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Cited by 193Mesenchymal stem cell researchNeonatal Respiratory Health ResearchTransplantation: Methods and Outcomes

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Mesenchymal Stem Cell-Based Therapy of Inflammatory Lung Diseases: Current Understanding and Future Perspectives

Open access
Harrell, C. Randall, Sadikot, Ruxana, Pascual, Jose, Fellabaum, Crissy, Jankovic, Marina Gazdic, Jovicic, Nemanja, Djonov, Valentin, Arsenijevic, Nebojsa, Volarevic, Vladislav·2019·Stem Cells International
DOI 10.1155/2019/4236973PMC PMC6525794
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Abstract

During acute or chronic lung injury, inappropriate immune response and/or aberrant repair process causes irreversible damage in lung tissue and most usually results in the development of fibrosis followed by decline in lung function. Inhaled corticosteroids and other anti-inflammatory drugs are very effective in patients with inflammatory lung disorders, but their long-term use is associated with severe side effects. Accordingly, new therapeutic agents that will attenuate ongoing inflammation and, at the same time, promote regeneration of injured alveolar epithelial cells are urgently needed. Mesenchymal stem cells (MSCs) are able to modulate proliferation, activation, and effector function of all immune cells that play an important role in the pathogenesis of acute and chronic inflammatory lung diseases. In addition to the suppression of lung-infiltrated immune cells, MSCs have potential to differentiate into alveolar epithelial cells in vitro and, accordingly, represent new players in cell-based therapy of inflammatory lung disorders. In this review article, we described molecular mechanisms involved in MSC-based therapy of acute and chronic pulmonary diseases and emphasized current knowledge and future perspectives related to the therapeutic application of MSCs in patients suffering from acute respiratory distress syndrome, pneumonia, asthma, chronic obstructive pulmonary diseases, and idiopathic pulmonary fibrosis.

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Crossref · 10.1155/2019/4236973

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Figure 1 Molecular mechanisms responsible for MSC-based attenuation of ARDS. Intravenously injected MSCs engrafted in the ARDS-injured lungs and, in a paracrine manner (through the production of KGF, VEGF, HGF), promoted proliferation of epithelial cells, induced protection of vascular permeability, and prevented apoptosis of endothelial cells. Additionally, MSC-based therapy reduced the presence of neutrophils in bronchoalveolar lavage fluid (BLF) and in a PGE2-dependent manner suppressed the production of inflammatory cytokines (TNF-α and IL-6) and stimulated the secretion of immunosuppressive IL-10 in alveolar macrophages.
Figure 1 Molecular mechanisms responsible for MSC-based attenuation of ARDS. Intravenously injected MSCs engrafted in the ARDS-injured lungs and, in a paracrine manner (through the production of KGF, VEGF, HGF), promoted proliferation of epithelial cells, induced protection of vascular permeability, and prevented apoptosis of endothelial cells. Additionally, MSC-based therapy reduced the presence of neutrophils in bronchoalveolar lavage fluid (BLF) and in a PGE2-dependent manner suppressed the production of inflammatory cytokines (TNF-α and IL-6) and stimulated the secretion of immunosuppressive IL-10 in alveolar macrophages.CC BY · PubMed Central
Figure 2 Therapeutic effects of intravenously injected MSCs in an animal model of asthma. Reduced deposition of collagen and lower bronchoconstrictive index accompanied with reduced resistive and viscoelastic pressures were noticed in MSC-treated asthmatic animals. Transplanted MSCs altered the phenotype of antigen-specific CD4 T cells in asthmatic animals via MSC-derived extracellular vesicles (EVs). Additionally, MSCs reduced eosinophil infiltration and mucus production in the lungs and downregulated levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, as well as serum levels of IgG1 and IgE. Alveolar macrophages become alternatively activated and developed an anti-inflammatory and immunosuppressive M2 phenotype after phagocytosis of transplanted MSCs.
Figure 2 Therapeutic effects of intravenously injected MSCs in an animal model of asthma. Reduced deposition of collagen and lower bronchoconstrictive index accompanied with reduced resistive and viscoelastic pressures were noticed in MSC-treated asthmatic animals. Transplanted MSCs altered the phenotype of antigen-specific CD4 T cells in asthmatic animals via MSC-derived extracellular vesicles (EVs). Additionally, MSCs reduced eosinophil infiltration and mucus production in the lungs and downregulated levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, as well as serum levels of IgG1 and IgE. Alveolar macrophages become alternatively activated and developed an anti-inflammatory and immunosuppressive M2 phenotype after phagocytosis of transplanted MSCs.CC BY · PubMed Central
Figure 3 Molecular and cellular mechanisms responsible for beneficial effects of MSCs in the therapy of COPD. Reduced emphysematous changes and alveolar damage, accompanied with increased FEVs, were noticed in MSC-treated COPD animals. MSC-dependent downregulation of the COX2/PGE2 pathway in inflammatory M1 macrophages occurs via the p38 MAPKs and ERK pathways and resulted in macrophage polarization toward an anti-inflammatory M2 phenotype. Transplantation of MSCs significantly improved the lung architecture of COPD animals by decreasing the production of macrophage-derived MMP-2, MMP-9, and MMP-12. Additionally, transplanted MSCs either directly (through the differentiation into ATII-like cells) or indirectly (by inducing proliferation and differentiation of lung resident (CD45-/CD31-/Sca-1+) stem cells) regenerated injured lungs.
Figure 3 Molecular and cellular mechanisms responsible for beneficial effects of MSCs in the therapy of COPD. Reduced emphysematous changes and alveolar damage, accompanied with increased FEVs, were noticed in MSC-treated COPD animals. MSC-dependent downregulation of the COX2/PGE2 pathway in inflammatory M1 macrophages occurs via the p38 MAPKs and ERK pathways and resulted in macrophage polarization toward an anti-inflammatory M2 phenotype. Transplantation of MSCs significantly improved the lung architecture of COPD animals by decreasing the production of macrophage-derived MMP-2, MMP-9, and MMP-12. Additionally, transplanted MSCs either directly (through the differentiation into ATII-like cells) or indirectly (by inducing proliferation and differentiation of lung resident (CD45-/CD31-/Sca-1+) stem cells) regenerated injured lungs.CC BY · PubMed Central

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2 retracted

Research works printed but not linked: 3

  1. 2009, Journal of Inflammation Research, 2, 1
  2. 2013, Iranian Journal of Allergy, Asthma, and Immunology, 12, 228
  3. 2015, International Journal of Clinical and Experimental Pathology, 8, 8958

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Metadata

Authors
Harrell, C. R., Sadikot, R., Pascual, J., Fellabaum, C., Jankovic, M. G., Jovicic, N., Djonov, V., Arsenijevic, N., & Volarevic, V.
Affiliations
  • Regenerative Processing Plant, LLC, 34176 UD Highway 19 N Palm Harbor, Palm Harbor, Florida, USA
  • Emory University (US)
  • Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Serbia
  • Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, Kragujevac, Serbia
  • University of Bern (CH)
  • West Pasco Pulmonary Associates, 7545 Medical Dr, Hudson, Florida, USA
  • Institute of Anatomy, University of Bern, 2 Baltzerstrasse, Switzerland
ORCID
Venue
Stem Cells International
Publisher
Wiley
Published
2019-05-02
Volume
2019
Pages
1-14
ISSN
  • 1687-966X (ISSN-L)
  • 1687-9678
DOI
10.1155/2019/4236973
PMC
PMC6525794
OpenAlex
W2943233832
Cited by
193
References
126
Citations by year
2026: 3 · 2025: 14 · 2024: 18 · 2023: 22 · 2022: 37 · 2021: 58 · 2020: 34 · 2019: 7
FWCI
4.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cells International (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • BORIS (University Library Bern) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Open Access CRIS of the University of Bern
Funders
  • University of Kragujevac (MP01/18, ON175103, ON175069, 16C197)
  • Serbian Ministry of Science (MP01/18, ON175103, ON175069, 16C197)
  • Novartis Foundation (MP01/18, ON175103, ON175069, 16C197)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Neonatal Respiratory Health Research
  • Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
Keywords
mesenchymal stem cells, cell therapy, inflammatory lung disease, pulmonary fibrosis, acute respiratory distress syndrome, pneumonia, asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, immunomodulation, lung injury

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