FREE SHIPPING over $40
OVER 10000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Veterinary immunology and immunopathology2016; 171; 57-65; doi: 10.1016/j.vetimm.2016.02.007

Effect of inflammatory environment on equine bone marrow derived mesenchymal stem cells immunogenicity and immunomodulatory properties.

Abstract: Mesenchymal stem cells (MSCs) are being investigated for the treatment of equine joint diseases because of their regenerative potential. Recently, the focus mainly has addressed to their immunomodulatory capacities. Inflammation plays a central role in joint pathologies, since the release of proinflammatory mediators to the synovial fluid (SF) leads to the activation of enzymatic degradation of the cartilage. MSCs can modulate the local immune environment through direct or paracrine interaction with immune cells, suppressing their proliferation and re-addressing their functions. Proinflammatory molecules can induce MSC immunoregulatory potential, but they could also increase the expression of immunogenic molecules. Studying the effect of inflammatory environment on MSC immunomodulation and immunogenicity profiles is mandatory to improve cellular therapies. The aim of this study was to analyse the response of equine bone marrow MSCs (eBM-MSCs) to three inflammatory conditions. Equine BM-MSCs from three animals were exposed to: (a) 20% allogeneic inflammatory SF (SF); (b) 50 ng/ml of TNFα and IFNγ (CK50) and (c) 20 ng/ml of TNFα and IFNγ (CK20). After 72 h of exposure, expression of immunogenic and immunomodulation-related molecules, including cell-to-cell contact and paracrine signalling molecules, were analysed by RT-qPCR and flow cytometry. The gene expression of adhesion molecules was upregulated whereas MSC migration-related genes were downregulated by all inflammatory conditions tested. CK culture conditions significantly upregulated the expression of COX-2, iNOS, IDO and IL-6. MHC-I gene expression was upregulated by all conditions, whereas MHC-II was upregulated only after CK priming. The expression of CD40 did not significantly change, whereas the ligand, CD40L, was downregulated in CK conditions. Flow cytometry showed an increase in the percentage of positive cells and mean fluorescence intensity (MFI) of the MHC-I and MHC-II molecules at CK50 conditions, supporting the gene expression results. These outcomes reinforce the change of the immunophenotype of the eBM-MSCs according to the surrounding conditions. Inflammatory synovial environment did not lead to significant changes, so the environment found by eBM-MSCs when they are intraarticular administered may not be enough to activate their immunomodulatory potential. CK priming at tested doses enhances the immunoregulatory profile of eBM-MSCs, which may promote a therapeutic benefit. Even if CK priming induced an upregulation of MHC expression, costimulatory molecule expression however was not upregulated, suggesting that immunogenicity might not be increased. This study provides a better understanding about the behaviour of eBM-MSCs inside the inflamed joint and constitutes a first step to improve MSC-based therapies for equine joint diseases.
Copyright © 2016 Elsevier B.V. All rights reserved.
Get Full Text
Publication Date: 2016-02-12 PubMed ID: 26964718DOI: 10.1016/j.vetimm.2016.02.007Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article

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.

The research explores the response of equine bone marrow Mesenchymal stem cells (eBM-MSCs) to three inflammatory conditions. The study findings contribute to better understanding how these cells behave in inflamed joints, a knowledge that can help improve MSC-based therapies for equine joint diseases.

Background of the Study

  • The study revolves around Mesenchymal stem cells (MSCs) which are known for their regenerative potential and are currently under investigation for treating equine joint diseases.
  • Inflammatory environment, caused due to release of proinflammatory mediators into synovial fluid, plays a significant role in joint diseases, leading to cartilage degradation.
  • The authors point out that MSCs can modulate this local immune environment either through direct or indirect interaction with immune cells.
  • While proinflammatory molecules can induce MSC immunoregulatory potential, they can also increase the expression of immunogenic molecules. Hence, it is important to study the effects of an inflammatory environment on MSC immunomodulation and immunogenicity profiles to enhance cellular therapies.

Aim and Methodology of the Study

  • This study primarily aims to analyse the response of eBM-MSCs to three kinds of inflammatory conditions.
  • Three sets of eBM-MSCs were exposed to: 20% allogenic inflammatory synovial fluid (SF); 50 ng/ml of TNFα and IFNγ (CK50); and 20 ng/ml of TNFα and IFNγ (CK20).
  • After 72 hours, the team studied the expression of immunogenic and immunomodulation-related molecules, such as cell-to-cell contact and paracrine signaling molecules.

Results of the Study

  • Inflammatory conditions resulted in the upregulation of adhesion molecules’ gene expression and the downregulation of MSC migration-related genes.
  • CK conditions especially resulted in the significant upregulation of several molecules, including COX-2, iNOS, IDO, and IL-6.
  • All the tested conditions upregulated MHC-I gene’s expression, but MHC-II was upregulated only under CK exposure.
  • No significant change was found in the expression of CD40, but its ligand CD40L downregulated in CK conditions.
  • Flow cytometry provided additional support to these results showing an increase in MHC-I and MHC-II positive cells and mean fluorescence intensity (MFI) under CK50 conditions.

Conclusion Derived from the Study

  • From these results, researchers concluded that the immunophenotype of eBM-MSCs changes as per the surrounding conditions.
  • Study reveals that, inflammatory synovial environments did not lead to significant changes, signalling that the environment inside an inflamed joint where eBM-MSCs are typically administered might not be sufficient to activate their immunomodulatory potential.
  • On the other hand, CK priming at tested doses heightened the immunoregulatory profile of eBM-MSCs and might promote therapeutic benefits.
  • Even though CK priming resulted in MHC upregulation, it did not upregulate costimulatory molecule expression, thus suggesting that immunogenicity might not be increased.
  • This research provides insights into the behaviour of eBM-MSCs in inflamed joints, marking an important step toward enhancing MSC-based therapies for equine joint diseases.

Cite This Article

APA
Barrachina L, Remacha AR, Romero A, Vázquez FJ, Albareda J, Prades M, Ranera B, Zaragoza P, Martín-Burriel I, Rodellar C. (2016). Effect of inflammatory environment on equine bone marrow derived mesenchymal stem cells immunogenicity and immunomodulatory properties. Vet Immunol Immunopathol, 171, 57-65. https://doi.org/10.1016/j.vetimm.2016.02.007

Publication

Veterinary immunology and immunopathology
ISSN: 1873-2534
NlmUniqueID: 8002006
Country: Netherlands
Language: English
Volume: 171
Pages: 57-65

Researcher Affiliations

Barrachina, L
  • Laboratorio de Genética Bioquímica LAGENBIO, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain. Electronic address: lbarrach@unizar.es.
Remacha, A R
  • Laboratorio de Genética Bioquímica LAGENBIO, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain. Electronic address: aremacha@unizar.es.
Romero, A
  • Laboratorio de Genética Bioquímica LAGENBIO, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain. Electronic address: aromerol@unizar.es.
Vázquez, F J
  • Laboratorio de Genética Bioquímica LAGENBIO, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain. Electronic address: pvazquez@unizar.es.
Albareda, J
  • Laboratorio de Genética Bioquímica LAGENBIO, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; Servicio de Cirugía Ortopédica y Traumatología. Hospital Clínico Universitario Lozano Blesa, Zaragoza, Avda. San Juan Bosco, 15, 50009 Zaragoza Spain. Electronic address: albaredajorge@gmail.com.
Prades, M
  • Laboratorio de Genética Bioquímica LAGENBIO, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; Departament de Medicina i Cirugia Animal, Universidad Autónoma de Barcelona, Edifici H, UAB, 08193 Bellaterra, Barcelona, Spain. Electronic address: marta.prades@uab.cat.
Ranera, B
  • Laboratorio de Genética Bioquímica LAGENBIO, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain. Electronic address: beatrizranera@gmail.com.
Zaragoza, P
  • Laboratorio de Genética Bioquímica LAGENBIO, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain. Electronic address: pilarzar@unizar.es.
Martín-Burriel, I
  • Laboratorio de Genética Bioquímica LAGENBIO, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain. Electronic address: minma@unizar.es.
Rodellar, C
  • Laboratorio de Genética Bioquímica LAGENBIO, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain. Electronic address: rodellar@unizar.es.

MeSH Terms

  • Animals
  • Bone Marrow Cells / immunology
  • Cells, Cultured
  • Horse Diseases / immunology
  • Horses
  • Immunomodulation
  • Inflammation / immunology
  • Inflammation / veterinary
  • Inflammation Mediators / immunology
  • Interferon-gamma / immunology
  • Joint Diseases / immunology
  • Joint Diseases / veterinary
  • Joints / immunology
  • Male
  • Mesenchymal Stem Cells / immunology
  • Synovial Fluid / immunology
  • Tumor Necrosis Factor-alpha / immunology

Citations

This article has been cited 35 times.
  1. Shahid MA, Guitart AS, Bertin FR, Simon O, Ceusters J, Serteyn D, Whitworth DJ. Characterization and priming of equine muscle-derived mesenchymal stem cells to enhance their anti-inflammatory and immunomodulatory profiles. Front Vet Sci 2025;12:1741322.
    doi: 10.3389/fvets.2025.1741322pubmed: 41602612google scholar: lookup
  2. Vachkova E, Arnhold S, Petrova V, Heimann M, Koynarski T, Simeonova G, Piperkov P. Transcriptional Factors Related to Cellular Kinetics, Apoptosis, and Tumorigenicity in Equine Adipose-Derived Mesenchymal Stem Cells (ASCs) Are Influenced by the Age of the Donors. Animals (Basel) 2025 Jun 28;15(13).
    doi: 10.3390/ani15131910pubmed: 40646808google scholar: lookup
  3. Marais AL, Logan MG, Mellet J, Ambele MA, Pepper MS. Differentiation of Mesenchymal Stromal/Stem Cells from Induced Pluripotent Stem Cells. Methods Mol Biol 2025;2938:155-170.
    doi: 10.1007/978-1-0716-4607-6_18pubmed: 40445291google scholar: lookup
  4. Yaneselli K, Ávila G, Rossi A, Rial A, Castro S, Estradé MJ, Suárez G, Algorta A. Impact of different formulations of platelet lysate on proliferative and immune profile of equine mesenchymal stromal cells. Front Vet Sci 2024;11:1410855.
    doi: 10.3389/fvets.2024.1410855pubmed: 39161460google scholar: lookup
  5. Moellerberndt J, Niebert S, Fey K, Hagen A, Burk J. Impact of platelet lysate on immunoregulatory characteristics of equine mesenchymal stromal cells. Front Vet Sci 2024;11:1385395.
    doi: 10.3389/fvets.2024.1385395pubmed: 38725585google scholar: lookup
  6. Wihadmadyatami H, Zulfikar MA, Herawati H, Pratama DAOA, Saragih GR, Kustiati U, Handayani AN. Chitosan hydrogel nanoparticle enhance therapeutic effect of bovine umbilical mesenchymal stem cell conditioned medium on canine cognitive dysfunction or canine Alzheimer's like mediated by inhibition of neuronal apoptotic. Open Vet J 2023 Dec;13(12):1504-1516.
    doi: 10.5455/OVJ.2023.v13.i12.1pubmed: 38292722google scholar: lookup
  7. Walewska A, Janucik A, Tynecka M, Moniuszko M, Eljaszewicz A. Mesenchymal stem cells under epigenetic control - the role of epigenetic machinery in fate decision and functional properties. Cell Death Dis 2023 Nov 6;14(11):720.
    doi: 10.1038/s41419-023-06239-4pubmed: 37932257google scholar: lookup
  8. Jammes M, Contentin R, Audigié F, Cassé F, Galéra P. Effect of pro-inflammatory cytokine priming and storage temperature of the mesenchymal stromal cell (MSC) secretome on equine articular chondrocytes. Front Bioeng Biotechnol 2023;11:1204737.
    doi: 10.3389/fbioe.2023.1204737pubmed: 37720315google scholar: lookup
  9. Phyo H, Aburza A, Mellanby K, Esteves CL. Characterization of canine adipose- and endometrium-derived Mesenchymal Stem/Stromal Cells and response to lipopolysaccharide. Front Vet Sci 2023;10:1180760.
    doi: 10.3389/fvets.2023.1180760pubmed: 37275605google scholar: lookup
  10. Hackel A, Vollmer S, Bruderek K, Lang S, Brandau S. Immunological priming of mesenchymal stromal/stem cells and their extracellular vesicles augments their therapeutic benefits in experimental graft-versus-host disease via engagement of PD-1 ligands. Front Immunol 2023;14:1078551.
    doi: 10.3389/fimmu.2023.1078551pubmed: 36875112google scholar: lookup
  11. Yang X, Li Q, Liu W, Zong C, Wei L, Shi Y, Han Z. Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: from pathogenesis to treatment. Cell Mol Immunol 2023 Jun;20(6):583-599.
    doi: 10.1038/s41423-023-00983-5pubmed: 36823236google scholar: lookup
  12. Li W, Liu Q, Shi J, Xu X, Xu J. The role of TNF-α in the fate regulation and functional reprogramming of mesenchymal stem cells in an inflammatory microenvironment. Front Immunol 2023;14:1074863.
    doi: 10.3389/fimmu.2023.1074863pubmed: 36814921google scholar: lookup
  13. Even KM, Gaesser AM, Ciamillo SA, Linardi RL, Ortved KF. Comparing the immunomodulatory properties of equine BM-MSCs culture expanded in autologous platelet lysate, pooled platelet lysate, equine serum and fetal bovine serum supplemented culture media. Front Vet Sci 2022;9:958724.
    doi: 10.3389/fvets.2022.958724pubmed: 36090170google scholar: lookup
  14. Taylor SD, Serpa PBS, Santos AP, Hart KA, Vaughn SA, Moore GE, Mukhopadhyay A, Page AE. Effects of intravenous administration of peripheral blood-derived mesenchymal stromal cells after infusion of lipopolysaccharide in horses. J Vet Intern Med 2022 Jul;36(4):1491-1501.
    doi: 10.1111/jvim.16447pubmed: 35698909google scholar: lookup
  15. Schnabel CL, Fletemeyer B, Lübke S, Marti E, Wagner B, Alber G. CD154 Expression Indicates T Cell Activation Following Tetanus Toxoid Vaccination of Horses. Front Immunol 2022;13:805026.
    doi: 10.3389/fimmu.2022.805026pubmed: 35493462google scholar: lookup
  16. Cequier A, Romero A, Vázquez FJ, Vitoria A, Bernad E, Fuente S, Zaragoza P, Rodellar C, Barrachina L. Equine Mesenchymal Stem Cells Influence the Proliferative Response of Lymphocytes: Effect of Inflammation, Differentiation and MHC-Compatibility. Animals (Basel) 2022 Apr 11;12(8).
    doi: 10.3390/ani12080984pubmed: 35454231google scholar: lookup
  17. Uberti B, Plaza A, Henríquez C. Pre-conditioning Strategies for Mesenchymal Stromal/Stem Cells in Inflammatory Conditions of Livestock Species. Front Vet Sci 2022;9:806069.
    doi: 10.3389/fvets.2022.806069pubmed: 35372550google scholar: lookup
  18. Yue D, Du L, Zhang B, Wu H, Yang Q, Wang M, Pan J. Time-dependently Appeared Microenvironmental Changes and Mechanism after Cartilage or Joint Damage and the Influences on Cartilage Regeneration. Organogenesis 2021 Oct 2;17(3-4):85-99.
    doi: 10.1080/15476278.2021.1991199pubmed: 34806543google scholar: lookup
  19. Rady D, Abbass MMS, El-Rashidy AA, El Moshy S, Radwan IA, Dörfer CE, Fawzy El-Sayed KM. Mesenchymal Stem/Progenitor Cells: The Prospect of Human Clinical Translation. Stem Cells Int 2020;2020:8837654.
    doi: 10.1155/2020/8837654pubmed: 33953753google scholar: lookup
  20. Harman RM, Marx C, Van de Walle GR. Translational Animal Models Provide Insight Into Mesenchymal Stromal Cell (MSC) Secretome Therapy. Front Cell Dev Biol 2021;9:654885.
    doi: 10.3389/fcell.2021.654885pubmed: 33869217google scholar: lookup
  21. Shahsavari A, Weeratunga P, Ovchinnikov DA, Whitworth DJ. Pluripotency and immunomodulatory signatures of canine induced pluripotent stem cell-derived mesenchymal stromal cells are similar to harvested mesenchymal stromal cells. Sci Rep 2021 Feb 10;11(1):3486.
    doi: 10.1038/s41598-021-82856-3pubmed: 33568729google scholar: lookup
  22. Ribitsch I, Oreff GL, Jenner F. Regenerative Medicine for Equine Musculoskeletal Diseases. Animals (Basel) 2021 Jan 19;11(1).
    doi: 10.3390/ani11010234pubmed: 33477808google scholar: lookup
  23. Bundgaard L, Stensballe A, Elbæk KJ, Berg LC. Mass spectrometric analysis of the in vitro secretome from equine bone marrow-derived mesenchymal stromal cells to assess the effect of chondrogenic differentiation on response to interleukin-1β treatment. Stem Cell Res Ther 2020 May 20;11(1):187.
    doi: 10.1186/s13287-020-01706-7pubmed: 32434555google scholar: lookup
  24. Mund SJK, Kawamura E, Awang-Junaidi AH, Campbell J, Wobeser B, MacPhee DJ, Honaramooz A, Barber S. Homing and Engraftment of Intravenously Administered Equine Cord Blood-Derived Multipotent Mesenchymal Stromal Cells to Surgically Created Cutaneous Wound in Horses: A Pilot Project. Cells 2020 May 8;9(5).
    doi: 10.3390/cells9051162pubmed: 32397125google scholar: lookup
  25. Canisso IF, Segabinazzi LGTM, Fedorka CE. Persistent Breeding-Induced Endometritis in Mares - a Multifaceted Challenge: From Clinical Aspects to Immunopathogenesis and Pathobiology. Int J Mol Sci 2020 Feb 20;21(4).
    doi: 10.3390/ijms21041432pubmed: 32093296google scholar: lookup
  26. MacDonald ES, Barrett JG. The Potential of Mesenchymal Stem Cells to Treat Systemic Inflammation in Horses. Front Vet Sci 2019;6:507.
    doi: 10.3389/fvets.2019.00507pubmed: 32039250google scholar: lookup
  27. Barrachina L, Cequier A, Romero A, Vitoria A, Zaragoza P, Vázquez FJ, Rodellar C. Allo-antibody production after intraarticular administration of mesenchymal stem cells (MSCs) in an equine osteoarthritis model: effect of repeated administration, MSC inflammatory stimulation, and equine leukocyte antigen (ELA) compatibility. Stem Cell Res Ther 2020 Feb 7;11(1):52.
    doi: 10.1186/s13287-020-1571-8pubmed: 32028995google scholar: lookup
  28. Gugjoo MB, Hussain S, Amarpal, Shah RA, Dhama K. Mesenchymal Stem Cell-Mediated Immuno-Modulatory and Anti- Inflammatory Mechanisms in Immune and Allergic Disorders. Recent Pat Inflamm Allergy Drug Discov 2020;14(1):3-14.
    doi: 10.2174/1872213X14666200130100236pubmed: 32000656google scholar: lookup
  29. Kamm JL, Parlane NA, Riley CB, Gee EK, Dittmer KE, McIlwraith CW. Blood type and breed-associated differences in cell marker expression on equine bone marrow-derived mesenchymal stem cells including major histocompatibility complex class II antigen expression. PLoS One 2019;14(11):e0225161.
    doi: 10.1371/journal.pone.0225161pubmed: 31747418google scholar: lookup
  30. Gugjoo MB, Fazili MR, Gayas MA, Ahmad RA, Dhama K. Animal mesenchymal stem cell research in cartilage regenerative medicine - a review. Vet Q 2019 Dec;39(1):95-120.
    doi: 10.1080/01652176.2019.1643051pubmed: 31291836google scholar: lookup
  31. Hillmann A, Paebst F, Brehm W, Piehler D, Schubert S, Tárnok A, Burk J. A novel direct co-culture assay analyzed by multicolor flow cytometry reveals context- and cell type-specific immunomodulatory effects of equine mesenchymal stromal cells. PLoS One 2019;14(6):e0218949.
    doi: 10.1371/journal.pone.0218949pubmed: 31247035google scholar: lookup
  32. Wang Y, Huang J, Gong L, Yu D, An C, Bunpetch V, Dai J, Huang H, Zou X, Ouyang H, Liu H. The Plasticity of Mesenchymal Stem Cells in Regulating Surface HLA-I. iScience 2019 May 31;15:66-78.
    doi: 10.1016/j.isci.2019.04.011pubmed: 31030183google scholar: lookup
  33. Barrachina L, Remacha AR, Romero A, Vitoria A, Albareda J, Prades M, Roca M, Zaragoza P, Vázquez FJ, Rodellar C. Assessment of effectiveness and safety of repeat administration of proinflammatory primed allogeneic mesenchymal stem cells in an equine model of chemically induced osteoarthritis. BMC Vet Res 2018 Aug 17;14(1):241.
    doi: 10.1186/s12917-018-1556-3pubmed: 30119668google scholar: lookup
  34. Cassano JM, Schnabel LV, Goodale MB, Fortier LA. Inflammatory licensed equine MSCs are chondroprotective and exhibit enhanced immunomodulation in an inflammatory environment. Stem Cell Res Ther 2018 Apr 3;9(1):82.
    doi: 10.1186/s13287-018-0840-2pubmed: 29615127google scholar: lookup
  35. Reesink HL, Sutton RM, Shurer CR, Peterson RP, Tan JS, Su J, Paszek MJ, Nixon AJ. Galectin-1 and galectin-3 expression in equine mesenchymal stromal cells (MSCs), synovial fibroblasts and chondrocytes, and the effect of inflammation on MSC motility. Stem Cell Res Ther 2017 Nov 2;8(1):243.
    doi: 10.1186/s13287-017-0691-2pubmed: 29096716google scholar: lookup
Subscribe to our newsletter
Join 99,658 horse owners like you who receive our email updates on horse health and nutrition.