Critical Reviews in Oncology/Hematology 90 (2014) 93–98
Human umbilical cord blood-derived stromal cells: A new source of stromal cells in hematopoietic stem cell transplantation Shan-Shan Liu 1 , Cheng Zhang 1 , Xi Zhang, Xing-Hua Chen ∗ Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, People’s Republic of China Accepted 3 December 2013
Contents 1. 2.
3.
4. 5.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological characteristics of hUCBDSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. The definition of hUCBDSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The role of hUCBDSCs in hematopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Immune properties of hUCBDSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The functions of hUCBDSCs in HSCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Promotion of engraftment after HSCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Treatment of GVHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The superiority of hUCBDSCs in clinical applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract The hematopoietic inductive microenvironment (HIM), which is composed of stromal cells, extracellular matrix and cytokines, plays a vital role in hematopoietic stem cell transplantation (HSCT). Bone marrow stromal cells (BMSCs), as the main component of HIM, have been well studied. However, the highly invasive procedure of bone marrow (BM) collection limits the clinical application of BMSCs. Human umbilical cord blood-derived stromal cells (hUCBDSCs) isolated and cultured in our laboratory have attracted much attention for their ease collection and low probability of pathophoresis. Previous research demonstrated that hUCBDSCs have numerous functions that are identical to those of BMSCs, for example, hUCBDSCs can support the growth of hematopoietic stem and progenitor cells, especially during the expansion of megakaryocyte colony-forming units (CFU-Mk), promote engraftment after hematopoietic stem cell transplantation (HSCT), exert immunosuppressive effects on xenogenic T cells in vitro and suppress acute graft-versus-host disease (aGVHD) in vivo. Although hUCBDSCs, as new stromal cells, have not been used in clinical practice, they have great practical significance because of their superiority in hematopoiesis and the regulation of immunity. © 2013 Elsevier Ireland Ltd. All rights reserved. Keywords: Human umbilical cord blood-derived stromal cells; Human umbilical cord blood-derived mesenchymal cells; Hematopoietic stem cell transplantation; Graft-versus-host disease
1. Introduction ∗ 1
Corresponding author. Tel.: +86 023 68774309; fax: +86 023 6876 3198. E-mail address: [email protected] (X.-H. Chen). These authors contributed equally to this work.
1040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2013.12.002
Hematopoietic stem cell transplantation (HSCT) is an effective curative therapy for a variety of hematologic
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Cell type
CD34
Fn
CD44
Stro-1
CD45
hUCBDSC
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hUCBDMSC
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CD106
CD29
Lm
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Fig. 1. Surface markers for hUCBDSCs and hUCBDMSCs.
malignancies and marrow failure syndromes [1,2]. The hematopoietic inductive microenvironment (HIM) plays a significant role in HSCT because it is the site of origin, proliferation, and development of HSCs. Bone marrow stromal cells (BMSCs), as an important component of HIM, have been extensively studied since they were first cultured in vitro by Dexter in 1977. The BMSCs have a close relationship not only with the development of HSC, but also with the occurrence, progression, and prognosis of hematologic diseases [3–10]. However, the collection of BM is an invasive procedure, which is disadvantageous for donors. Human umbilical cord blood-derived stromal cells (hUCBDSCs) isolated and cultured in our laboratory are advantageous because they can be used in the expansion of hematopoietic stem and progenitor cells as well as engraftment after hematopoietic stem cell transplantation (HSCT) [11–13]. Importantly, hUCBDSCs exert an immunoregulatory effect in vitro and vivo, which may have a broad prospects for various applications [13–15]. In this study, we address the characteristics of hUCBDSCs in engraftment and immune regulation in HSCT. 2. Biological characteristics of hUCBDSCs 2.1. The definition of hUCBDSCs Umbilical cord blood (UCB) has many advantages for use as a primary source of HSCs. It is known that human umbilical cord blood-derived mesenchymal cells (hUCBDMSCs) and hUCBDSCs are two important components of umbilical cord blood. Both cells types play important roles in hematopoiesis and HSCT. Because there are some similarities between these cells, it is necessary to accurately discriminate between the two cell types to avoid confusion. Sun et al. made great efforts to solve this problem by demonstrating that hUCBDSCs can be distinguished from hUCBDMSCs based on morphology, proliferation, cell cycle, passage, immunophenotype, and the capacity for classical tri-lineage [16]. The cell morphology of hUCBDSCs is heterogeneous, they are mainly composed of macrophage-like, fibroblastlike, and small-sphere-like cells during prolonged culture, whereas hUCBDMSCs tend to be homogeneous and fibroblast-like [11,17]. It is also possible to distinguish between these two cells using a panel of surface markers. Both cell types are positive for Fn, CD44, and Stro-1 but negative for CD34.However, hUCBDSCs express CD45 and CD106 but do not express Lm or CD29, whereas
hUCBDMSCs expressed Lm and CD29 but do not express CD45 and CD106 (Fig. 1). Additionally, hUCBDSCs display no differentiation potential, whereas hUCBDMSCs possess the capacity to differentiate into osteoblasts, adipocytes, and chondrocytes under induction conditions in vitro [16–20]. 2.2. The role of hUCBDSCs in hematopoiesis Data from previous research shows that hUCBDSCs secrete thrombopoietin (TPO), stem cell factor (SCF), and granulocyte macrophage colony-stimulating factor (GM-CSF). These factors are closely linked with the development of hematopoietic stem cells (HSCs). Gao et al. [11] found that hUCBDSCs support the growth of hematopoietic stem cells and promote the expansion of megakaryocyte colony-forming units (CFU-Mk) even more efficiently than hBMSCs. To investigate the means by which hUCBDSCs promote megakaryocytopoiesis, a megakaryocyte/hUCBDSCs co-culture model and a hematopoietic microenvironment injury model in nude mice were been developed by Gao et al. These authors demonstrated that hUCBDSCs contribute to the expansion of human megakaryocytes in vitro and megakaryocytopoiesis in vivo. The TPO and SDF-1 path-ways both play important roles in this process [21]. Additionally, it has been demonstrated that hUCBDSCs can efficiently facilitate hematopoietic reconstitution, particularly in megakaryocytic lineage, and restore the impaired stromal microenvironment after radiation-induced damages in vivo [12]. 2.3. Immune properties of hUCBDSCs hUCBDSCs constitutively express HLA-I but not HLA-II or other costimulators, and this process is not influenced by cryopreservation. Hao et al. demonstrated that the addition of hUCBDSCs did not evoke xenogeneic T-cell proliferation in an in vitro culture, however, the proliferation induced by PHA or allogeneic dendritic cells was suppressed. This result might due to the generation of Tregs and the reversion of mature dendritic cells, rather than the induction of T-cell apoptosis [14]. These results demonstrate that hUCBDSCs have low immunogenicity and immunomodulatory effects, which are important for their application in the regulation of GVHD in HSCT. Zhang et al. showed that hUCBDSCs could promote engraftment of donor hematopoietic cells in a
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mouse haploidentical stem cell transplantation model, which suggested that hUCBDSCs may not be immunologically rejected instead they likely help hematopoietic cells to settle into the bone marrow in a manner that is still unclear [13]. Taken together, owing to their low immunogenicity and immunomodulatory effects, hUCBDSCs will be very useful in HSCT applications.
3. The functions of hUCBDSCs in HSCT 3.1. Promotion of engraftment after HSCT The engraftment of stem cells is necessary to reconstitute post-transplantation hematopoiesis, and successful engraftment is dependent on the ability of the transplanted HSCs to migrate to the BM microenvironment and become situated in their specialized marrow niches [22,23]. Using a nude mice model, Gao et al. [21] demonstrated that hUCBDSCs possess “homing” characteristics similar to those of hematopoietic stem cells. Liu et al. also showed that engraftment was improved in transplanted mice, when infused hUCBDSCs migrated to the bone marrow. Consistent with this findings, Zhang et al. [12,13] showed that hUCBDSCs improved engraftment in haploidentical transplantation in mice. 3.2. Treatment of GVHD Graft-versus-host disease (GVHD), which is the immune response of donor T lymphocytes to the recipient’s alloantigens, is one of the major causes of morbidity and mortality after HSCT and hampers the widespread application of this treatment [24]. Although many immunosuppressive drugs are available, none of these drugs (either alone or in combination) is able to completely abolish GVHD [25]. Recently, cellular therapy for GVHD has attracted much attention because cellular and cytokine mechanisms may be responsible for the incidence of GVHD [26]. During the last several decades, it has been demonstrated that MSCs are the most promising candidates. Human, baboon and murine MSCs fail to elicit allogeneic and xenogeneic T-cell responses and are also able to exert immunosuppressive effects in vitro [27–31], Additionally, MSCs have also been shown to effectively prevent GVHD in several animal models and clinical trials [32–36]. The immunomodulatory effects of hUCBDSCs on T cells in vitro were identical to those of MSCs across MHC species barriers [14]. Hao et al. showed that hUCBDSCs can reduce the incidence and severity of GVHD in mice after haploidentical stem cell transplantation. hUCBDSCs effectively reduced GVHD-associated mortality, prolonged the survival time of transplanted mice and ameliorated the severity of GVHD. These authors also found that the alleviation of GVHD may depend on the suppression of DC and the induction of CD4+Treg cells [15]. Additionally, Zhang et al. showed that hUCBDSCs significantly increased the expression of CD49b NK cells and IL-4 protein and decreased the
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expression of CD3+T-cells and IFN-␥ protein both in vitro and in vivo, which can effectively reduce the incidence of GVHD [13]. Furthermore, it was shown that hUCBDSCs can elicit decreased lymphocyte expression of very late activation antigen-4 (VLA-4), which has been associated with GVHD, and hUCBDSCs elicited a stronger decrease compared with hBMSCs, when cocultured with splenocytes of donor mice in vitro. Zhang et al. also demonstrated that hUCBDSCs protect haploidentical transplanted mice from aGVHD by downregulating the expression of VLA-4 in vivo, which could provide indirect insight into whether and how hUCBDSCs could protect human transplant recipients from GVHD [37,38].
4. The superiority of hUCBDSCs in clinical applications BMSCs, as the main component of the hematopoietic inductive microenvironment (HIM), have been extensively studied since they were first cultured in vitro, and most of the knowledge concerning stromal cells has been obtained from BMSCs studies. However, the application of BMSCs has been largely limited in clinical practice due to several factors. First, bone marrow extraction is an invasive procedure which may bring few risks to the donors, such as anesthesia reactions, infections and pain at the punctural site. Additionally, the number and expansion capacity of stromal cells derived from the BM declines with increasing age [39,40]. Furthermore, in the setting of bone marrow transplant for the treatment of hematologic malignancies, autologous BMSCs from patients are often contaminated with tumor cells, and allogeneic transplants may be complicated by histocompatibility. During the last several decades, many hematologists have made significant efforts to identify a new alternative source of stromal cells. It has been demonstrated that mesenchymal stromal cells also exist in other tissues and organs such as the spleen, lung, liver and placenta [41–45], however, it is difficult to isolate and obtain a sufficient amount of stromal cells to meet the laboratory or clinical needs because these cells only constitute a very small fraction of these tissues. Several groups have found that MSCs also exist in UCB [46–48]. Due to its ease of collection and younger donor cells, UCB has become one of the most attractive alternative sources of stromal cells. Sun et al. found that hUCBDSCs, which are an additional important component of UCB, are superior to hUCBDMSCs [16]. On one hand, hUCBDSCs are easier to obtain because they can be easily isolated from any umbilical cord blood sample, on the other hand, hUCBDMSCs are present in low numbers [48–51], and the successful rate of culture ranges from 23.1% to 63% [48,52,53]. Additionally, hUCBDSCs secrete higher levels of G-CSF, TPO, and GM-CSF and they induce HSC differentiation into myeloid lineage cells, especially differentiation into the granulocyte lineage, at an earlier co-culture stage in vitro [16]. Moreover, it has been demonstrated that hUCBDSCs express high levels of HLA-I and negligible levels of HLA-II and
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other costimulators, which was similar to what was observed for MSCs isolated from other sources. This immunological property was maintained after cryopreservation, which is a common procedure used in cell manipulation in clinics [14]. Taken together, these characteristics support the clinical use of hUCBDSCs. The superiority of hUCBDSCs in HSCT is apparent and deserves more attention.
5. Conclusion In summary, hUCBDSCs are easy to isolate, culture and preserve, which is vital to their clinical application. Previous research demonstrated that hUCBDSCs can support the development of hematopoietic stem cells, benefit engraftment and treat GVHD. Although, hUCBDSCs have not been applied in clinical settings, the results of the previous studies provide indirect insights into the potential clinical role of hUCBDSCs. There is no doubt that hUCBDSCs have great prospects for application in immune system regulation and HSCT.
Conflict of interest None declared.
Reviewers Maria Gkotzamanidou, MD, PhD, Dana Farber Cancer Institute, Harvard Medical School, Medical Oncology, 450 Brookline Avenue M551, Mayer Building, Boston, MA 02215, United States. Rakhee Vaidya, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States.
Acknowledgments This study was funded by grants from the National Natural Science Foundation (No. 81170467), the Key Discipline of Medical Science of Chongqing and the special foundation for the “1130 project” of Xinqiao Hospital of the Third Military Medical University.
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Biographies Shan-Shan Liu, Medical Master, Hematolgy, Xinqiao Hospital Of Third Military Medical University, Chongqing, 400037, P.R. China. The research areas are as follows: (1) Hematopoietic microenviroment and hematopoiesis, (2) Basic and clinical research on hematopoietic stem cell transplantation, (3) Immunity regulation. Cheng Zhang, Medical doctor, Assistant Professor, Hematolgy, Xinqiao Hospital of Third Military Medical University, Chongqing, 400037, P.R. China. The research areas are as follows: (1) Hematopoietic microenviroment and hematopoiesis, (2) Basic and clinical research on
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hematopoietic stem cell transplantation, (3) Stem cell and leukemia stem cell, (4) Immunity regulation. XingHua Chen, Professor, Hematology, Xinqiao Hospital of the Third Military Medical University,
P.R. China. The research areas are as follows: (1) Hematopoietic microenviroment and hematopoiesis, (2) Basic and clinical research on hematopoietic stem cell transplantation.
Human umbilical cord blood-derived stromal cells: A new source of stromal cells in hematopoietic stem cell transplantation Shan-Shan Liu 1 , Cheng Zhang 1 , Xi Zhang, Xing-Hua Chen ∗ Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, People’s Republic of China Accepted 3 December 2013
Contents 1. 2.
3.
4. 5.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological characteristics of hUCBDSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. The definition of hUCBDSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The role of hUCBDSCs in hematopoiesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Immune properties of hUCBDSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The functions of hUCBDSCs in HSCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Promotion of engraftment after HSCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Treatment of GVHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The superiority of hUCBDSCs in clinical applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract The hematopoietic inductive microenvironment (HIM), which is composed of stromal cells, extracellular matrix and cytokines, plays a vital role in hematopoietic stem cell transplantation (HSCT). Bone marrow stromal cells (BMSCs), as the main component of HIM, have been well studied. However, the highly invasive procedure of bone marrow (BM) collection limits the clinical application of BMSCs. Human umbilical cord blood-derived stromal cells (hUCBDSCs) isolated and cultured in our laboratory have attracted much attention for their ease collection and low probability of pathophoresis. Previous research demonstrated that hUCBDSCs have numerous functions that are identical to those of BMSCs, for example, hUCBDSCs can support the growth of hematopoietic stem and progenitor cells, especially during the expansion of megakaryocyte colony-forming units (CFU-Mk), promote engraftment after hematopoietic stem cell transplantation (HSCT), exert immunosuppressive effects on xenogenic T cells in vitro and suppress acute graft-versus-host disease (aGVHD) in vivo. Although hUCBDSCs, as new stromal cells, have not been used in clinical practice, they have great practical significance because of their superiority in hematopoiesis and the regulation of immunity. © 2013 Elsevier Ireland Ltd. All rights reserved. Keywords: Human umbilical cord blood-derived stromal cells; Human umbilical cord blood-derived mesenchymal cells; Hematopoietic stem cell transplantation; Graft-versus-host disease
1. Introduction ∗ 1
Corresponding author. Tel.: +86 023 68774309; fax: +86 023 6876 3198. E-mail address: [email protected] (X.-H. Chen). These authors contributed equally to this work.
1040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2013.12.002
Hematopoietic stem cell transplantation (HSCT) is an effective curative therapy for a variety of hematologic
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Cell type
CD34
Fn
CD44
Stro-1
CD45
hUCBDSC
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hUCBDMSC
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CD106
CD29
Lm
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Fig. 1. Surface markers for hUCBDSCs and hUCBDMSCs.
malignancies and marrow failure syndromes [1,2]. The hematopoietic inductive microenvironment (HIM) plays a significant role in HSCT because it is the site of origin, proliferation, and development of HSCs. Bone marrow stromal cells (BMSCs), as an important component of HIM, have been extensively studied since they were first cultured in vitro by Dexter in 1977. The BMSCs have a close relationship not only with the development of HSC, but also with the occurrence, progression, and prognosis of hematologic diseases [3–10]. However, the collection of BM is an invasive procedure, which is disadvantageous for donors. Human umbilical cord blood-derived stromal cells (hUCBDSCs) isolated and cultured in our laboratory are advantageous because they can be used in the expansion of hematopoietic stem and progenitor cells as well as engraftment after hematopoietic stem cell transplantation (HSCT) [11–13]. Importantly, hUCBDSCs exert an immunoregulatory effect in vitro and vivo, which may have a broad prospects for various applications [13–15]. In this study, we address the characteristics of hUCBDSCs in engraftment and immune regulation in HSCT. 2. Biological characteristics of hUCBDSCs 2.1. The definition of hUCBDSCs Umbilical cord blood (UCB) has many advantages for use as a primary source of HSCs. It is known that human umbilical cord blood-derived mesenchymal cells (hUCBDMSCs) and hUCBDSCs are two important components of umbilical cord blood. Both cells types play important roles in hematopoiesis and HSCT. Because there are some similarities between these cells, it is necessary to accurately discriminate between the two cell types to avoid confusion. Sun et al. made great efforts to solve this problem by demonstrating that hUCBDSCs can be distinguished from hUCBDMSCs based on morphology, proliferation, cell cycle, passage, immunophenotype, and the capacity for classical tri-lineage [16]. The cell morphology of hUCBDSCs is heterogeneous, they are mainly composed of macrophage-like, fibroblastlike, and small-sphere-like cells during prolonged culture, whereas hUCBDMSCs tend to be homogeneous and fibroblast-like [11,17]. It is also possible to distinguish between these two cells using a panel of surface markers. Both cell types are positive for Fn, CD44, and Stro-1 but negative for CD34.However, hUCBDSCs express CD45 and CD106 but do not express Lm or CD29, whereas
hUCBDMSCs expressed Lm and CD29 but do not express CD45 and CD106 (Fig. 1). Additionally, hUCBDSCs display no differentiation potential, whereas hUCBDMSCs possess the capacity to differentiate into osteoblasts, adipocytes, and chondrocytes under induction conditions in vitro [16–20]. 2.2. The role of hUCBDSCs in hematopoiesis Data from previous research shows that hUCBDSCs secrete thrombopoietin (TPO), stem cell factor (SCF), and granulocyte macrophage colony-stimulating factor (GM-CSF). These factors are closely linked with the development of hematopoietic stem cells (HSCs). Gao et al. [11] found that hUCBDSCs support the growth of hematopoietic stem cells and promote the expansion of megakaryocyte colony-forming units (CFU-Mk) even more efficiently than hBMSCs. To investigate the means by which hUCBDSCs promote megakaryocytopoiesis, a megakaryocyte/hUCBDSCs co-culture model and a hematopoietic microenvironment injury model in nude mice were been developed by Gao et al. These authors demonstrated that hUCBDSCs contribute to the expansion of human megakaryocytes in vitro and megakaryocytopoiesis in vivo. The TPO and SDF-1 path-ways both play important roles in this process [21]. Additionally, it has been demonstrated that hUCBDSCs can efficiently facilitate hematopoietic reconstitution, particularly in megakaryocytic lineage, and restore the impaired stromal microenvironment after radiation-induced damages in vivo [12]. 2.3. Immune properties of hUCBDSCs hUCBDSCs constitutively express HLA-I but not HLA-II or other costimulators, and this process is not influenced by cryopreservation. Hao et al. demonstrated that the addition of hUCBDSCs did not evoke xenogeneic T-cell proliferation in an in vitro culture, however, the proliferation induced by PHA or allogeneic dendritic cells was suppressed. This result might due to the generation of Tregs and the reversion of mature dendritic cells, rather than the induction of T-cell apoptosis [14]. These results demonstrate that hUCBDSCs have low immunogenicity and immunomodulatory effects, which are important for their application in the regulation of GVHD in HSCT. Zhang et al. showed that hUCBDSCs could promote engraftment of donor hematopoietic cells in a
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mouse haploidentical stem cell transplantation model, which suggested that hUCBDSCs may not be immunologically rejected instead they likely help hematopoietic cells to settle into the bone marrow in a manner that is still unclear [13]. Taken together, owing to their low immunogenicity and immunomodulatory effects, hUCBDSCs will be very useful in HSCT applications.
3. The functions of hUCBDSCs in HSCT 3.1. Promotion of engraftment after HSCT The engraftment of stem cells is necessary to reconstitute post-transplantation hematopoiesis, and successful engraftment is dependent on the ability of the transplanted HSCs to migrate to the BM microenvironment and become situated in their specialized marrow niches [22,23]. Using a nude mice model, Gao et al. [21] demonstrated that hUCBDSCs possess “homing” characteristics similar to those of hematopoietic stem cells. Liu et al. also showed that engraftment was improved in transplanted mice, when infused hUCBDSCs migrated to the bone marrow. Consistent with this findings, Zhang et al. [12,13] showed that hUCBDSCs improved engraftment in haploidentical transplantation in mice. 3.2. Treatment of GVHD Graft-versus-host disease (GVHD), which is the immune response of donor T lymphocytes to the recipient’s alloantigens, is one of the major causes of morbidity and mortality after HSCT and hampers the widespread application of this treatment [24]. Although many immunosuppressive drugs are available, none of these drugs (either alone or in combination) is able to completely abolish GVHD [25]. Recently, cellular therapy for GVHD has attracted much attention because cellular and cytokine mechanisms may be responsible for the incidence of GVHD [26]. During the last several decades, it has been demonstrated that MSCs are the most promising candidates. Human, baboon and murine MSCs fail to elicit allogeneic and xenogeneic T-cell responses and are also able to exert immunosuppressive effects in vitro [27–31], Additionally, MSCs have also been shown to effectively prevent GVHD in several animal models and clinical trials [32–36]. The immunomodulatory effects of hUCBDSCs on T cells in vitro were identical to those of MSCs across MHC species barriers [14]. Hao et al. showed that hUCBDSCs can reduce the incidence and severity of GVHD in mice after haploidentical stem cell transplantation. hUCBDSCs effectively reduced GVHD-associated mortality, prolonged the survival time of transplanted mice and ameliorated the severity of GVHD. These authors also found that the alleviation of GVHD may depend on the suppression of DC and the induction of CD4+Treg cells [15]. Additionally, Zhang et al. showed that hUCBDSCs significantly increased the expression of CD49b NK cells and IL-4 protein and decreased the
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expression of CD3+T-cells and IFN-␥ protein both in vitro and in vivo, which can effectively reduce the incidence of GVHD [13]. Furthermore, it was shown that hUCBDSCs can elicit decreased lymphocyte expression of very late activation antigen-4 (VLA-4), which has been associated with GVHD, and hUCBDSCs elicited a stronger decrease compared with hBMSCs, when cocultured with splenocytes of donor mice in vitro. Zhang et al. also demonstrated that hUCBDSCs protect haploidentical transplanted mice from aGVHD by downregulating the expression of VLA-4 in vivo, which could provide indirect insight into whether and how hUCBDSCs could protect human transplant recipients from GVHD [37,38].
4. The superiority of hUCBDSCs in clinical applications BMSCs, as the main component of the hematopoietic inductive microenvironment (HIM), have been extensively studied since they were first cultured in vitro, and most of the knowledge concerning stromal cells has been obtained from BMSCs studies. However, the application of BMSCs has been largely limited in clinical practice due to several factors. First, bone marrow extraction is an invasive procedure which may bring few risks to the donors, such as anesthesia reactions, infections and pain at the punctural site. Additionally, the number and expansion capacity of stromal cells derived from the BM declines with increasing age [39,40]. Furthermore, in the setting of bone marrow transplant for the treatment of hematologic malignancies, autologous BMSCs from patients are often contaminated with tumor cells, and allogeneic transplants may be complicated by histocompatibility. During the last several decades, many hematologists have made significant efforts to identify a new alternative source of stromal cells. It has been demonstrated that mesenchymal stromal cells also exist in other tissues and organs such as the spleen, lung, liver and placenta [41–45], however, it is difficult to isolate and obtain a sufficient amount of stromal cells to meet the laboratory or clinical needs because these cells only constitute a very small fraction of these tissues. Several groups have found that MSCs also exist in UCB [46–48]. Due to its ease of collection and younger donor cells, UCB has become one of the most attractive alternative sources of stromal cells. Sun et al. found that hUCBDSCs, which are an additional important component of UCB, are superior to hUCBDMSCs [16]. On one hand, hUCBDSCs are easier to obtain because they can be easily isolated from any umbilical cord blood sample, on the other hand, hUCBDMSCs are present in low numbers [48–51], and the successful rate of culture ranges from 23.1% to 63% [48,52,53]. Additionally, hUCBDSCs secrete higher levels of G-CSF, TPO, and GM-CSF and they induce HSC differentiation into myeloid lineage cells, especially differentiation into the granulocyte lineage, at an earlier co-culture stage in vitro [16]. Moreover, it has been demonstrated that hUCBDSCs express high levels of HLA-I and negligible levels of HLA-II and
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other costimulators, which was similar to what was observed for MSCs isolated from other sources. This immunological property was maintained after cryopreservation, which is a common procedure used in cell manipulation in clinics [14]. Taken together, these characteristics support the clinical use of hUCBDSCs. The superiority of hUCBDSCs in HSCT is apparent and deserves more attention.
5. Conclusion In summary, hUCBDSCs are easy to isolate, culture and preserve, which is vital to their clinical application. Previous research demonstrated that hUCBDSCs can support the development of hematopoietic stem cells, benefit engraftment and treat GVHD. Although, hUCBDSCs have not been applied in clinical settings, the results of the previous studies provide indirect insights into the potential clinical role of hUCBDSCs. There is no doubt that hUCBDSCs have great prospects for application in immune system regulation and HSCT.
Conflict of interest None declared.
Reviewers Maria Gkotzamanidou, MD, PhD, Dana Farber Cancer Institute, Harvard Medical School, Medical Oncology, 450 Brookline Avenue M551, Mayer Building, Boston, MA 02215, United States. Rakhee Vaidya, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States.
Acknowledgments This study was funded by grants from the National Natural Science Foundation (No. 81170467), the Key Discipline of Medical Science of Chongqing and the special foundation for the “1130 project” of Xinqiao Hospital of the Third Military Medical University.
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Biographies Shan-Shan Liu, Medical Master, Hematolgy, Xinqiao Hospital Of Third Military Medical University, Chongqing, 400037, P.R. China. The research areas are as follows: (1) Hematopoietic microenviroment and hematopoiesis, (2) Basic and clinical research on hematopoietic stem cell transplantation, (3) Immunity regulation. Cheng Zhang, Medical doctor, Assistant Professor, Hematolgy, Xinqiao Hospital of Third Military Medical University, Chongqing, 400037, P.R. China. The research areas are as follows: (1) Hematopoietic microenviroment and hematopoiesis, (2) Basic and clinical research on
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hematopoietic stem cell transplantation, (3) Stem cell and leukemia stem cell, (4) Immunity regulation. XingHua Chen, Professor, Hematology, Xinqiao Hospital of the Third Military Medical University,
P.R. China. The research areas are as follows: (1) Hematopoietic microenviroment and hematopoiesis, (2) Basic and clinical research on hematopoietic stem cell transplantation.
