Human macrophage migration inhibitory factor potentiates mesenchymal stromal cell efficacy in a clinically relevant model of allergic asthma

Ian J Hawthorne; Hazel Dunbar; Courteney Tunstead; Tamara Schorpp; Daniel J Weiss; Sara Rolandsson Enes; Claudia C dos Santos; Michelle E Armstrong; Seamas C Donnelly; Karen English

doi:10.1016/j.ymthe.2023.09.013

. 2023 Sep 20;31(11):3243–3258. doi: 10.1016/j.ymthe.2023.09.013

Human macrophage migration inhibitory factor potentiates mesenchymal stromal cell efficacy in a clinically relevant model of allergic asthma

Ian J Hawthorne ^1,^2,⁸, Hazel Dunbar ^1,^2,⁸, Courteney Tunstead ^1,², Tamara Schorpp ^1,², Daniel J Weiss ³, Sara Rolandsson Enes ⁴, Claudia C dos Santos ^5,⁶, Michelle E Armstrong ⁷, Seamas C Donnelly ⁷, Karen English ^1,^2,^∗

PMCID: PMC10638061 PMID: 37735872

Abstract

Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodeling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. A polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility to and severity of asthma. We investigated the efficacy of human MSCs in high- vs. low-hMIF environments and the impact of MIF pre-licensing of MSCs using humanized MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs significantly attenuated airway inflammation and airway remodeling in high-MIF-expressing CATT₇ mice but not in CATT₅ or wild-type littermates. Differences in efficacy were correlated with increased MSC retention in the lungs of CATT₇ mice. MIF licensing potentiated MSC anti-inflammatory effects at a previously ineffective dose. Mechanistically, MIF binding to CD74 expressed on MSCs leads to upregulation of cyclooxygenase 2 (COX-2) expression. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo. These findings suggest that MSC administration may be more efficacious in severe asthma patients with high MIF genotypes (CATT_6/7/8).

Keywords: mesenchymal stromal cells, house dust mite, allergic asthma, macrophage migration inhibitory factor, cyclooxygenase

Graphical abstract

English and colleagues discuss how mesenchymal stromal cells significantly attenuated house dust mite-induced airway inflammation and airway remodeling in high-MIF-expressing CATT₇ mice. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo.

Introduction

Allergic asthma is characterized by chronic airway inflammation and airway remodeling, which refers to the structural changes in the airways. Currently, there is a heavy reliance on inhaled corticosteroids and long-acting β2-adrenoceptor agonists in the treatment of allergic asthma. The recent introduction of novel biologics, such as benralizumab and dupilumab targeting Th2 cytokine receptors and tezepelumab targeting the alarmin thymic stromal lymphopoietin (TSLP), have been shown to significantly reduce allergic airway inflammation, leading to reduced exacerbation and improved forced expiratory volume 1 (FEV₁₎ values.¹^,²^,³^,⁴ However, not all patients are responders, and evidence for biologics to reverse existing airway remodeling in patients is limited so far.⁵ Thus, there is scope for novel therapeutics with the capacity to attenuate inflammation and reverse remodeling to address the pitfalls in the current treatment and management of allergic asthma.

Mesenchymal stromal cells (MSCs) have immunomodulatory and anti-fibrotic properties and proven therapeutic effects in a range of allergic airway inflammation models and are currently under investigation in two clinical trials for asthma (ClinicalTrials.gov: NCT05147688 and NCT05035862). Administration of MSCs intratracheally or intravenously has been shown to be effective in reducing airway inflammation and airway hyperresponsiveness in ovalbumin (OVA),⁶^,⁷^,⁸^,⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷ house dust mite (HDM),¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴ and Aspergillus hyphal extract²⁵^,²⁶ models. However, other studies have failed to demonstrate efficacy in experimental asthma models.⁷^,¹⁴^,²³^,²⁴^,²⁷^,²⁸ To understand the mechanisms involved and to make MSCs a viable therapeutic in the clinic, more focused translational work is needed.

Under basal conditions (for example, in healthy animals or individuals), MSC administration does not seem to alter immunological status or function (homeostasis is preserved). MSCs only become licensed to an anti-inflammatory phenotype in the presence of extrinsic factors.²⁹ When licensed, MSCs modulate their surrounding microenvironment.³⁰ Importantly, their therapeutic effect is blunted in the presence of interferon γ (IFNγ), nuclear factor κB (NF-κB), or tumor necrosis factor alpha (TNF-α) receptor blockade/inhibition.³¹^,³²^,³³ Moreover, in the absence of appropriate signals to license anti-inflammatory functions, MSCs may even exacerbate disease.³⁴^,³⁵^,³⁶ Licensing has been shown to improve MSC therapeutic efficacy by activating MSC anti-inflammatory characteristics prior to administration. Licensing through exposure to hypoxia,³⁷^,³⁸ inflammatory cytokines,³⁹^,⁴⁰ and pharmacological factors⁴¹ has been shown to improve MSC efficacy in a range of inflammatory diseases. Moreover, licensing of MSCs with serum from HDM-challenged mice¹⁸ or with serum from acute respiratory distress syndrome (ARDS) patients⁴² enhanced MSC therapeutic efficacy in vivo in pre-clinical lung disease models. However, there are also in vitro studies reporting differential and, in some cases, negative effects of patient samples (ARDS versus cystic fibrosis (CF)) on MSC survival and function.⁴²^,⁴³^,⁴⁴

Macrophage migration inhibitory factor (MIF) is an important regulator of host inflammatory responses, demonstrated by its ability to promote the production of other inflammatory mediators. For example, MIF has been shown to amplify the expression of TNF, IFNγ, interleukin-1β (IL-1β), IL-2, IL-6, and IL-8 from immune cells.⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸ This augmentation of immune signals contributes to MIF-mediated pathogenesis by acting to sustain inflammatory responses. This has been shown in a range of inflammatory diseases where the absence of MIF is associated with lower levels of pro-inflammatory cytokines, resulting in reduced pathology. For example, MIF knockout (MIF^−/−) mice display a less severe phenotype when exposed to OVA compared with control mice,⁴⁹^,⁵⁰^,⁵¹^,⁵² and the use of anti-MIF antibodies or a small-molecule inhibitor (ISO-1) results in reduced Th2 cytokines in models of allergic airway inflammation.⁵¹^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶ High levels of MIF as a result of longer CATT repeats, such as CATT₇, have been shown to increase severity in a range of diseases, including severe anemia,⁵⁷ pneumococcal meningitis,⁵⁸ multiple sclerosis,⁵⁹ tuberculosis,⁶⁰ and coronavirus disease 2019 (COVID-19).⁶¹ Importantly, associations between the CATT polymorphism and asthma incidence and severity have been observed.⁵² Not only do these studies show the pivotal role that MIF plays in pro-inflammatory diseases, they also affirm the importance of differences in the MIF CATT polymorphism.

Our previous work established a dominant role of MIF allelic variants in the severity of HDM-induced allergic asthma.⁶² Using humanized high-expressing and low-expressing MIF mice in an HDM model of allergic airway inflammation, we demonstrated the pivotal role MIF plays in exacerbating asthma pathogenesis. High levels of human MIF resulted in a significant increase in airway inflammation as a result of elevated levels of Th2 cytokines promoting infiltration of eosinophils into the airways. Furthermore, high levels of MIF were associated with airway remodeling with significant mucus hyperplasia, subepithelial collagen deposition, and airway hyperresponsiveness generating a more severe asthma phenotype. MIF has been shown to promote MSC migration in vitro;⁶³ however, the effect of MIF on MSC immunosuppressive function or therapeutic efficacy in vivo is unknown. Here, we sought to investigate the relationship between MIF and MSCs in vivo and to define conditions for optimal MSC therapeutic efficacy. High-MIF-expressing CATT₇, low-MIF-expressing CATT₅, and wild-type (WT) mice were used as a platform to investigate the role of MIF on MSC efficacy in a clinically relevant HDM-induced mouse model of allergic airway inflammation.

Results

Human bone marrow-derived MSCs (BM-MSCs) significantly reduce airway remodeling in CATT₇ mice challenged with HDM

First, to investigate the impact of high- and low-expressing MIF alleles on MSC treatment of allergic airway inflammation, we examined the lung histology. CATT₇, CATT₅, and the WT were randomized to HDM or mock (saline) intranasally 3 times a week for 3 weeks. Mice were then further randomized to 1 × 10⁶ human BM-MSCs or equal-volume saline administered via tail vein injection on day 14. On day 21, lung tissue was removed, formalin fixed, and sectioned onto slides (Figure 1A). Slides were stained with periodic acid-Schiff (PAS) to highlight mucin production to assess the level of goblet cell hyperplasia. CATT₇ mice exhibit significantly higher levels of goblet cell hyperplasia compared with WT and CATT₅ mice. Administration of BM-MSCs reduced the level of goblet cell hyperplasia in all groups to almost background levels, with a significant reduction in the number of mucin-secreting cells in the airways of HDM-challenged CATT₇ mice (Figures 1B and 1C).

Human BM-MSCs significantly reduce goblet cell metaplasia and collagen deposition in CATT₇ mice challenged with HDM

(A) PBS and HDM groups received PBS or HDM i.n. 3 times a week for 3 consecutive weeks. 1 × 10⁶ human BM-MSCs were administered i.v. to the HDM+MSC groups on day 14. Mice were sacrificed on day 21 (schematic created with BioRender). (B) Representative images of lung tissue from WT, CATT₅, and CATT₇ mice stained with periodic acid-Schiff (PAS) at 20× magnification; scale bar, 20 μm. Arrows show examples of mucin-containing goblet cells. (C) Goblet cell hyperplasia was investigated through the quantitation of PAS-positive cells. (D) Representative images of lung tissue stained with Masson’s trichome at 4× magnification; scale bar, 200 μm.

(E) Quantitation of the percentage of subepithelial collagen. Data are presented as mean $\pm$ SEM; n = 6 per group. Human BM-MSC donors 001-177 and 003-310 were used (RoosterBio). Statistical analysis was carried out using one-way ANOVA followed by the post hoc Tukey’s multiple-comparisons test: ∗p < 0.05, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001; ns, non-significant.

Subepithelial fibrosis was significantly increased in HDM-challenged CATT₇ mice compared with the lower-MIF-expressing CATT₅ and WT groups. BM-MSC administration reduced the level of subepithelial fibrosis to almost background levels in all groups, with significantly reduced subepithelial collagen deposition in HDM-challenged CATT₇ mice (Figures 1D and 1E). In CATT₅ and WT mice challenged with HDM, BM-MSC administration had a small but not significant therapeutic effect. BM-MSC administration significantly mitigated increased inflammatory infiltrate and H&E pathological score in CATT₇ mice challenged with HDM (Figure S1).

Human BM-MSCs significantly reduce airway inflammation in CATT₇ mice challenged with HDM

Total cell counts were significantly elevated in the bronchoalveolar lavage fluid (BALF) of CATT₇ mice following HDM challenge (Figure 2A). MSCs significantly reduced the number of total infiltrating cells in the BALF of CATT₇ mice (Figure 2A). Differential cell counts identified eosinophils as the main cells infiltrating the lung tissue following HDM challenge, and MSCs significantly decreased infiltrating eosinophils in CATT₇ mice but had no effect in the CATT₅ and WT groups (Figure 2B). IL-4 and IL-13 were significantly elevated in the BALF of CATT₇ mice following HDM challenge (Figures 2C and 2D). These Th2 cytokines are not significantly upregulated in CATT₅ or WT mice. While MSCs significantly decreased IL-4 and IL-13 in CATT₇ mice, MSC treatment did not reduce and, in some cases, increased Th2 cytokines in the BALF of CATT₅ and WT mice (Figures 2C and 2D). These data show that BM-MSCs are effective at alleviating eosinophil infiltration and reducing Th2 cytokines in a high-MIF-expressing model of allergic asthma and that MSCs require a threshold level of inflammation to mediate their therapeutic effects.

Human BM-MSCs significantly reduce levels of Th2 cytokines in the BALF of CATT₇ mice challenged with HDM

PBS and HDM groups received PBS or HDM i.n. 3 times a week for 3 consecutive weeks. 1 × 10⁶ human BM-MSCs were administered i.v. to the HDM+MSC groups on day 14. BAL was performed 4 h post final HDM challenge on day 18. (A) Total cell count recovered from the BALF.

(B) BALF eosinophil count, determined by differential staining of cytospins. (C and D) Cytokine levels of (C) IL-4 and (D) IL-13 in the BALF, determined by ELISA. White bars, PBS; gray bars, HDM blue bars, HDM+MSC. Data are presented as mean $\pm$ SEM; n = 5–6 per group. Human BM-MSC donors 001-177 and 003-310 were used (RoosterBio). Statistical analysis was carried out using one-way ANOVA followed by the post hoc Tukey’s multiple-comparisons test: ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001, ns, non-significant.

High levels of human MIF (hMIF) significantly enhance BM-MSC retention in an HDM model of allergic asthma

Next, we analyzed the biodistribution of MSCs following administration into HDM-challenged WT, CATT₅, and CATT₇ mice. 1 × 10⁶ fluorescently labeled BM-MSCs were administered intravenously (i.v.) via tail vein injection on day 14. On day 15, mice were sacrificed, and the lungs were prepared for CryoViz imaging (Figures 3A–3C). Significantly higher numbers of labeled MSCs were detected in the lungs of high-MIF-expressing CATT₇ mice compared with the low-expressing CATT₅ or WT littermate control (Figures 3C and 3D). However, the number of clusters of labeled BM-MSCs within the lungs remained unchanged among the groups (Figure 3E). Taken together, these data suggest that prolonged MSC pulmonary retention time increases the number of MSCs retained at the site of inflammation 24 h post administration. These data suggest that high levels of MIF may provide a longer window for MSCs to carry out their therapeutic effects.

High levels of hMIF significantly enhance BM-MSC retention in an HDM model of allergic asthma

HDM were administered i.n. 3 times a week for 2 weeks. On day 14, 1 × 10⁶ Qtracker 625-labeled hMSCs were administered i.v. to WT, CATT₅, or CATT₇ mice. 24 h later the lungs were harvested, embedded in OCT compound and frozen at −80. Tissue blocks were sectioned and imaged using the CryoViz (BioInvision) imaging system. (A–C) 3D images show representative lung images from (A) WT, (B) CATT₅, and (C) CATT₇ mice, with detected MSCs shown in yellow. (D and E) Total number of MSCs detected in the lungs (D) and number of clusters (E) were quantified using CryoViz quantification software. Data are presented as mean $\pm$ SEM; n = 3 per group. Human BM-MSC donor 001-177 was used (RoosterBio). Statistical analysis was carried out using one-way ANOVA followed by the post hoc Tukey’s multiple-comparisons test: ∗∗p < 0.01.

The influence of MIF on MSC expression of immunomodulatory factors and MSC cytokine licensing in vitro

MSCs mediate their therapeutic effects via expression or production of secreted factors in vitro and in vivo,⁶⁴ and licensing with proinflammatory cytokines such as IFNγ οr TNF-α⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸^,⁶⁹ can enhance expression of immunomodulatory mediators. Here, we characterized the effect of recombinant hMIF on the expression of indolamine 2-3-dioxygenase (IDO), cyclooxygenase 2 (COX-2), prostaglandin E synthase (PTGES), intercellular adhesion molecule-1 (ICAM-1), and hepatocyte growth factor (HGF) in untreated MSCs or MSCs licensed with IFNγ or TNF-α. Recombinant hMIF (rhMIF; 1 ng/mL) stimulation alone did not increase expression of IDO, COX-2, PTGES, ICAM-1, or HGF (Figures 4A–4E) in human BM-MSCs. Following licensing with TNF-α, MIF stimulation enhanced MSC expression of COX-2 and PTGES (Figures 4B and 4C). In IFNγ-licensed MSCs, rhMIF stimulation did not enhance MSC expression of IDO or HGF and significantly reduced ICAM-1 expression (Figures 4A, 4D, and 4E). We confirmed these findings at the protein level for IDO and COX-2 using intracellular flow cytometry (Figures 4F and 4G). Using increasing doses of rhMIF (1, 10, or 100 ng/mL), we showed that COX-2 expression is increased in a dose-dependent manner by rhMIF stimulation in TNF-α-licensed MSCs, with COX-2 expression plateauing at 10 ng/mL of rhMIF (Figure 4H). The MIF receptor CD74 is expressed by MSCs; however, rhMIF stimulation (dose range 1, 10, or 100 ng/mL) does not enhance CD74 expression (Figure 4I).

Influence of rhMIF licensing on MSC expression of immunomodulatory factors *in vitro*

(A–E) Gene expression of IDO, COX-2, PTGES, ICAM-1, and HGF by hBM-MSCs after stimulation with rhMIF (1 ng/mL), human TNF-α or human IFNγ for 24 h. Data are presented as mean ± SEM and are representative of 3 independent experiments. Human BM-MSC donors 001-177, 003-310, and 003-307 were used (RoosterBio). Statistical analysis was carried out using one-way ANOVA: ∗p < 0.05, ∗∗p < 0.01, ∗∗∗∗p < 0.0001, ns, non-significant.

CATT₇ MIF licensing enhances MSC expansion and immunosuppressive function in vitro

To investigate the effect of endogenous MIF from CATT₇ mice on MSC expression of immunomodulatory factors, we generated BM-derived macrophages (BMDMs) from CATT₇ mice and used the conditioned medium (CM) as a source of endogenous hMIF (Figure 5A) to license MSCs. The concentration of hMIF in CATT₇ BMDM CM ranged from ∼3,000–4,000 pg/mL (Figure S2).

MIF may have a negative role in the regulation of IDO expression as MIF^−/− mice produce more IDO;⁷⁰ however, MIF has an established role as an upstream positive regulator of COX-2 through activation of the mitogen-activated protein kinase (MAPK) signaling pathway.⁷¹^,⁷² IDO, COX-2, and PGE2 are widely reported mediators of MSC immunosuppression.³⁹^,⁷³ MSCs constitutively express COX-2 but not IDO. IFNγ licensing of MSCs leads to expression of IDO, while TNF-α enhances MSC COX-2 expression.⁶⁸ Here we show that CATT₇ MIF stimulation reduces MSC IDO production (Figures 5B and 5C); however, the percentage of COX-2 expressing MSCs was significantly increased following CATT₇ MIF stimulation (Figures 5D and 5E). Human MSCs express the MIF receptor CD74, and this expression is maintained and not increased following exposure to CATT₇ MIF CM (Figure 5F). In line with another study,⁷⁴ we show that IFNγ stimulation leads to significantly increased MSC CD74 expression and that CATT₇ MIF CM does not significantly alter that (Figure 5F). This aligns with our data showing that MIF does not enhance IFNγ-regulated IDO expression. Given the potentiating effect of MIF on the TNF-α-regulated gene COX-2 in MSCs, we examined the influence of CATT₇ MIF on MSC expression of the TNF-α-regulated genes tumor necrosis factor-inducible gene 6 (TSG-6) and prostaglandin-endoperoxide synthase 2 (PTGS2). The presence of CATT₇ MIF CM significantly reduced TSG-6 in TNF-α-stimulated MSCs (Figure 5G) but did not significantly alter the expression of PTGS2 (Figure 5H). MSCs licensed with high levels of hMIF from CATT₇ CM displayed enhanced suppression of T cell proliferation compared with the untreated MSCs; however, this was not statistically significant in the frequency of proliferating CD3⁺ T cells (Figure 5I) or the number of proliferating CD3⁺ T cells (Figure 5J). The presence of SCD-19 abrogated the enhanced suppression mediated by hMIF-licensed MSCs because the number of proliferating CD3⁺ T cells was significantly increased compared with the ^CATT7MSC group (Figure 5J).

Previous studies have shown that MIF has the ability to support cell proliferation in vitro.⁷⁵^,⁷⁶^,⁷⁷ Increasing the number of MSCs within the inflammatory niche could prove to be important in enhancing MSC immunoregulatory effects. High levels of MIF significantly enhanced MSC expansion in vitro compared with the complete medium control group (Figure 5K). Blockade of MIF using SCD-19 confirmed the role of MIF in driving MSC expansion (Figure 5K). These data might help to explain the enhanced retention of MSCs in CATT₇ HDM-challenged mice (Figure 3), but further experiments would be required to confirm that.

Titration of BM-MSC doses in CATT₇ mice challenged with HDM

Next, we investigated whether MIF licensing could improve MSC efficacy in the high-MIF-expressing CATT₇ mice challenged with HDM. To do this, we first investigated the dose at which MSCs lose efficacy. MSCs at doses of 1 × 10⁶, 5 × 10⁵, 1 × 10⁵, and 5 × 10⁴ were administered i.v. into HDM-challenged CATT₇ on day 14 (Figure 6A). MSCs maintained efficacy as low as 1 × 10⁵ cells with reduced immune cell infiltration (Figures 6B and 6C) and reduced Th2 cytokines IL-4 (Figure 6D) and IL-13 (Figure 6E). We observed that BM-MSCs were no longer able to carry out their immunosuppressive effects at a dose of 5 × 10⁴. At 5 × 10⁴, BM-MSCs were unable to reduce the number of eosinophils infiltrating the lungs (Figures 6B and 6C) or regulate Th2 cytokine production (Figures 6D and 6E).

MIF licensing restores MSC efficacy at low doses in CATT₇ mice

To investigate the effect of MIF licensing on MSC therapeutic efficacy, MSCs were first licensed in vitro by stimulation with BMDM CM from CATT₇ or knockout (KO) mice for 24 h 5 × 10⁴ MSCs, MIF-licensed MSCs (^CATT7MSC), or MIF KO-licensed MSCs (^KOMSC) were administered i.v. into CATT₇ mice via tail vein injection on day 14 in HDM-challenged mice. On day 18, BALF was collected, cell counts were performed, and Th2 cytokines were measured (Figure 7A). Only ^CATT7MSC administration significantly reduced total cell counts and the number of eosinophils in CATT₇ mice challenged with HDM (Figures 7B and 7C). ^CATT7MSCs markedly reduced IL-4 and IL-13 levels compared with the control group although not significantly (Figures 7D and 7E). The control MSC group and the ^KOMSC group displayed similar levels of immune cell infiltration and Th2 cytokine production, suggesting that the effects observed in the ^CATT7MSC group are specific to MIF-licensed MSCs. These data show that MIF licensing can restore MSC immunosuppressive function at doses that would normally be ineffective.

Blocking COX-2 abrogates therapeutic efficacy of MIF licensed BM-MSCs

COX-2 is the rate-limiting enzyme involved in the synthesis of arachidonic acid to PGE2, a key mediator in the immunomodulatory effects of MSCs.⁷⁸ To assess the role of COX-2 on MIF-licensed MSCs, we inhibited COX-2 with indomethacin. MSCs were treated with indomethacin (10 μM) for 30 min. Following the 30-min pre-treatment, cells were incubated with CATT₇ CM for 24 h. To further validate the involvement of MIF in the improvement of MSC efficacy, MSCs were exposed to an anti-CD74 neutralizing antibody (10 μg/mL) or immunoglobulin G1 (IgG1) isotype control (10 μg/mL) for 30 min. MSCs were then incubated with CATT₇ CM for 24 h (Figure 8A). Analysis of the BALF cell counts showed that pre-treating MSCs with indomethacin before administration significantly reduces ^CATT7MSCs’ ability to suppress immune cell infiltration in the BALF of CATT₇ mice challenged with HDM (Figures 8B and 8C). Additionally, the analysis of the Th2 cytokines in the BALF showed a marked increase in IL-4 (Figure 8D) and a significant increase in the level of IL-13 (Figure 8E) in the indomethacin group compared with the control MIF-licensed MSC group. Taken together, these results show that COX-2 is an important mediator in the enhancement of therapeutic efficacy associated with MIF licensing. Furthermore, blocking of CD74 abrogates MIF licensed BM-MSC suppression of eosinophil infiltration and type 2 cytokines in the BALF (Figure 8). These data indicate that MIF enhances MSCs’ immunomodulatory capacity mainly through CD74 signaling to upregulate COX-2 production.

MIF-Licensed MSCs mediate their protective effects in HDM-induced allergic airway inflammation in a CD74- and COX-2-dependent manner in CATT₇ mice

(A) 5 × 10⁴ MSCs were exposed to the COX-2 inhibitor indomethacin, an anti-CD74 neutralizing antibody, or an isotype control antibody for 24 h *in vitro*. All MSCs were licensed with CATT₇ BMDM supernatant for 24 h prior to i.v. administration. BAL was performed 4 h post final HDM challenge on day 18 (schematic created with BioRender). (B and C) Total number of cells in the BALF were determined (B), and differential cell counts were performed on the collected cells to determine the numbers of eosinophils (C). (D and E) Cytokine levels of (D) IL-4 and (E) IL-13 in the BALF, determined by ELISA. Data are presented as mean $\pm$ SEM; n = 5–6 per group. Human BM-MSC donors 001-177 and 003-310 were used (RoosterBio). Statistical analysis was carried out using one-way ANOVA followed by the post hoc Tukey’s multiple-comparisons test: ∗∗p < 0.01, ∗∗∗ p < 0.001, ∗∗∗∗p < 0.0001.

Discussion

Our main results advance the field of MSC-based therapeutics for asthma by demonstrating that (1) MSC treatment is highly effective in ameliorating airway inflammation; (2) their therapeutic potential can be enhanced by MSC-MIF licensing, as demonstrated in high-MIF-expressing CATT₇ mice; and finally (3) the mechanism of MIF licensing is dependent on MSC-CD74 expression levels that drive COX-2 expression in MSCs. Our data align with the literature demonstrating the ability of human MSCs to ameliorate eosinophil infiltration by reducing the levels of Th2 cytokines.⁸^,¹⁰^,¹¹^,¹²^,²⁵^,⁷⁹ In addition to reducing inflammation, MSCs also alleviate features of airway remodeling in the CATT₇ mice. Interestingly, while MSCs were effective at reducing the severity of goblet cell hyperplasia and subepithelial fibrosis in all groups, we did not observe the same changes in type 2 inflammatory markers in the BALF of WT and low-MIF-expressing CATT₅ mice, suggesting that high levels of MIF may be responsible for improving MSC efficacy. The reduced efficacy of MSCs in the WT and CATT₅ mice can likely be attributed to a lack of inflammation present, associated with a bias toward Th1 immunity in C57BL/6 mice compared with more Th2 bias in BALB/c mice, influencing the level of Th2 response in our HDM challenge model.⁸⁰ There have been several instances where researchers also observed poor responses to MSC treatment of allergic airway inflammation in C57BL/6 mice.⁷^,²³ More recently, Castro et al.²¹ report the requirement of at least 2 doses of human adipose derived (AD)-MSCs to reverse airway remodeling and alleviate inflammation in HDM-challenged C57BL/6 mice.

We show that a single human MSC dose is capable of significantly decreasing airway remodeling in CATT₇ mice. This suggests that high levels of MIF may facilitate activation of MSCs, improving their therapeutic efficacy and leading to reversal of airway remodeling. The literature surrounding MSCs’ effect on airway remodeling is conflicting; however, the majority of the current literature demonstrates that MSCs can attenuate airway remodeling.⁸^,¹⁰^,¹⁴^,¹⁵^,¹⁷^,¹⁸^,²⁸ Others report a deficit in MSCs capacity to ameliorate goblet cell hyperplasia¹⁴^,¹⁹^,²³ or subepithelial collagen deposition.⁹^,²⁸ Reasons for these discrepancies include the source of MSCs,⁸^,²³^,⁸¹ genotypic mouse model differences, severity of the mouse models, time of infusion, MSC fitness, dosing, and route of administration.²⁷

Our previous studies have demonstrated that pro-inflammatory cytokine licensing of MSCs or MSC-like cells; multipotent adult progenitor cells (MAPCs) enhance their retention under inflammatory conditions and correlate with enhanced therapeutic efficacy.³⁹^,⁸² We detected significantly higher numbers of MSCs in the lungs of HDM-challenged CATT₇ mice compared with CATT₅ or littermate controls 24 h following administration. It has been suggested that short-term effects of MSCs are mediated by their diverse secretome and that the longer-term effects of MSC therapy are a result of direct interaction with other cell types.⁸³ Increased longevity at the site of injury allows MSCs a longer period to secrete soluble factors and interact with cells in the inflammatory microenvironment. MSC retention in the CATT₇ HDM-challenged mice is an important observation, and future work will determine whether enhanced retention is also involved in the enhanced MSC efficacy observed.

Taken together, these data suggest that MSCs are more efficacious in the high-MIF environment of CATT₇ mice. By investigating the effects of different concentrations of a human cytokine on the efficacy of human MSCs in a model of allergic asthma using a clinically relevant allergen, we identified a specific disease microenvironment that supports and enhances MSC efficacy. The use of our humanized model aims to provide a more accurate depiction of how human MSCs would interact in subsets of patients compared with conventional murine models. Of course, despite exploring the effect of a human cytokine on human MSCs, there are still limitations because we are unable to fully mimic clinical severe allergic asthma, and the use of transgenic MIF mice on a C57BL/6 background meant that control WT mice do not develop a high level of type 2 inflammation. However, these results may have implications for tailoring MSC treatment in cases of severe asthma. Our results have demonstrated that MSCs are less efficacious in low-MIF environments. Patients with 5/5 haplotypes tend to have lower levels of circulating MIF⁸⁴ and therefore may not respond as well to MSC treatment. Patients with 6/6, 7/7, or 8/8 haplotypes are more likely to have high levels of circulating MIF,⁵²^,⁸⁵^,⁸⁶ which may lead to greater MSC activation and enhanced therapeutic efficacy.

Following the discovery that MSC administration into CATT₇ mice led to improved MSC efficacy, we investigated strategies to use high-MIF microenvironments to potentiate the effects of MSCs. Past work in our lab has focused on different licensing strategies of MSCs to enhance MSC efficacy. Previously, we have demonstrated how IFNγ licensing can improve MSC efficacy in a humanized model of acute graft versus host disease (GvHD) and how endogenous factors such as peroxisome proliferator-activated receptor (PPAR) δ ligands or treatments like cyclosporine A can influence this.³⁹^,⁴⁰ Other studies have shown how licensing with pharmacological agents or endogenous factors can further enhance the effects of MSC therapy in preclinical models of asthma.¹⁸^,¹⁹^,⁸⁷

One of the main criticisms of preclinical research is the use of doses that far exceed what would be reasonable in the clinic. Analysis of clinical trials using i.v. injection of MSCs reveals that the minimal effective dose used ranges from 1–2 million cells/kg.⁸⁸ Studies that have investigated i.v. administration of MSCs in preclinical models of allergic asthma, administering doses that equate to 4–40 million cells/kg, with the majority at the higher end of the scale.⁸^,¹⁰^,¹²^,¹⁶^,²⁰^,²¹^,²²^,²⁵^,²⁶^,²⁸^,⁷⁹^,⁸⁹^,⁹⁰^,⁹¹^,⁹² The efficacy observed with MIF-licensed MSCs using 5 × 10⁴ cells per mouse results in an effective dose of 2 million cells/kg. This shows that, through MIF licensing, we are able to restore MSC efficacy at a dose akin to what is used in clinical trials.

We then sought to elucidate the mechanisms involved. Given our use of human MSCs in a mouse host, the interspecies ligand/receptor non-functionality can raise questions about how human MSCs might mediate their effects in a mouse host. We and others have shown that human MSCs can indeed mediate protective effects in mouse hosts.⁸^,¹⁰^,¹¹^,¹²^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,²¹^,²⁴^,²⁵^,³³^,⁹³ Four studies have tracked human MSC biodistribution following i.v. administration in patients with chronic obstructive pulmonary disease (COPD),⁹⁴ liver cirrhosis,⁹⁵ hemophilia A,⁹⁶ or breast cancer.⁹⁷ No MSCs were detected in the blood 1 h post infusion. MSCs were distributed mainly in the lungs⁹⁵ or lungs and liver⁹⁶ 48 h post i.v. infusion, with the signal decreasing thereafter. Therefore, these studies suggest that biodistribution of human MSCs following i.v. administration in humans aligns with the studies investigating MSC biodistribution in mouse models.⁹⁸

In terms of mechanism, MIF-mediated signal transduction is primarily initiated by binding to MIF’s classical receptor, CD74.⁹⁹ We showed that blocking CD74 on the surface of MSCs ultimately abolished their immunosuppressive abilities. These findings not only reaffirmed that the licensing with CATT₇ CM was MIF mediated, but it also showed that these effects were dependent on binding to CD74. MIF signal transduction through CD74 binding has been shown to initiate a range of signaling pathways that induce cell proliferation, resistance to apoptosis, and the promotion of repair.¹⁰⁰^,¹⁰¹^,¹⁰²^,¹⁰³^,¹⁰⁴ Furthermore, MIF binding to CD74 has been shown to activate cytosolic phospholipase A2 (cPLA₂). Moreover, cPLA₂ activation results in the mobilization of arachidonic acid from membrane phospholipids, which is a precursor to the synthesis of prostaglandins.¹⁰⁵ Interestingly, MIF can upregulate COX-2 expression, a rate-limiting step in the synthesis of prostaglandins such as PGE2;⁷¹^,⁷²^,¹⁰⁶ however, MIF has been shown to have no effect on the expression of COX-1.⁷¹

The COX-2/PGE2 pathway has been extensively documented as being one of the key mediators driving MSC immunomodulation.³⁹^,⁶⁸^,¹⁰⁷^,¹⁰⁸ Our data show that MIF stimulation enhances the expression of COX-2, but not TSG-6 or PTGS2, in untreated and TNF-α-licensed MSCs. We hypothesized that the COX-2/PGE2 pathway could be involved in the restoration of MSCs’ immunomodulatory capacity following CATT₇ licensing. To investigate, we pre-treated MSCs with indomethacin prior to licensing. Indomethacin is a potent non-selective inhibitor of COX-1 and COX-2.¹⁰⁹ We showed that blocking COX-2 abrogated the therapeutic efficacy of CATT₇ licensed MSCs. Interestingly we observed that blocking of COX-2 via indomethacin had a more pronounced effect than blocking CD74. COX-2 is constitutively expressed in human MSCs; therefore, inhibition with indomethacin also blocks basal COX-2 expression, which will contribute to the effects observed.

These data show that MIF licensing can improve MSC therapeutic efficacy through the upregulation of COX-2, which likely drives PGE2 production. Our data agree with several studies in the literature that also reveal the ability of MIF to improve MSC efficacy in vivo.¹¹⁰^,¹¹¹^,¹¹² Zhu et al.,¹¹⁰ Liu et al.,¹¹¹ and Zhang et al.¹¹² demonstrated the ability of MIF to improve MSC therapeutic efficacy by transducing MSCs with a lentiviral vector containing Mif cDNA, thus promoting MIF overexpression.¹¹⁰^,¹¹¹^,¹¹² Furthermore, Zhang et al.¹¹³ demonstrated the ability of MIF to upregulate COX-2 expression and promote PGE2 production in astrocytes. Here, we further demonstrate the effects of ex vivo MIF licensing on MSC therapeutic efficacy by showing that binding to CD74 and increased COX-2 expression enhances MSCs’ immunomodulatory abilities.

The knowledge gained from this study can be used to further optimize MSCs as a therapy and provide a basis for future studies regarding the effects of MSCs on the immune response in high-MIF environments, such as in asthma patients exhibiting the CATT₇ polymorphism.

Materials and methods

Ethics approval

All procedures involving the use of animals or human materials were carried out by licensed personnel. Ethics approval for all work was granted by the biological research ethics committee of Maynooth University (BRESC-2018-013). Project authorization was received from the Scientific Animal Protection Unit of the Health Products Regulatory Agency (HPRA) under AE19124/P022, where the terms of the animal experiments within this project were outlined and adhered to in accordance with the Animal Research: Reporting of In Vivo Experiments (ARRIVE) criteria.

Human BM-MSC culture

BM-MSCs from three different human donors were obtained from RoosterBio (Frederick, MD, USA). MSCs were first expanded in RoosterBio proprietary expansion medium (RoosterBasal and RoosterBooster) for the first two passages according to the manufacturer’s instructions. Following this, MSCs were cultured and maintained in Dulbecco’s modified Eagle’s medium (DMEM) low glucose (Sigma-Aldrich, Arklow, Wicklow, Ireland) supplemented with 10% (v/v) fetal bovine serum (FBS; BioSera, Cholet, France) and 1% (v/v) penicillin/streptomycin (Sigma-Aldrich). Human MSCs were seeded at 1 × 10⁶ cells per T175 flask and cultured at 37 °c in 5% CO₂. Medium was replenished every 2–3 days, and cells were passaged when they achieved 80% confluency. All experiments were carried out between passages 2–5.

MSC characterization

BM-MSCs from three different human donors (identified as 001-177, 003-307, and 003-310) from RoosterBio were characterized by analyzing the expression of cell surface markers. All MSCs donors were found to be negative for CD34 (fluorescein isothiocyanate [FITC]), CD45 (Allophycocyanin (APC)), and human leukocyte antigen-DR (HLA-DR) (phycoerythrin (PE)) and positive for CD73 (APC), CD90 (FITC), and CD105 (PE) (BD Pharmingen, San Diego, CA, USA) by the Attune Nxt flow cytometer (Figure S3).

Animal strains

Two C57BL/6 mouse strains expressing the human high- or low-expression MIF alleles (MIF^CATT7 [(C57BL/6NTac-Miftm3884.1(MIF)Tac-Tg(CAG-Flpe)2Arte] and MIF^CATT5 [C57BL/6NTac-Miftm3883.1(MIF)Tac-Tg(CAG-Flpe)2Arte] mice) were created using vector-based recombinant replacement of murine Mif by Taconic Biosciences (Rensselaer, NY, USA) (Figure 1). Validation of the expression of human and not murine MIF mRNA was verified by qPCR, and −794 CATT-length-dependent stimulated MIF production was confirmed in vivo.⁶¹ Littermate WT and MIF^−/− (MIF KO)¹¹⁴ (a kind donation from R. Bucala, Yale School of Medicine, Yale University, New Haven, CT, USA) mice were used as controls.

HDM-induced airway inflammation model and therapeutic protocol

Both male and female MIF^CATT7, MIF^CATT5, or WT mice aged 6–12 weeks were challenged with 25 μg HDM extract (Dermatophagoides pteronyssinus; Greer Laboratories, Lenoir, NC, USA) in 25 μL phosphate-buffered saline (PBS) intranasally (i.n.) 3 days weekly for 3 weeks under light isoflurane anesthesia. Control mice were challenged with 25 μL PBS under the same conditions. On day 14, after HDM challenge, mice received an i.v. injection of 1 × 10⁶ MSCs in 300 μL into the tail vein.¹¹⁵ For the dose curve, 1 × 10⁶, 5 × 10⁵, 1 × 10⁵, and 5 × 10⁴ were administered i.v. into HDM-challenged CATT₇ mice on day 14. 5 × 10⁴ was selected as the dose at which MSCs lose efficacy.

Licensing of MSCs with endogenous hMIF

Supernatants containing endogenous hMIF were generated from BMDMs of C57BL/6 mouse strains expressing the high-expressing MIF allele (CATT₇). CATT₇ mice were challenged with HDM in 25 μL PBS i.n. 3 days weekly for 3 weeks under light isoflurane anesthesia. 4 h post final challenge, femora and tibiae were flushed with warm Roswell Park Memorial Institute (RPMI) 1640 medium GlutaMAX (Gibco, Paisley, UK) supplemented with 10% (v/v) heat-inactivated FBS (BioSera) and 1% (v/v) penicillin/streptomycin (Sigma-Aldrich). Cells were collected and seeded into T175 flasks in cRPMI supplemented with 10% L929 CM. The L929 cell line produces high amounts of macrophage colony stimulating factor (M-CSF) and other proteins stimulating macrophage differentiation. After 96 h, supernatants were collected, sterile filtered (0.22 μM pore size), and stored at −20°C. The CM generated in this manner will be referred to as CATT₇ CM. Additionally, KO CM was generated from MIF KO mice as a control. Licensing MSCs was performed by removing existing medium, washing with PBS, and incubating cells with CATT₇ CM (^CATT7MSC) or MIF KO CM (^KOMSC) for 24 h. To account for variability of hMIF levels between CATT₇ mice and to ensure that WT mice did not produce hMIF, CATT₇, CATT₅, and WT supernatants were measured by hMIF ELISA (R&D Systems, MN, USA) as described previously (Figure S2).⁶² 5 × 10⁴ licensed MSCs were administered i.v. into HDM-challenged CATT₇ mice on day 14. Where indicated, MSCs were treated with the COX-2 inhibitor indomethacin (10 μM) for 30 min. Following pre-treatment, MSCs were licensed with CATT₇ CM for 24 h as described above. Moreover, mouse anti-CD74 neutralizing antibody and isotype control were added to the assay. MSCs were pre-treated with anti-CD74 neutralizing antibody (clone LN2; 10 μg/mL) or IgG1 κ isotype control (clone T8E5; 10 μg/mL) for 30 min. MSCs were then licensed with CATT₇ CM for 24 h before administration.

Collection of BALF

On day 18, 4 h post final challenge, mice were sacrificed for cell and cytokine analysis of the BALF. BALF was obtained through 3 gentle aspirations of PBS. After centrifugation, protease inhibitor cocktail (Roche Diagnostics, Mannheim, Germany) was added to the supernatants before Th2 cytokine analysis. Total numbers of viable BALF cells were counted using ethidium bromide/acridine orange staining on a hemocytometer and then pelleted onto microscope slides by cytocentrifugation. Slides were stained with Kwik Diff kit stain (Richard-Allan Scientific, Kalamazoo, MI, USA), and coverslips were mounted using dibutylphthalate polystyrene xylene (DPX) mounting medium (Sigma-Aldrich). Differential cells counts were derived by counting a minimum of 300 leukocytes on randomly selected fields under a light microscope at 20× magnification.

ELISA

Levels of mouse interleukin-4 (mIL-4) (BioLegend, San Diego, CA, USA) and mIL-13 (eBioscience, San Diego, CA, USA) were determined using commercial ELISA kits according to the manufacturer’s instructions.

Lung histology

On day 21, mice were sacrificed for histological analysis. Lungs were removed and fixed in 10% neutral buffered formalin and paraffin embedded, and 5-μm slices were mounted onto slides for histological analysis. Lung tissue was stained with H&E, PAS, or Masson’s trichrome to analyze immune cell infiltration, goblet cell hyperplasia, or subepithelial collagen deposition, respectively. H&E analysis was carried out as described previously.¹¹⁶ Goblet cell hyperplasia was determined by the percentage of PAS-positive cells in airways relative to airway diameter. Subepithelial collagen deposition was calculated by analyzing the percentage of positive staining using the trainable Weka segmentation plugin on Fiji open-source software.

Cryo-imaging

1 × 10⁶ MSCs were labeled with the Qtracker 625 labeling kit (Invitrogen, Paisley, UK) according to the manufacturer’s instructions before being administered i.v. on day 14. On day 15, mice were humanely euthanized, and the lungs were embedded in mounting medium for cryotomy (O.C.T. compound, VWR Chemicals, Leuven, Switzerland), frozen in liquid nitrogen, and stored at −80°C. Lungs were sectioned into 40-μm slices and imaged with the automated CryoViz imaging system (BioInvision, Cleveland, OH, USA). Images were then processed to generate 3D images using CryoViz processing, and the number of detected cells was quantified using cell detection software (BioInvision).³⁹

Analysis of gene expression

Total RNA was extracted using TRIzol (Ambion Life Sciences, Cambridgeshire, UK) according to manufacturer’s instructions. RNA concentrations were measured using a spectrophotometer (Nanodrop 2000, Thermo Scientific, Wilmington, DE, USA) and equalized to 100 ng/μL before cDNA synthesis. cDNA synthesis was performed according to the manufacturer’s instructions (Quantabio, MA, USA). Real-time PCR was carried out using PerfeCta SYBR Green FastMix (Quantabio). Expression of human COX-2, PTGES, IDO, ICAM-1, HGF, TSG-6, and PTGS2 (primer sequence information is available in Table S1) was quantified in relation to the housekeeper gene HPRT using the ΔCT method. The fold change in the relative gene expression was determined by calculating the 2^−ΔΔCT values.

MSC expansion assay

1.4 × 10⁵ MSCs were seeded out into T25 flasks in complete Dulbecco's Modified Eagle Medium (cDMEM) or 50:50 cDMEM and WT CM or CATT₇ CM for 72 h. Cells were trypsinized and stained with ethidium bromide/acridine orange and counted on a hemocytometer. The MIF inhibitor SCD-19 (100 μM) was used to determine MIF specificity. In such cases, CM was pre-incubated with SCD-19 1 h before the expansion assay.

Intracellular staining of COX-2 and IDO

MSCs were seeded at 1 × 10⁵ cells per well in 6-well plates. MSCs were stimulated with recombinant human IFNγ at low (5 ng/mL) or high (40 ng/mL) concentration, TNF-α (5–10 ng/mL; PeproTech, London, UK), rhMIF (1 ng/mL; provided by Rick Bucala, Yale), or endogenous MIF (CATT₇ CM) for 24 h. Cells were prepared for intracellular staining using the Intracellular FoxP3 kit according to the manufacturer’s instructions. Cells were stained with COX-2 (PE) or IDO (APC) (BD Pharmingen) for 45 min. Cells were then washed in flow cytometry staining buffer and acquired using the Attune Nxt flow cytometer.

Surface staining of CD74

MSCs were seeded at 1 × 10⁵ cells per well in 6-well plates. MSCs were stimulated with recombinant human IFNγ (5 ng/mL, PeproTech), rhMIF (1, 10, or 100 ng/mL), or endogenous MIF (CATT₇ CM) for 24 h. Cells were stained with CD74 (PE, BD Pharmingen) for 45 min. Cells were then washed in flow cytometry staining buffer and acquired using the Attune Nxt flow cytometer.

T cell suppression assay

Human PBMCs were isolated from buffy packs (Irish Blood Transfusion Service) by Ficoll density gradient centrifugation. 5 × 10⁴ carboxyfluorescein succinimidyl ester (CFSE)-labeled PBMC were co-cultured (Thermo Fisher Scientific, Eugene, OR, USA) with BM-MSCs at a 1:20 ratio (2.5 × 10³ cells/well). 24 h prior to co-culture, BM-MSCs were incubated with CATT₇ CM or CATT₇ CM + SCD-19 (100 μM). After 24 h, BM-MSCs were washed with PBS before adding the PBMCs. Activation and expansion of human T cells was carried out using ImmunoCult human CD3/CD28 T cell activator antibody mix (STEMCELL Technologies, Cambridge, UK). After 4 days, PBMCs were harvested, and the frequency (percent) and number of proliferating CD3⁺ T cells were analyzed by flow cytometry (Attune Nxt flow cytometer).

Statistical analysis

Mice were randomized. Observers assessing endpoints were blinded to group assignment. Data for individual animals and independent experiments are presented as individual symbols. All data are presented as mean ± SEM. Results of two or more groups were compared by one-way analysis of variance (ANOVA) followed by the post hoc Tukey’s multiple comparison test. GraphPad Prism (GraphPad, San Diego, CA, USA) was used for all statistical analyses.

Acknowledgments

This research was supported by an Irish Research Council Laureate Award to K.E. (IRCLA/2017/288). This publication has emanated from research supported in part by a research grant from Science Foundation Ireland (SFI) under grant 12/RI/2346 (2), an infrastructure award supporting the CryoViz and SFI grant 16/RI/3399, and an infrastructure award supporting the Attune Nxt. We would like to thank Deirdre Daly, Gillian O’Meara, and Shannon Grellan for exceptional care of our animals used in this study.

Author contributions

I.J.H. performed research, data analysis, and study design and wrote the manuscript. H.D. performed research, data analysis, and study design and wrote the manuscript. C.T. and T.S. performed research and data analysis. D.J.W., S.R.E., and C.C.d.S. contributed to study design and data analysis. S.C.D. and M.E.A. provided reagents and contributed to study design and data analysis. K.E. designed and supervised the study and wrote the manuscript. All authors approved the final manuscript.

Declaration of interests

The authors declare no competing interests.

Footnotes

Supplemental information can be found online at https://doi.org/10.1016/j.ymthe.2023.09.013.

Supplemental information

Document S1. Figures S1–S3 and Table S1

mmc1.pdf^{(1.4MB, pdf)}

Document S2. Article plus supplemental information

mmc2.pdf^{(6MB, pdf)}

Data and code availability

The data that support the findings of this study are available upon request from the corresponding author.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Document S1. Figures S1–S3 and Table S1

mmc1.pdf^{(1.4MB, pdf)}

Document S2. Article plus supplemental information

mmc2.pdf^{(6MB, pdf)}

Data Availability Statement

The data that support the findings of this study are available upon request from the corresponding author.

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PERMALINK

Human macrophage migration inhibitory factor potentiates mesenchymal stromal cell efficacy in a clinically relevant model of allergic asthma

Ian J Hawthorne

Hazel Dunbar

Courteney Tunstead

Tamara Schorpp

Daniel J Weiss

Sara Rolandsson Enes

Claudia C dos Santos

Michelle E Armstrong

Seamas C Donnelly

Karen English

Abstract

Graphical abstract

Introduction

Results

Human bone marrow-derived MSCs (BM-MSCs) significantly reduce airway remodeling in CATT7 mice challenged with HDM

Figure 1.

Human BM-MSCs significantly reduce airway inflammation in CATT7 mice challenged with HDM

Figure 2.

High levels of human MIF (hMIF) significantly enhance BM-MSC retention in an HDM model of allergic asthma

Figure 3.

The influence of MIF on MSC expression of immunomodulatory factors and MSC cytokine licensing in vitro

Figure 4.

CATT7 MIF licensing enhances MSC expansion and immunosuppressive function in vitro

Figure 5.

Titration of BM-MSC doses in CATT7 mice challenged with HDM

Figure 6.

MIF licensing restores MSC efficacy at low doses in CATT7 mice

Figure 7.

Blocking COX-2 abrogates therapeutic efficacy of MIF licensed BM-MSCs

Figure 8.

Discussion

Materials and methods

Ethics approval

Human BM-MSC culture

MSC characterization

Animal strains

HDM-induced airway inflammation model and therapeutic protocol

Licensing of MSCs with endogenous hMIF

Collection of BALF

ELISA

Lung histology

Cryo-imaging

Analysis of gene expression

MSC expansion assay

Intracellular staining of COX-2 and IDO

Surface staining of CD74

T cell suppression assay

Statistical analysis

Acknowledgments

Author contributions

Declaration of interests

Footnotes

Supplemental information

Data and code availability

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases

Human bone marrow-derived MSCs (BM-MSCs) significantly reduce airway remodeling in CATT₇ mice challenged with HDM

Human BM-MSCs significantly reduce airway inflammation in CATT₇ mice challenged with HDM

CATT₇ MIF licensing enhances MSC expansion and immunosuppressive function in vitro

Titration of BM-MSC doses in CATT₇ mice challenged with HDM

MIF licensing restores MSC efficacy at low doses in CATT₇ mice