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Cited by 146Mesenchymal stem cell researchImmunotherapy and Immune ResponsesRespiratory Support and Mechanisms

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Mesenchymal stem cells induce dendritic cell immune tolerance via paracrine hepatocyte growth factor to alleviate acute lung injury

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Lu, Zhonghua, Chang, Wei, Meng, Shanshan, Xu, Xiuping, Xie, Jianfeng, Guo, Fengmei, Yang, Yi, Qiu, Haibo, Liu, Ling·2019·Stem Cell Research & Therapy
DOI 10.1186/s13287-019-1488-2PMC PMC6894226
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Abstract

Background: Mesenchymal stem cells (MSCs) have been shown to alleviate acute lung injury (ALI) via paracrine hepatocyte growth factor (HGF) and to induce the differentiation of dendritic cells (DCs) into tolerogenic dendritic cells (DCregs) and participate in the immune response. However, whether MSCs induce the production of DCregs by secreting HGF to alleviate early ALI remains unclear. We observed that the protective effect of mouse bone marrow-derived MSCs against lipopolysaccharide (LPS)-induced ALI was achieved by inducing mature DCs (mDCs) to differentiate into DCregs, and its mechanism is related to the activation of the HGF/Akt pathway. Methods: MSCs or MSCs with overexpression or knockdown of HGF were cocultured with DCs derived from mouse bone marrow using a Transwell system for 3 days. Moreover, we used MSCs or MSCs with overexpression or knockdown of HGF to treat LPS-induced ALI mice for 24 h. Flow cytometry was performed to measure the phagocytosis, accumulation, and maturation of DCs, as well as proliferation of T cells. Lung injury was estimated by lung wet weight to body weight ratio (LWW/BW) and histopathological analysis. Furthermore, we used the Akt inhibitor MK-2206 in a coculture system to elucidate the role of the HGF/Akt pathway in regulating the differentiation of DCs into regulatory DCs and relieving lung injury in early ALI mice. Results: Immature DCs (imDCs) were induced to mature after 24 h of LPS (50 ng/ml) stimulation. MSCs or HGF induced the differentiation of mDCs into regulatory DCs characterized by low expression of MHCII, CD86, and CD40 molecules, strong phagocytic function, and the ability to inhibit T cell proliferation. The effect of MSCs on DCregs was enhanced with the increase in HGF secretion and was weakened with the decrease in HGF secretion. DCregs induced by recombinant HGF were attenuated by the Akt inhibitor MK-2206. Lung DC aggregation and mDC ratio increased in LPS-induced ALI mice, while treatment with MSCs decreased lung DC aggregation and maturation and alleviated lung pathological injury. High expression of the HGF gene enhanced the above effect of MSCs, while decreased expression of HGF weakened the above effect of MSCs. Conclusions: MSCs alleviate early ALI via paracrine HGF by inducing mDCs to differentiate into regulatory DCs. Furthermore, the mechanism of HGF-induced differentiation of mDCs into DCregs is related to the activation of the Akt pathway.

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Fig. 1 Induction and identification of DCs. a The morphology of DCs. Cell morphology on days 1, 3 (left and middle, monocytes in the presence of GM-CSF and IL-4), and 7 (right, imDC cultured for 24 h under LPS stimulation) (×200 magnification). b Immunophenotype analysis of DCs (expression of MHCII, CD86, and CD40 in DCs cultured for 24 h in the presence of LPS at concentrations ranging from 0 to 1000 ng/ml). c The percentage of DCs positive for MHCII, CD86, and CD40 after incubation for 24 h with LPS at concentrations ranging from 0 to 1000 ng/ml. d Immunophenotype analysis of DCs (expression of MHCII, CD86, and CD40 on DCs after culture for 0 h, 24 h, and 48 h with an LPS concentration of 50 ng/ml). e The percentage of DCs expressing MHCII, CD86, and CD40 after 0 h, 24 h, and 48 h cultured at an LPS concentration of 50 ng/ml. n = 3. c *P < 0.05 versus LPS 0 ng/ml group; #P < 0.05 versus LPS 10 ng/ml group; &P < 0.05 versus LPS 50 ng/ml group. e *P < 0.05 versus Con group; #P < 0.05 versus 24 h group. Data are expressed as mean ± SD. Each experiment was repeated three times
Fig. 1 Induction and identification of DCs. a The morphology of DCs. Cell morphology on days 1, 3 (left and middle, monocytes in the presence of GM-CSF and IL-4), and 7 (right, imDC cultured for 24 h under LPS stimulation) (×200 magnification). b Immunophenotype analysis of DCs (expression of MHCII, CD86, and CD40 in DCs cultured for 24 h in the presence of LPS at concentrations ranging from 0 to 1000 ng/ml). c The percentage of DCs positive for MHCII, CD86, and CD40 after incubation for 24 h with LPS at concentrations ranging from 0 to 1000 ng/ml. d Immunophenotype analysis of DCs (expression of MHCII, CD86, and CD40 on DCs after culture for 0 h, 24 h, and 48 h with an LPS concentration of 50 ng/ml). e The percentage of DCs expressing MHCII, CD86, and CD40 after 0 h, 24 h, and 48 h cultured at an LPS concentration of 50 ng/ml. n = 3. c *P < 0.05 versus LPS 0 ng/ml group; #P < 0.05 versus LPS 10 ng/ml group; &P < 0.05 versus LPS 50 ng/ml group. e *P < 0.05 versus Con group; #P < 0.05 versus 24 h group. Data are expressed as mean ± SD. Each experiment was repeated three timesCC BY · PubMed Central
Fig. 2 Effects of MSCs and rhHGF on mDC differentiation. a Immunophenotype analysis of DCs (expression of MHCII, CD86, and CD40 in mDCs cultured for 72 h in the presence of MSC or rhHGF, and expression of MHCII, CD86, and CD40 in MSC-induced DCs after LPS stimulation for 24 h). Percentage of MHCII, CD86, and CD40 expression on DCs after 72 h of incubation with or without MSC or rhHGF. b Phagocytic ability analysis of DCs (expression of OVA-FITC in DCs and percentage of OVA-FITC-positive cells of DCs). c Lymphocyte proliferation stimulated by mitotic proenzyme ConA, mDCs, MSC-DCs, or rhHGF-DCs. Splenocytes from normal BALB/c mice were used as responder cells in the mitogen proliferative assay. mDCs, MSC-DCs, rhHGF-DCs, or ConA were used as stimulators. Splenocytes from normal mice served as controls. The proliferative responses were assessed by CFSE labeling and FACS (gray line, unstimulated spleen cell). d Immunophenotype analysis of DCs (expression of PD-L1 and IL-27 in mDCs cultured for 72 h in the presence of MSC or rhHGF). Percentage of PD-L1 and IL-27 expression in DCs after 72 h of incubation with or without MSC or rhHGF. e Cytokine secretion profiles of mDCs, MSC-DCs, and rhHGF-DCs after culture for 24 h. f Changes in c-met and phosphorylated c-met levels in dendritic cells cultured for 72 h in the presence of MSCs or rhHGF (n = 3, *P < 0.05 versus mDC group; data are expressed as mean ± SD). Each experiment was repeated times
Fig. 2 Effects of MSCs and rhHGF on mDC differentiation. a Immunophenotype analysis of DCs (expression of MHCII, CD86, and CD40 in mDCs cultured for 72 h in the presence of MSC or rhHGF, and expression of MHCII, CD86, and CD40 in MSC-induced DCs after LPS stimulation for 24 h). Percentage of MHCII, CD86, and CD40 expression on DCs after 72 h of incubation with or without MSC or rhHGF. b Phagocytic ability analysis of DCs (expression of OVA-FITC in DCs and percentage of OVA-FITC-positive cells of DCs). c Lymphocyte proliferation stimulated by mitotic proenzyme ConA, mDCs, MSC-DCs, or rhHGF-DCs. Splenocytes from normal BALB/c mice were used as responder cells in the mitogen proliferative assay. mDCs, MSC-DCs, rhHGF-DCs, or ConA were used as stimulators. Splenocytes from normal mice served as controls. The proliferative responses were assessed by CFSE labeling and FACS (gray line, unstimulated spleen cell). d Immunophenotype analysis of DCs (expression of PD-L1 and IL-27 in mDCs cultured for 72 h in the presence of MSC or rhHGF). Percentage of PD-L1 and IL-27 expression in DCs after 72 h of incubation with or without MSC or rhHGF. e Cytokine secretion profiles of mDCs, MSC-DCs, and rhHGF-DCs after culture for 24 h. f Changes in c-met and phosphorylated c-met levels in dendritic cells cultured for 72 h in the presence of MSCs or rhHGF (n = 3, *P < 0.05 versus mDC group; data are expressed as mean ± SD). Each experiment was repeated timesCC BY · PubMed Central
Fig. 3 Long-term transgene expression efficiency in MSCs after lentiviral vector transduction. a The MSCs transduced separately with PDS087-EGFP (NC-MSCs), CL1017-PDS087_pL6-CMV-EGFP-IRES-HGF (HGF-MSCs), PDS019-EGFP (NC-shHGF-MSCs), and VL1012_pL-m-HGF-shRNA-1173 (shHGF-MSCs) lentiviral vectors cultured for 20 passages and observed with light microscopy (top) and fluorescence microscopy with green fluorescent protein (bottom), ×200. b The percentage of GFP-positive cells analyzed by flow cytometry at passage 20 after transduction (Based on untransfected MSCs in the green line, gates on the panel in the red line represent transfection-positive cells). c Quantitative real-time PCR analysis of HGF mRNA expression in MSCs after transduction. d The expression of HGF protein in MSCs after transduction evaluated using Western blot analysis. e The cytokine HGF secreted by MSCs after transduction cultured for 48 h detected by ELISA (n = 3, *P < 0.05 versus NC-HGF-MSC; #P < 0.05 versus NC-shHGF-MSC; data are expressed as mean ± SD). Each experiment was repeated three times
Fig. 3 Long-term transgene expression efficiency in MSCs after lentiviral vector transduction. a The MSCs transduced separately with PDS087-EGFP (NC-MSCs), CL1017-PDS087_pL6-CMV-EGFP-IRES-HGF (HGF-MSCs), PDS019-EGFP (NC-shHGF-MSCs), and VL1012_pL-m-HGF-shRNA-1173 (shHGF-MSCs) lentiviral vectors cultured for 20 passages and observed with light microscopy (top) and fluorescence microscopy with green fluorescent protein (bottom), ×200. b The percentage of GFP-positive cells analyzed by flow cytometry at passage 20 after transduction (Based on untransfected MSCs in the green line, gates on the panel in the red line represent transfection-positive cells). c Quantitative real-time PCR analysis of HGF mRNA expression in MSCs after transduction. d The expression of HGF protein in MSCs after transduction evaluated using Western blot analysis. e The cytokine HGF secreted by MSCs after transduction cultured for 48 h detected by ELISA (n = 3, *P < 0.05 versus NC-HGF-MSC; #P < 0.05 versus NC-shHGF-MSC; data are expressed as mean ± SD). Each experiment was repeated three timesCC BY · PubMed Central
Fig. 4 HGF plays a role in the MSC-induced differentiation of DCs. a Immunophenotype analysis of DCs (expression of MHCII, CD86, and CD40 on mDCs cultured for 72 h in the presence of MSCs or MSCs after transduction). The percentage of DCs positive for MHCII, CD86, and CD40 after coculture for 72 h with MSCs or transduced MSCs. b Cytokine secretion profiles of mDCs, MSC-DCs, NC-HGF-MSC-DCs, HGF-MSC-DCs, NC-shHGF-MSC-DCs, and shHGF-MSC-DCs after culture for 24 h. c Phagocytic ability analysis of MSC-induced DCs (percentage of OVA-FITC-positive cells). d, e Lymphocyte proliferation stimulated by ConA, mDCs, MSC-DCs, NC-HGF-MSC-DCs, HGF-MSC-DCs, NC-shHGF-MSC-DCs, and shHGF-MSC-DCs. Normal BALB/c mouse solenocytes were used as responder cells in the mitogen proliferative assay. The proliferative responses were assessed by CFSE labeling and FACS. (Inside the gray line, there are unstimulated splenic cells.) (n = 3, *P < 0.05 versus mDC; #P < 0.05 versus NC-HGF-MSC; &P < 0.05 versus NC-shHGF-MSC; data are expressed as mean ± SD). Each experiment was repeated at least three times
Fig. 4 HGF plays a role in the MSC-induced differentiation of DCs. a Immunophenotype analysis of DCs (expression of MHCII, CD86, and CD40 on mDCs cultured for 72 h in the presence of MSCs or MSCs after transduction). The percentage of DCs positive for MHCII, CD86, and CD40 after coculture for 72 h with MSCs or transduced MSCs. b Cytokine secretion profiles of mDCs, MSC-DCs, NC-HGF-MSC-DCs, HGF-MSC-DCs, NC-shHGF-MSC-DCs, and shHGF-MSC-DCs after culture for 24 h. c Phagocytic ability analysis of MSC-induced DCs (percentage of OVA-FITC-positive cells). d, e Lymphocyte proliferation stimulated by ConA, mDCs, MSC-DCs, NC-HGF-MSC-DCs, HGF-MSC-DCs, NC-shHGF-MSC-DCs, and shHGF-MSC-DCs. Normal BALB/c mouse solenocytes were used as responder cells in the mitogen proliferative assay. The proliferative responses were assessed by CFSE labeling and FACS. (Inside the gray line, there are unstimulated splenic cells.) (n = 3, *P < 0.05 versus mDC; #P < 0.05 versus NC-HGF-MSC; &P < 0.05 versus NC-shHGF-MSC; data are expressed as mean ± SD). Each experiment was repeated at least three timesCC BY · PubMed Central
Fig. 5 The role of the AKT pathway in MSC-secreted HGF induction of DC differentiation. a The expression of Akt protein and Akt phosphorylation levels in DCs cultured for 72 h in the presence of MSCs or MSCs after transduction was evaluated using Western blot analysis. b, c Immunophenotype analysis of DCs (expression of MHCII, CD86, and CD40 in mDCs cultured for 72 h in the presence of rhHGF or MK2206 and rhHGF). d Cytokine secretion profiles of DCs cultured for 72 h in the presence of rhHGF or MK2206 and rhHGF. e Phagocytic ability of HGF-induced DCs (percentage of OVA-FITC-positive cells). f Lymphocyte proliferation stimulated by ConA, mDCs, rhHGF-DCs, and rhHGF + MK2206-DCs. Normal BALB/c mouse solenocytes were used as responder cells in the mitogen proliferative assay. The proliferative responses were assessed by CFSE labeling and FACS (n = 3, *P < 0.05 versus mDC; #P < 0.05 versus rhHGF-DC; data are expressed as mean ± SD). Each experiment was repeated three times
Fig. 5 The role of the AKT pathway in MSC-secreted HGF induction of DC differentiation. a The expression of Akt protein and Akt phosphorylation levels in DCs cultured for 72 h in the presence of MSCs or MSCs after transduction was evaluated using Western blot analysis. b, c Immunophenotype analysis of DCs (expression of MHCII, CD86, and CD40 in mDCs cultured for 72 h in the presence of rhHGF or MK2206 and rhHGF). d Cytokine secretion profiles of DCs cultured for 72 h in the presence of rhHGF or MK2206 and rhHGF. e Phagocytic ability of HGF-induced DCs (percentage of OVA-FITC-positive cells). f Lymphocyte proliferation stimulated by ConA, mDCs, rhHGF-DCs, and rhHGF + MK2206-DCs. Normal BALB/c mouse solenocytes were used as responder cells in the mitogen proliferative assay. The proliferative responses were assessed by CFSE labeling and FACS (n = 3, *P < 0.05 versus mDC; #P < 0.05 versus rhHGF-DC; data are expressed as mean ± SD). Each experiment was repeated three timesCC BY · PubMed Central
Fig. 6 Effects of MSCs on pulmonary DCs in ALI mice by secreting HGF. a Immunophenotype analysis of pulmonary DCs in ALI mice treated with transfected or untransfected MSCs. Representative dot plots and bar graph showing the percentage of respiratory cDCs (gate on the upper right quadrant) in the presence of normal saline, MSCs, NC-HGF-MSCs, HGF-MSCs, NC-shHGF-MSCs, and shHGF-MSCs. b Charts and bar graph showing the expression of MHCII on respiratory cDCs (gate on the right in each panel, M1). Pulmonary cDC phenotype changes were statistically analyzed. c Charts and bar graph showing the expression of CD86 on respiratory cDCs (gate on the right in each panel, M2). Pulmonary DC phenotype changes were statistically analyzed. d Representative histology sections of lung tissue at 24 h (hematoxylin and eosin staining; magnification, ×200) and the pathological lung injury score at 24 h. e Comparison of the lung wet weight to body weight ratio (LWW/BW) in different groups at 24 h. These data are expressed as the mean ± SD (n = 5, for each group at 24 h, *P < 0.05 versus the Con group; #P < 0.05 versus the ALI mice, &P < 0.05 versus the NC-HGF-MSC mice; $P < 0.05 versus the NC-shHGF-MSC mice; data are expressed as the mean ± SD)
Fig. 6 Effects of MSCs on pulmonary DCs in ALI mice by secreting HGF. a Immunophenotype analysis of pulmonary DCs in ALI mice treated with transfected or untransfected MSCs. Representative dot plots and bar graph showing the percentage of respiratory cDCs (gate on the upper right quadrant) in the presence of normal saline, MSCs, NC-HGF-MSCs, HGF-MSCs, NC-shHGF-MSCs, and shHGF-MSCs. b Charts and bar graph showing the expression of MHCII on respiratory cDCs (gate on the right in each panel, M1). Pulmonary cDC phenotype changes were statistically analyzed. c Charts and bar graph showing the expression of CD86 on respiratory cDCs (gate on the right in each panel, M2). Pulmonary DC phenotype changes were statistically analyzed. d Representative histology sections of lung tissue at 24 h (hematoxylin and eosin staining; magnification, ×200) and the pathological lung injury score at 24 h. e Comparison of the lung wet weight to body weight ratio (LWW/BW) in different groups at 24 h. These data are expressed as the mean ± SD (n = 5, for each group at 24 h, *P < 0.05 versus the Con group; #P < 0.05 versus the ALI mice, &P < 0.05 versus the NC-HGF-MSC mice; $P < 0.05 versus the NC-shHGF-MSC mice; data are expressed as the mean ± SD)CC BY · PubMed Central

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Authors
Lu, Z., Chang, W., Meng, S., Xu, X., Xie, J., Guo, F., Yang, Y., Qiu, H., & Liu, L.
Affiliations
Zhongda Hospital Southeast University (CN)
Corresponding author
Liu, Ling
ORCID
Venue
Stem Cell Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2019-12
Volume
10
Issue
1
Pages
372-372
ISSN
1757-6512 (ISSN-L)
DOI
10.1186/s13287-019-1488-2
PMC
PMC6894226
OpenAlex
W2992845257
Cited by
146
References
3
Citations by year
2026: 9 · 2025: 16 · 2024: 17 · 2023: 24 · 2022: 29 · 2021: 31 · 2020: 20
FWCI
11.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cell Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81670074, 81000822, and 81871602)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
Keywords
mesenchymal stem cells, acute lung injury, hepatocyte growth factor, dendritic cells, regulatory dendritic cells, immune tolerance, lipopolysaccharide-induced lung injury, T cell proliferation, MK-2206, paracrine signaling, bone marrow-derived stem cells, lung repair, phagocytosis, dendritic cell maturation
MeSH terms
Animals, Cell Differentiation, Dendritic Cells, Heterocyclic Compounds, 3-Ring, Immune Tolerance, Lipopolysaccharides, Lung, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Signal Transduction, Hepatocyte Growth Factor, Coculture Techniques, Paracrine Communication, Mesenchymal Stem Cell Transplantation, Cell Proliferation, Proto-Oncogene Proteins c-akt, Mice, Acute Lung Injury, Mesenchymal Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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