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Stem cell research & therapy2018; 9(1); 82; doi: 10.1186/s13287-018-0840-2

Inflammatory licensed equine MSCs are chondroprotective and exhibit enhanced immunomodulation in an inflammatory environment.

Abstract: Inflammatory licensed mesenchymal stem cells (MSCs) have the ability to promote functional tissue repair. This study specifically sought to understand how the recipient tissue environment reciprocally affects MSC function. Inflammatory polarized macrophages, modeling an injured tissue environment, were exposed to licensed MSCs, and the resultant effects of MSC immunomodulation and functionality of the MSC secretome on chondrocyte homeostasis were studied. Inflammatory licensed MSCs were generated through priming with either IFN-γ or polyinosinic:polycytidylic acid (poly I:C). Macrophages were polarized to an inflammatory phenotype using IFN-γ. Licensed MSCs were co-cultured with inflammatory macrophages and immunomodulation of MSCs was assessed in a T-cell proliferation assay. MSC gene expression was analyzed for changes in immunogenicity (MHC-I, MHC-II), immunomodulation (IDO, PTGS2, NOS2, TGF-β1), cytokine (IL-6, IL-8), and chemokine (CCL2, CXCL10) expression. Macrophages were assessed for changes in cytokine (IL-6, IL-10, TNF-α, IFN-γ) and chemokine (CCL2, CXCL10) expression. Conditioned medium representing the secretome from IFN-γ or poly I:C-primed MSCs was applied to IL-1β-stimulated chondrocytes, which were analyzed for catabolic (IL-6, TNF-α, CCL2, CXCL10, MMP-13, PTGS2) and matrix synthesis (ACAN, COL2A1) genes. IFN-γ-primed MSCs had a superior ability to suppress T-cell proliferation compared to naïve MSCs, and this ability was maintained following exposure to proinflammatory macrophages. In naïve and licensed MSCs exposed to inflammatory macrophages, MHC-I and MHC-II gene expression was upregulated. The secretome from licensed MSCs was chondroprotective and downregulated inflammatory gene expression in IL-1β-stimulated chondrocytes. In-vitro inflammatory licensing agents enhanced the immunomodulatory ability of MSCs exposed to inflammatory macrophages, and the resultant secretome was biologically active, protecting chondrocytes from catabolic stimulation. Use of licensing agents produced a more consistent immunomodulatory MSC population compared to exposure to inflammatory macrophages. The clinical implications of this study are that in-vitro licensing prior to therapeutic application could result in a more predictable immunomodulatory and reparative response to MSC therapy compared to in-vivo inflammatory licensing by the recipient environment.
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Publication Date: 2018-04-03 PubMed ID: 29615127PubMed Central: PMC5883371DOI: 10.1186/s13287-018-0840-2Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study explores the effects of using inflammatory licensed mesenchymal stem cells (MSCs) to promote tissue repair. The researchers found that these stem cells not only modulate immune responses but are also protective of cartilage cells, providing potential new avenues for MSC therapies.

Objective of Research

The primary goal of this research was to understand how the environmental conditions inside a recipient body affect the functioning of mesenchymal stem cells (MSCs) that have been modified through inflammatory licensing. The researchers also wanted to understand the impact of the MSC secretome – the substances secreted by these stem cells – on the stability of chondrocytes, or cartilage cells.

Methodology

  • The scientists generated inflammatory licensed MSCs by priming with interferon-gamma (IFN-γ) or polyinosinic:polycytidylic acid, also known as poly I:C.
  • They then polarized macrophages, a type of white blood cell, to an inflammatory phenotype using IFN-γ. These macrophages were designed to mimic an injured tissue environment.
  • The licensed MSCs were co-cultured with this inflammatory environment and their ability to modulate the immune response was assessed.
  • They analyzed gene expression in the MSCs to observe any changes relating to immunogenicity, immunomodulation, cytokine levels, and chemokine expression.
  • The scientists also studied the effects on macrophages, looking at changes in cytokine and chemokine expression there.
  • The medium from the IFN-γ or poly I:C-primed MSCs, representing their secretome, was applied to chondrocytes that had been stimulated by IL-1β. They then analyzed these chondrocytes for alterations in genes associated with catabolic action and matrix synthesis.

Findings of the Research

  • The study found that IFN-γ-primed MSCs were better equipped at suppressing T-cell proliferation compared to their unprimed counterparts. Their ability was preserved even after exposure to inflammatory macrophages.
  • MHC-I and MHC-II gene expression was upregulated in both licensed and unlicensed MSCs when exposed to inflammatory macrophages.
  • The secretome from licensed MSCs had a protective effect on chondrocytes and decreased inflammatory gene expression in chondrocytes triggered by IL-1β.
  • Furthermore, they found that inflammatory agents in vitro improved immunomodulation ability of MSCs exposed to inflammatory macrophages and the resulting secretome protected chondrocytes against catabolic stimulation.

Clinical Implications

The study found that in-vitro licensing prior to therapeutic application can result in a more consistent and predictable immune and reparative response to MSC therapy compared to in-vivo inflammatory licensing. This is a significant finding, as it could lead to the development of more effective MSC therapies for conditions that involve cartilage damage or degeneration, such as osteoarthritis or rheumatoid arthritis.

Cite This Article

APA
Cassano JM, Schnabel LV, Goodale MB, Fortier LA. (2018). Inflammatory licensed equine MSCs are chondroprotective and exhibit enhanced immunomodulation in an inflammatory environment. Stem Cell Res Ther, 9(1), 82. https://doi.org/10.1186/s13287-018-0840-2

Publication

Stem cell research & therapy
ISSN: 1757-6512
NlmUniqueID: 101527581
Country: England
Language: English
Volume: 9
Issue: 1
Pages: 82
PII: 82

Researcher Affiliations

Cassano, Jennifer M
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
Schnabel, Lauren V
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA.
Goodale, Margaret B
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
Fortier, Lisa A
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA. laf4@cornell.edu.

MeSH Terms

  • Animals
  • Cells, Cultured
  • Chondrocytes / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / metabolism
  • Horses
  • Immunomodulation
  • Macrophages / immunology
  • Male
  • Mesenchymal Stem Cells / immunology

Conflict of Interest Statement

ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All procedures for sample collection were approved by the Institutional Animal Care and Use Committee of Cornell University. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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