematopoietic engraftment, reduce the incidence of GVHD, accelerate lymphocyte recovery, and reduce the risk of graft failure (7,32,33,37,41,48). Intravenous infusion of bone marrow (BM)-derived MSCs (BMMSCs) is also efficient to treat patients with severe steroid-resistant GVHD (35,36,51). In this review article, we address the biological characteristics of MSCs and the clinical application of MSCs to HSCT. We hope that more patients in the near future undergoing HSCT may benefit from the therapeutic effects of MSCs.

The Biological Properties of MSCs

Definition of MSCs

Biological interest in MSCs, first described by Friedenstein and colleagues in 1966 (22), has risen dramatically over the last decade. However, defining the characteristics of MSCs varies considerably among investigators. According to the minimal criteria of the International Society for Cellular Therapy, MSCs are defined by their growth pattern in vitro, the specific surface antigen expression, and the multipotent differentiation potential (21). MSCs are able to regenerate and have a high proliferative capacity. MSCs proliferate as fibroblastic spindle-shaped cells and must be plastic-adherent when maintained in standard culture conditions (21). MSCs can be characterized by a panel of surface markers, which are negative for hematopoietic antigens (CD34, CD45, CD14, CD11b, CD19, and CD79α), and positive for mesenchymal markers (CD105 and CD73) and cell adhesion molecules (CD29, CD44, CD106, and CD90) (21,44,61). The biological property most unique to MSCs is the capacity for trilineage mesenchymal differentiation, including osteoblasts, adipocytes, and chondroblasts (21). In addition, MSCs display a broader differentiation potential and can differentiate into myocytes, tendinocytes, ligamentocytes, cardiomyocytes, neurons, and other cell types.

Where to Isolate MSCs From?

MSCs are derived from mesodermal progenitor cells. In the functional network analysis, Tsai et al. reported that a set of core gene expression profiles was preserved in spite of the different gene expression profiles observed in MSCs derived from different origins (56). MSCs isolated from adipose tissues (43) or BM (7,32,33,35–37,41,48,51) are adult-type MSCs, while MSCs collected from amniotic fluid (5), amniotic membranes (42), cord blood (11), or umbilical cords (25,54) are fetal-type MSCs. BM has been considered as the traditional source of MSCs, and most clinical experience comes from MSCs derived from adult BM (7,32,33,35–37,41,48,51). The number of MSCs in BM decreases significantly with the age of the donor (9), and acquiring BMMSCs involves an invasive procedure. On the contrary, obtaining fetal-type MSCs is safe for donors and easy. We demonstrated that fetal-type MSCs can proliferate significantly faster than adult-type MSCs (10), indicating that fetal-type MSCs are superior in rapid expansion and consequent downstream applications.

Umbilical cords are rich in MSCs, which can be easily collected and cultured (54). According to our experience, umbilical cord-derived MSCs (UCMSCs) were effective to treat patients with severe steroid-resistant acute GVHD without severe adverse effects (59). We also found that coinfusion of UCMSCs during HSCT can enhance hematopoietic engraftment in patients with severe aplastic anemia (13). Therefore, fetal-type MSCs, such as UCMSCs, are appealing for clinical application.

MSCs Having Low Immunogenicity

MSCs have low immunogenicity and express human leukocyte antigen (HLA)-class I, but not class II molecules (47,55). Compared with adult-type MSCs, fetal-type MSCs are less lineage-committed and express lower levels of HLA-class I molecules, indicating the lower immunogenicity (39,61). Several in vitro studies have demonstrated that using mismatched MSCs does not trigger a proliferative T-cell response in the allogeneic mixed lymphocyte reaction (29,38,47). Transplanted allogeneic MSCs can be detected in recipients at extended time points, suggesting a lack of immune recognition and clearance in vivo (1). In 2008, Le Blanc et al. found that the treatment response to BMMSCs for severe acute GVHD was not related to the degree of HLA compatibility between the recipient and the MSC donor (35). Unlike HSCs, MSCs appear feasible and safe to use even from HLA-incompatible donors. Thus, the utility of MSCs is convenient in clinical cell-based therapy.

The Immunomodulatory Properties of MSCs

MSCs possess immunomodulatory effects (19,60). Many investigations have shown that MSCs can exert profound immunosuppressive effects via modulation of both cellular and innate immune pathways. MSCs have been found to suppress the proliferative response of lymphocytes to allogenic antigens (31,53). The inhibitory effect on B-cell proliferation may be through an arrest in the G₀/G₁ phase of the cell cycle, and the major mechanism of B-cell suppression appears to be through soluble factors produced by MSCs (15). MSCs also inhibit B-cell differentiation and affect chemotactic properties of B-cells (15).

MSCs indirectly modify T-cell responses by changing the maturation of dendritic cells. They are able to block the differentiation of monocytes into dendritic cells and impair the antigen-presenting ability (42). MSCs also have direct effects on T-cell functioning. They inhibit T-cell proliferation by secreting soluble factors and cause division arrest of T-cells (20,24,49). Furthermore, MSCs alter the cytokine secretion profiles of dendritic cells, T-cells, and natural killer cells to induce a more anti-inflammatory and tolerant phenotype (1). Based on their immunomodulatory properties, MSCs are ideal candidates in the management of diseases associated with aberrant immune responses, such as GVHD.

Clinical Application of MSCs to HSCT

Promotion of Hematopoietic Engraftment

MSCs play an important role in providing the specialized BM microenvironment. BM stromal cells derived from MSCs provide an appropriate scaffold and a complex network of cytokines, adhesion molecules, and extracellular matrix proteins (17,34). They interact with HSCs and regulate hematopoiesis. Many studies have reported that MSCs can promote HSC expansion in vitro (16,28,38). In animal models, MSCs have been demonstrated to enhance the engraftment of donor HSCs after cotransplantation (2,3,46). Like BMMSCs, UCMSCs are shown to support engraftment of a limited number of human HSCs from cord blood in a nonobese diabetic-severe combined immunodeficient (NOD/SCID) transplant model (23).

MSCs are crucial for BM microenvironment. Chemotherapy and/or radiotherapy prior to HSCT damage the BM stroma and may affect and delay hematopoietic engraftment. In 2000, Koc et al. first reported rapid hematopoietic recovery after coinfusion of autologous BMMSCs at the time of HSCT without significant side effects (32). Accordingly, Lazarus et al. presented a multicenter trial involving 46 patients receiving allogeneic HSCs and MSCs from HLA-identical siblings and observed prompt hematopoietic recovery in most patients (33). Due to the limited number of HSCs in cord blood, cord blood transplantation often results in slower engraftment that may be associated with more complications, such as infections and hemorrhage. BMMSCs have also been reported to promote hematopoietic engraftment after cord blood transplantation (41). The beneficial effects of MSCs on engraftment after HSCT may relate to their supportive role in hematopoiesis, especially when available HSCs are limited.

Bacigalupo et al. found that BMMSCs from patients with severe aplastic anemia were deficient in suppressing T-cell proliferation and cytokine release, suggesting the lack of MSC immunoprotection in the BM (6). We demonstrated the poor potential of proliferation and differentiation in BMMSCs derived from children with severe aplastic anemia (12). Due to the possibility of MSC insufficiency in BM, we cotransplanted UCMSCs with HSCs in two children with severe aplastic anemia (13). Both children achieved faster hematopoietic engraftment without infusion-related toxicities and GVHD. We speculate that MSCs can promote hematopoiesis after HSCT, especially in patients with BM failure syndromes.

Treatment of GVHD

The pathophysiologies of GVHD involve increased secretion of proinflammatory cytokines, activation of a variety of immune cells, and host tissue damage. Severe acute GVHD after allogeneic HSCT is associated with a high mortality rate, especially in those who are refractory to steroid treatment (18). MSCs are capable of escaping recognition by the alloreactive immune system and can exert immunomodulatory and anti-inflammatory effects. These properties make MSCs a promising tool in the prevention and treatment of GVHD.

In 2004, Le Blanc et al. first reported a child with acute lymphoblastic leukemia receiving haploidentical MSC infusion for severe treatment-resistant grade IV acute GVHD of the gut and liver after HSCT, and the clinical response was striking (36). Thereafter, eight patients with steroid-refractory grades III–IV GVHD were treated with in vitro-expanded MSCs from HLA-identical or mismatched donors, and the survival rate was significantly better than that of 16 comparable controls treated for GVHD during the same period but not given MSCs (51). In a phase II study, 55 patients with therapy-resistant acute GVHD were treated with BMMSCs. Complete responses occurred in 30 of the 55 patients, and partial responses occurred in nine patients. At 2 years, the complete responders had a higher survival rate than the partial and non-responders (52% vs. 16%; p = 0.018) (35). Since then, many reports regarding the use of MSCs for GVHD have been encouraging (30,40,57,62).

By analyzing gene expression with microarray and Metacore pathway mapping, we speculate that the immunomodulatory effects of MSCs are achieved via a number of pathways and a network of complicated immune responses (10). In vitro, we demonstrated that fetal-type MSCs have stronger immunosuppressive effects than adult-type MSCs (10). We used UCMSCs to treat patients with severe steroid-resistant acute GVHD successfully and safely (59). As the promising results of MSCs for GVHD and the high mortality rate of severe GVHD, further clinical studies involving fetal-type MSCs in the management of GVHD are urgently needed.

Prevention and Treatment of Graft Failure

Apart from engraftment promotion, MSCs are efficient in prevention and treatment of graft failure. In 2007, Le Blanc et al. reported cotransplantation of MSCs with HSCs to prevent rejection in three patients with previous graft failure or rejection (37). All three patients achieved neutrophil and platelet engraftment and 100% donor chimerism, suggesting the potential role of MSCs in the management of graft failure. As T-cell-depleted HSCT from an HLA-haploidentical relative is a feasible option for children needing to receive allogeneic HSCT but lacking an HLA-compatible donor, the report of Ball et al. provided a promising result (7). While a graft failure rate of 15% occurred in 47 historic control patients, no graft failure occurred in the 14 children who received cotransplantation of in vitro-expanded MSCs from the same donors of HSCs during haploidentical HSCT. Moreover, the children also experienced fewer infection episodes and had a lower incidence of GVHD (7).

Repairing Tissue Damage

When undergoing HSCT, tissue damage, resulting from conditioning regimens and other drugs, GVHD, and other toxic factors, may lead to organ failure and subsequent mortality. In animal models, MSCs targeted injured tissues to treat radiation-induced multiorgan failure syndrome (14). Having the ability to repair damaged tissues in patients with acute GVHD, MSCs were used for other HSCT-related tissue damage. In 2007, Hassan et al. reported that two patients developed life-threatening hemorrhagic cystitis after HSCT, and the conditions improved dramatically after BMMSC infusion (26). Subsequently, BMMSCs were used to treat another nine patients with hemorrhagic cystitis. Seven had excellent responses, and gross hematuria subsided after a median of 3 days. Besides, BMMSCs have also been reported to successfully treat patients with pneumomediastinum, perforated colon, and severe hemorrhage after HSCT (26,50,52). Further work needs to be carried out to define the indications and efficacy of MSCs for repairing tissue damage in patients receiving HSCT.

Further Clinical Considerations

As described, MSCs play multiple important roles in HSCT. Nevertheless, several issues regarding their clinical application remain to be discussed, including the safety of use in humans, the available sources and the convenience of obtaining MSCs, the quality control of in vitro-cultured MSCs and the appropriate cell passages, the optimum cell dose, and the optimum number of infusions.

While acquiring BMMSCs involves an invasive and painful procedure, the process to obtain fetal-type MSCs is painless and harmless to the donor. Compared with BMMSCs, we found that fetal-type MSCs can proliferate faster (10), indicating a shorter amount of time needed to get sufficient cells for clinical use. These advantages make fetal-type MSCs considered to be an alternative source of MSCs for clinical application. Moreover, many investigations have demonstrated that infusion of BMMSCs into humans is safe without formation of ectopic tissues and other severe adverse events (7,26,30,32,33,35–37,40,41,48,50–52,57,62). However, the safety for MSC use is primarily based on experience in utilizing BMMSCs. In 2009, Amariglio et al. reported that a donor-derived brain tumor developed after transplantation of a mixture of fetally derived neural cells in an immunodeficient patient with ataxia telangiectasia (4). As fetal-type MSCs are more primitive than BMMSCs, the safety of their use remains uncertain in the limited experience thus far reported (13,25,59).

The number of MSCs obtained from the donor is usually insufficient for clinical use, and MSCs have a great propensity for expansion in vitro. Thus, passaged cells are used extensively in experimental and clinical practice. When MSCs are in vitro-cultured, transforming events potentially leading to the establishment of a novel cell line may occur (21). MSCs may also gradually lose the properties of early progenitors, such as the abilities to proliferate and differentiate (8). Therefore, MSCs within six passages are suggested for clinical application (55). In addition, to guarantee the quality of cells is difficult for physicians. MSC banks, which can cryopreserve manufactured MSCs, may serve to improve several issues regarding the application of MSCs to clinical practice, including the time needed to obtain sufficient cells, the variability of donors, and the risk of contamination. Like cord blood banks, MSC banks may have a ready supply of “off-the-shelf ” cells available for clinical use (45).

According to recent reports, the majority of patients received MSCs with dosages of 1–9 × 10⁶/kg (7,26,30, 32,33,35–37,40,41,48,50–52,57,62). However, the optimum cell dose has not been well established. In vitro, we found that the immunosuppressive effects of MSCs increased with the increasing cell dose in a dose-dependent manner (59). It has yet to be determined whether the therapeutic effects also increase when infusing more MSCs. Over time, the donor's MSCs are gradually eliminated from the recipient after infusion (45). Le Blanc et al. found that half of the patients required more than one BMMSC infusion to control severe acute GVHD adequately (35). Accordingly, several MSC infusions may be needed to develop immune tolerance in patients with severe immune disorders. Further studies are warranted to define the optimum dose of MSCs, as well as the optimum number of infusions.

The graft-versus-tumor effect plays a crucial role in the treatment of patients with malignant diseases receiving allogeneic HSCT. As is expected, patients who develop GVHD after HSCT have a lower risk of leukemia relapse (27,58). When using MSCs for GVHD, it is important to evaluate whether the rate of relapse in patients with malignancies increases. It is also important to assess whether MSCs suppress the immune responses of recipients against infections, thus increasing the rate of severe infections. There are still many questions regarding the role of MSCs in HSCT needed to be answered, and further studies are warranted.

Footnotes

Acknowledgments

The study was supported by grants from China Medical University Hospital (DMR-101-035) and Chung Shan Medical University Hospital (CSH-2012-A-004). The authors declare no conflicts of interest.

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The Role of Mesenchymal Stem Cells in Hematopoietic Stem Cell Transplantation: From Bench to Bedsides

Abstract

Keywords

Introduction

The Biological Properties of MSCs

Definition of MSCs

Where to Isolate MSCs From?

MSCs Having Low Immunogenicity

The Immunomodulatory Properties of MSCs

Clinical Application of MSCs to HSCT

Promotion of Hematopoietic Engraftment

Treatment of GVHD

Prevention and Treatment of Graft Failure

Repairing Tissue Damage

Further Clinical Considerations

Footnotes

Acknowledgments

References