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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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Metadata

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

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