- Open Access
Preconditioning human natural killer cells with chorionic villous mesenchymal stem cells stimulates their expression of inflammatory and anti-tumor molecules
© The Author(s). 2019
- Received: 16 August 2018
- Accepted: 24 January 2019
- Published: 6 February 2019
Mesenchymal stem cells derived from the chorionic villi of human placentae (pMSCs) produce a unique array of mediators that regulate the essential cellular functions of their target cells. These properties make pMSCs attractive candidates for cell-based therapy. Here, we examined the effects of culturing human natural killer (NK) cells with pMSCs on NK cell functions.
pMSCs were cultured with IL-2-activated and non-activated NK cells. NK cell proliferation and cytolytic activities were monitored. NK cell expression of receptors mediating their cytolytic activity against pMSCs, and the mechanisms underlying this effect on pMSCs, were also investigated.
Our findings show that IL-2-activated NK cells, but not freshly isolated NK cells, efficiently lyse pMSCs and that this response might involve the activating NK cell receptor CD69. Interestingly, although pMSCs expressed HLA class I molecules, they were nevertheless lysed by NK cells, suggesting that HLA class I antigens do not play a significant role in protecting pMSCs from NK cell cytolytic activity. Co-culturing NK cells with pMSCs also inhibited NK cell expression of receptors, including CD69, NKpG2D, CD94, and NKp30, although these co-cultured NK cells were not inhibited in lysing cancer cells in vitro. Importantly, co-cultured NK cells significantly increased their production of molecules with anti-tumor effects.
These findings suggest that pMSCs might have potential applications in cancer therapy.
- Chorionic villous mesenchymal stem/multipotent stromal cells
- NK cells
- Cytolytic activity
- NK cell proliferation
- Inflammatory molecules
Natural killer cells (NK cells) are lymphocytes, which function in the innate immune system, and have cytotoxic or cytolytic activities that are specifically targeted against virally infected cells and tumor cells . The cytolytic activities of NK cells on target cells are mediated by several cell surface-activating receptors (including NKp30, NKp44, NKp46, DNAM-1, and NKG2D) and inhibitory receptors (including the killer immunoglobulin-like receptors “KIRs” and CD94/NKG2A) [1–11], while other NK cell functions are mediated by a range of mediators including cytokines and their corresponding receptors, as well as their expression of Toll-like receptors (TLRs) [1, 12, 13].
The activating receptors mediate the cytolytic activity of NK cells by binding to their corresponding ligands [poliovirus receptor (PVR) and Nectin-2 for DNAM-1, as well as MICA/B (MHC class I chain-related genes A and B) and ULBPs (UL16-binding proteins) for NKG2D] on target cells [2, 3, 6–11]. NK inhibitory receptors, specifically KIRs and CD94/NKG2A, inhibit the cytolytic activity of NK cells against their target cells following their interaction with human leukocyte antigen (HLA) class I and non-classical MHC class I (HLA-E) molecules, respectively [4, 5]. In contrast, when NK cells interact with target cells that lack HLA molecules, NK cells are activated and this subsequently induces the lysis of target cells .
The interaction between human NK cells and mesenchymal stem/stromal cells (MSC) has been recently reported by us and others [15–19]. MSCs are multipotent, adult stem/stromal cells and with the ability of self-renewal and differentiation into the three mesenchymal lineages of adipocyte, osteocyte, and chondrocyte [20–23]. MSCs can be isolated from various adult tissues, such as human placenta [20–23]. We recently reported that the interaction between NK cells and MSCs from the maternal side of human placenta known as decidua parietalis (DPMSCs) results in the lysis of DPMSCs . Similarly, NK cells can also lyse human bone marrow-derived MSCs (BMMSCs) [15–18].
Previously, we isolated MSCs from the fetal part of human term placenta known as chorionic villi . These placental MSCs (pMSCs) have immunosuppressive properties [23–25]. pMSCs induce the differentiation of anti-inflammatory macrophages (M2 macrophages) from human monocytes  and exert inhibitory effects on the functions of human dendritic and T cells . Thus, pMSCs can control the functions of immune cells that mediate both the innate and adaptive immune responses. These properties make pMSCs attractive candidates for cell-based therapy.
The principle for the successful use of pMSCs as a cell-based therapy is to have a full description of their interaction with a wide range of immune cells. Currently, the consequences of the interaction between pMSCs and human NK cells are unknown. Therefore, we conducted this study to investigate the interactions between pMSCs and NK cells and the outcomes of this interaction. We found that pMSCs inhibit the proliferation of both resting non-activated NK cells (NK cells induced to proliferate by IL-2) and activated NK cells (NK cells pre-activated by IL-2). We also found that IL-2-activated NK cells produce a strong cytolytic response against pMSCs and that this response might involve the activating NK cell receptor CD69. pMSCs did not alter NK cell cytolytic activity against cancer cells; however, most important was that pMSCs induced NK cell expression of several molecules with anti-tumor properties.
Ethics and collection of human placentae and peripheral blood
This study was approved by the institutional research board (IRB), King Abdulla International Medical Research Centre (KAIMRC), Saudi Arabia. Placentae from uncomplicated human term pregnancies (38–40 weeks of gestation) and peripheral blood samples from healthy adult subjects were collected and processed immediately after consenting donors.
Isolation and culture of pMSCs
Monoclonal antibodies used in this study to characterize pMSCs and NK cells
MSC positive markers
NK cell marker
NK cell-activating receptors
NK cell inhibitory receptor
NK cell receptor ligands
Isolation of human NK cells
NK cells were isolated from mononuclear cells of a peripheral blood (PBMNCs) obtained from ten healthy donors as previously described by us . Trypan blue was used to determine the viability of NK cells, while NK cell purity was assessed using anti-CD56 monoclonal antibody (R & D Systems, Abingdon, UK) in a flow cytometry. The viability and purity of NK cells used in this study were more than 95%. After isolation, NK cells were used either immediately or after 72 h activation with 100 U/mL IL-2 (R & D Systems) in RPMI 1640 medium (Life Technologies) containing 10% FBS, 2 mM l-glutamine and the antibiotics described above (NK culture medium).
NK cell proliferation assay using a tetrazolium compound [3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] MTS
An MTS kit (catalogue number G5421, Promega, WI, USA) was used to evaluate NK cell proliferation as previously described by us . Briefly, resting non-activated NK cells (NK cells induced to proliferate by culturing with 100 U/mL IL-2) or activated NK cells (NK cells pre-cultured with 100 U/mL IL-2 for 72 h) as we previously published  were cultured with or without pMSCs at different ratios of NK to pMSC. The ratios of NK to pMSC ranged from 1:1, 1:5, 1:10, 1:25, 1:50, and 1:100. NK culture medium (described above) was used in all NK cell-pMSC co-culture experiments. Prior to the addition of pMSCs to NK cells in proliferation experiments, pMSCs were pre-incubated with mitomycin C to inhibit pMSC proliferation as previously described . After 3 days of culture, NK cell proliferation was determined by incubating cells in MTS solution as we previously published . Results from triplicate samples were presented as means (± standard errors). Experiments were performed in triplicate and repeated ten times using ten individual preparations of both pMSCs and NK cells.
NK cell cytolytic experiments
Monoclonal antibodies used in the blocking experiments
NK cell cytolytic activity against tumor cells
To study the NK cell cytolytic activity following their incubation with pMSCs for 24 h against MCF-7 cells (breast cancer cells, ATCC, Manassas, VA, USA), our previously published method was used . Briefly, NK cells [IL-2-activated NK cells cultured alone, or co-cultured with pMSCs, at NK to pMSC ratios of 15:1, 25:1, 50:1, and 100:1 in the NK/pMSC cytolytic experiment described above] were harvested and then purified as described above. CD56+ NK cells with viability and purity of more than 95% were used against MCF-7 cells at an NK to MCF-7 ratio of 10:1. 10NK to 1MCF-7 ratio was used, because it completely lyzed MCF-7 cells as previously reported by us . Cells were cultured in NK culture medium and then incubated at 37 °C. Cell lysis was then evaluated as described above. Controls were IL-2-treated NK cells cultured without pMSCs served as a control or MCF-7 cells cultured alone. The viability and purity of NK cells were determined as described above. Triplicate experiments were carried out and repeated ten times using NK cells isolated from ten independent pMSC/NK cytolytic assays and MC7 breast cancer cells.
NK cell cytolytic activity against pMSCs and tumor cells using xCELLigence real-time system
The cytolytic activities of NK cells against pMSCs or MCF-7 were also determined using a real-time cell analyzer system (xCELLigence RTCA-DP, Roche Diagnostics, Mannheim, Germany) as we and other previously described [19, 28]. For the NK/pMSC cytolytic experiment, NK cells [IL-2-non-activated or activated NK cells (as described above)] were used against pMSCs at different ratios (NK to pMSC ratios of 1:1, 15:1, 25:1, 50:1, and 100:1). For the NK/MCF-7 cytolytic experiment, NK cells [IL-2-activated NK cells cultured alone or with pMSCs in the NK/pMSC cytolytic experiment (see above)] were used against MCF-7 cells. After incubation of NK cells with pMSCs (see above), NK cells were isolated and their viability as well as purity was assessed as described above, and then used against MCF-7 cells at a NK to MCF-7 ratio of 10:1. For each experiment, 20 × 103 pMSCs or MCF-7 cells, with or without NK cells at the indicated ratios, were seeded in NK culture medium in quadruplicate wells of 16-well E-culture plates (catalog number 05469813001, Roche Diagnostics), and the cell growth of the pMSC/NK or MCF-7/NK cultures was monitored in a real time as previously described by us . The rate of cell growth (cell index) was determined by calculating the linear regression of the slopes between two given time points using the xCELLigence software (version 1.2.1), and data was expressed as mean ± SD. Five experiments were carried out using pMSCs (P2) and NK cells from five independent preparations each.
Quantitation of cytokines in culture supernatants
To examine the NK cell secretion of cytokines against pMSCs in the cytolytic experiments described above, the culture medium from the cytolytic experiment was collected after 24 h by centrifugation at 800×g for 10 min and then screened for several cytokines including interferon gamma (IFNγ), IL12, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL1β, IL10, interleukin-1 receptor antagonist (IL-1Ra), and macrophage migration inhibitory factor (MIF)] using quantitative sandwich immunoassay. ELISA kits were purchased from R & D Systems, Life Technology and MyBioSource (California, USA). Complete RPM-1640 medium was included as a negative control. Experiments were carried out in duplicate and repeated ten times using ten individual preparations of both pMSCs and NK cells.
NK cell expression of activating and inhibitory receptors and immune proteins
NK cell expression of activating and inhibitory receptors as well as immune proteins (Table 1) following their co-culture with pMSCs (see above) was determined by flow cytometry after harvesting them from the cytolytic assay and then purifying them as described above.
Cells (1 × 105) were incubated with antibodies listed in Table 1 for 30 min, and then flow cytometry for cell surface and intracellular proteins was performed as we previously described . Negative controls were cells incubated with FITC or PE-labeled mouse IgG isotype antibody.
GraphPad Prism 5 software (non-parametric tests (Mann-Whitney U and Kruskal-Wallis)) was used to analyze data, which were considered statistically significant if P < 0.05.
pMSC isolation from human placental chorionic villi
pMSCs were isolated from human placental chorionic villi and cultured as previously described . On the second passage of these cells, > 95% were positive for MSC markers and negative (i.e., < 5% positive) for hematopoietic markers (data not shown), supporting previously published results . In addition, pMSCs differentiated into adipocytes, osteocytes, and chondrocytes, as previously reported (data not shown) . On the basis of these findings, second-passage pMSCs were used in all pMSC experiments reported in this study.
pMSCs inhibit NK cell proliferation
pMSCs express ligands that bind NK cell receptors
Percentage of cells expressing surface ligands of NK activating receptors (DNAM-1 and NKG2D), and the ligands of NK cell inhibiting receptor (HLA-E) in different pMSCs
12.17% ± 1.92%
1.73% ± 0.63%
7.66% ± 3.28%
37.33% ± 10.27%
9.00% ± .5.56%
6.33% ± 2.33%
3.330% ± 1.45%
27.33% ± 9.26%
95.00% ± 4.40%
pMSC lysis by NK cells
The NK cell receptors that contribute to pMSC lysis
Functional activities of NK cells incubated with pMSCs
The expression of activating and inhibiting receptors by NK cells exposed to pMSCs
The expression of immune markers by NK cells exposed to pMSCs
pMSCs modulate NK cell secretion of cytokines
In this study, we investigated whether pMSCs interact with NK cells, thereby affecting the NK cell cytolytic activity and immune marker expression. Our results provide evidence that pMSCs are susceptible to lysis by NK cells and that this response is mediated by the interactions between NK activating receptors and pMSC ligands. pMSCs were also able to reduce the proliferation of IL-2-activated NK cells and of non-activated NK cells that were induced to proliferate by IL-2 (Fig. 1). These data are in agreement with previous studies that have demonstrated a reduction in NK cell proliferation after their interaction with bone marrow-derived MSCs (BMMSCs) [15, 30, 31]. However, our data contrast with our recent finding that MSCs from the maternal tissue of human placenta (DPMSCs) increase NK cell proliferation . One obvious reason for this is that the original microenvironment (i.e., the niche) from which the MSCs were derived may regulate the functional activities of MSCs on NK cell proliferation. pMSCs are in direct contact with the fetal circulation and therefore exposed to low level of oxidative stress mediators during normal pregnancy [32, 33]. Similarly, MSCs in healthy bone marrow are exposed to low level of oxidative stress . By contrast, DPMSCs in the maternal tissue of human placenta are exposed to increased level of oxidative stress during the course of human pregnancy [35, 36].
The mechanisms that underlie the pMSC-dependent reduction of NK cell proliferation are not known. However, this response is likely to be mediated by soluble factors secreted by pMSCs. This is because we have previously reported that pMSCs secrete molecules with anti-proliferative effects, such as prostaglandin E2 (PGE2) [25, 26]. The inhibition of PGE2 secretion by BMMSCs has been shown to reverse the anti-proliferative effect of BMMSCs on NK cells . PGE2 might therefore also mediate the anti-proliferative effects of pMSCs on NK cells in a similar fashion. This possibility remains a question for future studies to address.
A previous study has also shown that NK cells are stimulated to lyse BMMSCs when BMMSCs express low levels of HLA class I molecules . Our results show that although pMSCs expressed high levels HLA-E and HLA-ABC, they were nevertheless susceptible to being lysed by NK cells (Fig. 3). This finding therefore shows that the lysis of pMSCs by NK cells is not inhibited by HLA class I molecules as we recently reported that the cytolytic activity of NK cells against DPMSCs is independent of HLA class I molecules . We further confirmed this by showing that the preconditioning of NK cells by pMSCs did not interfere with NK cytolytic activity against MCF-7 cells, which also express HLA-class I antigens (Fig. 5). These data are also in agreement with our previous study which demonstrated that DPMSCs do not interfere with NK cell lysis of MCF-7 cells . However, our data contrast with a previous study, which reported that MCF-7 cell lysis by NK cells was decreased by preconditioning of NK cells with BMMSCs . This difference in response could be attributable to the influence of the different placental MSCs and bone marrow MSCs niches in their source tissues, which might influence their effects on the cytolytic activity of NK cells.
pMSCs express low levels of NK cell-activating receptor ligands (Table 3). This was further confirmed by antibody-blocking experiments, which revealed that blocking the NK cell-activating receptors (NKG2D, DNAM-1, NKp30, NKp44, and NKp46) did not inhibit NK cells from lysing pMSCs (Fig. 4). By contrast, blocking the NK-activating receptor, CD69, substantially inhibited NK cell lysis of pMSCs (Fig. 4). This suggests that CD69 might play a role in mediating pMSC lysis by NK cells, although the co-culturing of NK cells with pMSCs reduced their expression of CD69 relative to control NK cells (Fig. 6a). The NK cell inhibitory receptor CD94/NKG2A was found to play no role in pMSC lysis by NK cells.
The preconditioning of NK cells by pMSCs also inhibited the expression of other activating receptors by NK cells, including NKG2D, NKp30, and NKp46 (Fig. 6). This suggests that the cytolytic activity of NK cells could be reduced by pMSCs. However, this appears not to be the case, since NK cells preconditioned by pMSCs were still able to lyse MCF-7 cells (Fig. 5). This suggests that other NK cell-activating receptors might be responsible for the lysis of MCF-7 cells by NK cells. In this regard, we found that the preconditioning of NK cells by pMSCs induced the NK cell expression of DNAM, which indicates that this activating receptor might mediate the lysis of MCF-7 cells by NK cells. We also found that NK cell expression of NKp30 was enhanced by preconditioning the NK cells with pMSCs, but only at a low ratio of NK cells to pMSCs. This suggests that NKp30 might also mediate NK cell cytolytic activity but only under certain conditions.
The lysis of pMSCs by NK cells questions the suitability of using pMSCs in regenerative medicine where pMSCs must function to repair injured or damaged tissue. However, pMSCs may contribute to tissue repair via paracrine mechanisms as we recently reported for DPMSCs . pMSCs secrete numerous molecules that have reparative properties, such as IL-10, vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGFβ-1), B7-H4, and PGE2 [25, 26]. These molecules act on lymphocytes, including T, B, and NK cells, and other cell types to modulate their functions [22, 25, 26]. Consequently, these molecules are likely to mediate the functions of pMSCs in vivo. Future studies are therefore needed to elucidate the in vivo mechanisms that underlie the effects of pMSC functions on NK cells and on other immune or non-immune cells.
pMSCs were not lysed by resting, non-activated NK cells (Fig. 2b–e). Instead, their proliferation was decreased by NK cells (Fig. 2g, h). In contrast, when NK cells were activated with IL-2, this treatment enhanced their ability to lyse pMSCs (Fig. 3). These data demonstrate that inflammation, or an inflammatory milieu, increases the cytolytic activity of NK cells against pMSCs. This NK cell inflammatory phenotype is also increased by the exposure of these NK cells to pMSCs. We found that following co-culture with pMSCs, NK cells increased their expression of IL-18Rβ, while IFNγ R2 expression was reduced (Fig. 7a, e). It was noticeable that the ratio of pMSCs to NK cells affected the expression of some inflammatory molecules. A low pMSC to NK ratio increased the expression of IL-12 Rβ1 and IFNγ R1 by NK cells (Fig. 7b, c), while at high pMSC to NK ratios, IL-12Rβ1 expression was reduced (Fig. 7b). Our results indicate that, depending on their relative numbers, pMSCs can induce an inflammatory or anti-inflammatory phenotype in NK cells, although the mechanism underpinning this complex response is not known. The ratio of pMSCs to NK cells also affected the secretion by NK cells of both inflammatory and anti-inflammatory mediators (IFNγ, IL12, GM-CSF, IL1β, IL10, and MIF). However, pMSCs increased the secretion of IL1ra by NK cells, which is a naturally occurring anti-inflammatory cytokine that blocks the activity of IL-1 and has anti-tumor effects . Our results suggest that pMSCs might enhance the anti-tumor activities of NK cells through IL1ra or via other mediators including IL12, IL-18, and IFNγ receptors and their corresponding cytokines (IL-18, IL-12, and IFNγ), which are known to be involved in the anti-tumor activity of NK cells [38–40]. This possibility is further supported by the finding that pMSCs induce NK cell expression of TLR3, at least at a high pMSC ratio. TLR3 has a role in mediating the anti-tumor activities of NK cells . Therefore, our data suggest that pMSCs could be used to treat cancers by enhancing the anti-cancer activity of NK cells in vitro through different mechanisms that would involve IL-12, IL-18, and IFN-ɣ receptors, as well as TLR3 and IL1ra as we previously suggested for DPMSCs . Before realizing this possibility, further studies are needed to elucidate the molecular mechanisms that underlie the enhancement of the anti-tumor activities of NK cells by pMSCs.
Our data suggest that preconditioning NK cells with pMSCs stimulates NK cells to express inflammatory as well as anti-tumor molecules, which could be advantageous for cancer therapy.
We appreciate the staff and patients of the Delivery Unit, King Abdul Aziz Medical City for giving us placentae.
This study was supported by grants from KAIMRC (Grant No. RC12/117).
Availability of data and materials
All data generated or analysed during this study are included in this published article
MHA proposed and supervised the project, designed the experiments, and analyzed the data. NAA, AA, AMAS, and EB performed the experiments. MHA, FMA, TK, BK, MFEM, DJ, MAAJ, and ASAA wrote the manuscript and contributed to the data analysis and interpretation of the results. All authors reviewed the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The institutional research board (IRB) at King Abdulla International Medical Research Centre (KAIMRC), Saudi Arabia approved this study.
Consent for publication
All authors agree to publish this manuscript.
The authors declare that they have no competing interests.
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