Stem cell research & therapy2014; 5(1); 13; doi: 10.1186/scrt402

Equine bone marrow-derived mesenchymal stromal cells are heterogeneous in MHC class II expression and capable of inciting an immune response in vitro.

Abstract: The horse is a valuable species to assess the effect of allogeneic mesenchymal stromal cells (MSCs) in regenerative treatments. No studies to date have examined recipient response to major histocompatibility complex (MHC)-mismatched equine MSCs. The purposes of this study were to immunophenotype MSCs from horses of known MHC haplotype and to compare the immunogenicity of MSCs with differing MHC class II expression. Methods: MSCs and peripheral blood leukocytes (PBLs) were obtained from Thoroughbred horses (n=10) of known MHC haplotype (ELA-A2, -A3, and -A9 homozygotes). MSCs were cultured through P8; cells from each passage (P2 to P8) were cryopreserved until used. Immunophenotyping of MHC class I and II, CD44, CD29, CD90, LFA-1, and CD45RB was performed by using flow cytometry. Tri-lineage differentiation assays were performed to confirm MSC multipotency. Recombinant equine IFN-γ was used to stimulate MHC class II negative MSCs in culture, after which expression of MHC class II was re-examined. To assess the ability of MHC class II negative or positive MSCs to stimulate an immune response, modified one-way mixed leukocyte reactions (MLRs) were performed by using MHC-matched and mismatched responder PBLs and stimulator PBLs or MSCs. Proliferation of gated CFSE-labeled CD3+ responder T cells was evaluated via CFSE attenuation by using flow cytometry and reported as the number of cells in the proliferating T-cell gate. Results: MSCs varied widely in MHC class II expression despite being homogenous in terms of "stemness" marker expression and ability to undergo trilineage differentiation. Stimulation of MHC class II negative MSCs with IFN-γ resulted in markedly increased expression of MHC class II. MLR results revealed that MHC-mismatched MHC class II-positive MSCs caused significantly increased responder T-cell proliferation compared with MHC-mismatched MHC class II-negative and MHC-matched MSCs, and equivalent to that of the positive control of MHC-mismatched leukocytes. Conclusions: The results of this study suggest that MSCs should be confirmed as MHC class II negative before allogeneic application. Additionally, it must be considered that even MHC class II-negative MSCs could upregulate MHC class II expression if implanted into an area of active inflammation, as demonstrated with in vitro stimulation with IFN-γ.
Publication Date: 2014-01-24 PubMed ID: 24461709PubMed Central: PMC4055004DOI: 10.1186/scrt402Google Scholar: Lookup
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  • Journal Article
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Summary

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This research explores how horse mesenchymal stromal cells (MSCs), used in regenerative treatments, can incite an immune response. The team examined if variations in major histocompatibility complex (MHC) class II expression might be the cause and concluded that only MSCs confirmed as MHC class II negative should be used in treatment.

Research Objectives and Methodology

  • The aim of this study was two-fold: Firstly, to immunophenotype MSCs from horses whose MHC haplotype was known and, secondly, to compare the immunogenicity of MSCs with varying MHC class II expression.
  • MSCs and peripheral blood leukocytes (PBLs) were collected and cultured from ten thoroughbred horses, and cells from each passage stage were preserved for analysis.
  • The team used flow cytometry to immunophenotype crucial markers: MHC class I and II, CD44, CD29, CD90, LFA-1, and CD45RB.
  • To confirm the multipotency of the MSCs, tri-lineage differentiation assays were performed.
  • The researchers used recombinant equine IFN-γ to stimulate MHC class II negative MSCs in culture. Once stimulated, the MHC class II expression was evaluated again.
  • Lastly, to assess the ability of MHC class II negative or positive MSCs to stimulate an immune response, modified one-way mixed leukocyte reactions (MLRs) were performed.

Results of the Research

  • Despite the MSCs being homogeneous in terms of “stemness” marker expression, the study found significant variations in MHC class II expression.
  • Stimulation of MHC class II negative MSCs with IFN-γ resulted in a significant increase in MHC class II expression.
  • MLR results highlighted that MHC class II-positive MSCs, when MHC-mismatched, caused an increased T-cell response compared to MHC class II-negative and MHC-matched MSCs. The response was similar to the positive control of MHC-mismatched leukocytes.

Conclusions of the Research

  • The research concludes that for allogeneic applications, only MSCs confirmed as MHC class II negative should be used.
  • The researchers also warn that even MHC class II-negative MSCs could potentially upregulate MHC class II expression if implanted into a region with active inflammation. This conclusion was based on the in-vitro stimulation with IFN-γ.

Cite This Article

APA
Schnabel LV, Pezzanite LM, Antczak DF, Felippe MJ, Fortier LA. (2014). Equine bone marrow-derived mesenchymal stromal cells are heterogeneous in MHC class II expression and capable of inciting an immune response in vitro. Stem Cell Res Ther, 5(1), 13. https://doi.org/10.1186/scrt402

Publication

ISSN: 1757-6512
NlmUniqueID: 101527581
Country: England
Language: English
Volume: 5
Issue: 1
Pages: 13

Researcher Affiliations

Schnabel, Lauren V
    Pezzanite, Lynn M
      Antczak, Douglas F
        Felippe, M Julia Bevilaqua
          Fortier, Lisa A

            MeSH Terms

            • Animals
            • Cells, Cultured
            • Genes, MHC Class II / genetics
            • Genes, MHC Class II / immunology
            • Horses
            • Immunophenotyping
            • Interferon-gamma / pharmacology
            • Leukocytes / immunology
            • Mesenchymal Stem Cells / cytology
            • Mesenchymal Stem Cells / drug effects
            • Mesenchymal Stem Cells / immunology

            Grant Funding

            • K08 AR060875 / NIAMS NIH HHS
            • 1K08AR060875-01A1 / NIAMS NIH HHS
            • S10RR023781 / NCRR NIH HHS

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