Review
. 2020 Feb; 6:507.
doi: 10.3389/fvets.2019.00507.

The Potential of Mesenchymal Stem Cells to Treat Systemic Inflammation in Horses

Elizabeth S MacDonald 1 Jennifer G Barrett 1 
Affiliations
  • PMID: 32039250
  •     137 References
  •     11 citations

Abstract

One hallmark of mesenchymal stem cells (MSCs) is the ability to differentiate into multiple tissue types which assists in tissue regeneration. Another hallmark of MSCs is their potent anti-inflammatory and immunomodulatory properties and the potential to treat inflammatory, immune-mediated, and ischemic conditions. In equine practice, MSCs have shown efficacy in the treatment of musculoskeletal disorders such as tendinopathy, meniscal tears and cartilage injury. However, there are many equine disease processes and conditions that may benefit from the immunomodulatory properties of MSCs. Examples include conditions associated with overwhelming acute inflammatory response such as systemic inflammatory response syndrome to chronic diseases characterized by a prolonged low level of inflammation such as equine asthma and recurrent uveitis. For the acute inflammatory response processes, there is often high morbidity and mortality with no effective immunomodulatory treatment to prevent the overwhelming synthesis of proinflammatory mediators. For chronic inflammatory disease processes, frequently long-term corticosteroid treatment is the therapeutic mainstay, with serious potential complications. Thus, there is an unmet need for alternative anti-inflammatory treatments for both acute and chronic illnesses in horses. While MSCs show promise for such conditions, much research is needed before a clinically safe and effective treatment will be available. Optimal MSC tissue source, patient vs. donor source (autologous vs. allogeneic) and cell growth conditions need to be determined for each problem. For immediate use, allogeneic MSC treatments is preferable, but immune tolerance and adequate safety require further study. MSC collection and cryopreservation from horses before they are injured or ill, whether from umbilical cord tissue, bone marrow or adipose might become more widespread. Once these fundamental approaches to treating specific diseases with MSCs are determined, the route of administration, dose and timing of administration also need to be studied. To provide a framework for development of MSC immunomodulatory treatments, this article reviews the current understanding of equine MSC anti-inflammatory and immunomodulatory properties and proposes how MSC therapy may be further developed to treat acute onset systemic inflammatory processes and chronic inflammatory diseases.

Keywords: bone marrow derived mesenchymal stem cells; endotoxemia; equine; immunomodulation; inflammation.

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Stem Cell Res Ther, 2018 Apr 05; 9(1). PMID: 29615127    Free PMC article.
Intravenous application of allogenic peripheral blood-derived mesenchymal stem cells: a safety assessment in 291 equine recipients.
Sarah Broeckx, Bizunesh M Borena, +5 authors, Jan H Spaas.
Curr Stem Cell Res Ther, 2014 Feb 20; 9(6). PMID: 24548143
IV delivery of induced pluripotent stem cells attenuates endotoxin-induced acute lung injury in mice.
Kuang-Yao Yang, Hsin-Chin Shih, +10 authors, Shih-Hwa Chiou.
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Mesenchymal stem cells stimulate antibody secretion in human B cells.
I Rasmusson, K Le Blanc, B Sundberg, O Ringdén.
Scand J Immunol, 2007 Mar 28; 65(4). PMID: 17386024
Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: A Randomized, Single-Blind, Parallel Group, Placebo Controlled Trial.
Desiree Perlee, Lonneke A van Vught, +11 authors, Tom van der Poll.
Stem Cells, 2018 Aug 01; 36(11). PMID: 30063804
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Human adult bone marrow-derived stem cells decrease severity of lipopolysaccharide-induced acute respiratory distress syndrome in sheep.
Mauricio Rojas, Nayra Cárdenes, +5 authors, Christian Bermúdez.
Stem Cell Res Ther, 2014 Mar 29; 5(2). PMID: 24670268    Free PMC article.
Cellular Immunotherapy for Septic Shock. A Phase I Clinical Trial.
Lauralyn A McIntyre, Duncan J Stewart, +11 authors, Canadian Critical Care Translational Biology Group.
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Equine T-cell cytokines. Protection and pathology.
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Vet Clin North Am Equine Pract, 2000 Apr 07; 16(1). PMID: 10752135
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Immune-mediated keratoconjunctivitis sicca in dogs: current perspectives on management.
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Vet Med (Auckl), 2015 Oct 30; 6. PMID: 30101119    Free PMC article.
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Mesenchymal stem cells for cardiovascular regeneration.
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Cardiovasc Drugs Ther, 2011 Jun 04; 25(4). PMID: 21637968
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Allogeneic major histocompatibility complex-mismatched equine bone marrow-derived mesenchymal stem cells are targeted for death by cytotoxic anti-major histocompatibility complex antibodies.
A K Berglund, L V Schnabel.
Equine Vet J, 2016 Nov 20; 49(4). PMID: 27862236    Free PMC article.
Differentiation of equine bone marrow derived mesenchymal stem cells increases the expression of immunogenic genes.
Laura Barrachina, Ana Rosa Remacha, +3 authors, Clementina Rodellar.
Vet Immunol Immunopathol, 2018 May 20; 200. PMID: 29776607
Retrospective analysis of local injection site adverse reactions associated with 230 allogenic administrations of bone marrow-derived mesenchymal stem cells in 164 horses.
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Equine Vet J, 2018 Jul 12; 51(2). PMID: 29992618
Chronic idiopathic inflammatory bowel diseases of the horse.
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Intratracheal Administration of Mesenchymal Stem Cells Modulates Tachykinin System, Suppresses Airway Remodeling and Reduces Airway Hyperresponsiveness in an Animal Model.
Konrad Urbanek, Antonella De Angelis, +9 authors, Bruno D'Agostino.
PLoS One, 2016 Jul 21; 11(7). PMID: 27434719    Free PMC article.
Comparative Analysis of the Immunomodulatory Properties of Equine Adult-Derived Mesenchymal Stem Cells().
Danielle D Carrade, Michael W Lame, +3 authors, Dori L Borjesson.
Cell Med, 2012 Nov 16; 4(1). PMID: 23152950    Free PMC article.
Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model.
Tracey L Bonfield, Mary Koloze, +3 authors, Arnold I Caplan.
Am J Physiol Lung Cell Mol Physiol, 2010 Sep 08; 299(6). PMID: 20817776    Free PMC article.
Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases.
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Highly Cited. Review.
Equine bone marrow-derived mesenchymal stromal cells are heterogeneous in MHC class II expression and capable of inciting an immune response in vitro.
Lauren V Schnabel, Lynn M Pezzanite, +2 authors, Lisa A Fortier.
Stem Cell Res Ther, 2014 Jan 28; 5(1). PMID: 24461709    Free PMC article.
Incidence, diagnosis and treatment of postoperative complications in colic cases.
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Equine Vet J, 1986 Jul 01; 18(4). PMID: 3758002
Anti-Donor Immune Responses Elicited by Allogeneic Mesenchymal Stem Cells and Their Extracellular Vesicles: Are We Still Learning?
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Front Immunol, 2017 Dec 12; 8. PMID: 29225601    Free PMC article.
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Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion.
E Eggenhofer, V Benseler, +6 authors, M J Hoogduijn.
Front Immunol, 2012 Oct 12; 3. PMID: 23056000    Free PMC article.
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Uncovering the secretes of mesenchymal stem cells.
Jessie R Lavoie, Michael Rosu-Myles.
Biochimie, 2013 Jul 03; 95(12). PMID: 23810910
Review.
Equine mesenchymal stem cells from bone marrow, adipose tissue and umbilical cord: immunophenotypic characterization and differentiation potential.
Danielle Jaqueta Barberini, Natália Pereira Paiva Freitas, +7 authors, Rogério Martins Amorim.
Stem Cell Res Ther, 2014 Feb 25; 5(1). PMID: 24559797    Free PMC article.
Long-term therapeutic effects of mesenchymal stem cells compared to dexamethasone on recurrent experimental autoimmune uveitis of rats.
Lingjun Zhang, Hui Zheng, +8 authors, Xiaomin Zhang.
Invest Ophthalmol Vis Sci, 2014 Aug 16; 55(9). PMID: 25125599    Free PMC article.
Stem cell treatment for Crohn's disease.
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Expert Rev Clin Immunol, 2010 Jul 03; 6(4). PMID: 20594133
Characterization of T-lymphocytes in the anterior uvea of eyes with chronic equine recurrent uveitis.
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Vet Immunol Immunopathol, 1999 Oct 16; 71(1). PMID: 10522783
Human mesenchymal stromal cells transiently increase cytokine production by activated T cells before suppressing T-cell proliferation: effect of interferon-γ and tumor necrosis factor-α stimulation.
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Cytotherapy, 2014 Jan 21; 16(2). PMID: 24438900
Human endotoxemia as a model of systemic inflammation.
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Curr Med Chem, 2008 Aug 05; 15(17). PMID: 18673219
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Safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells for treatment of dogs with inflammatory bowel disease: Clinical and laboratory outcomes.
E M Pérez-Merino, J M Usón-Casaús, +5 authors, M Gualtieri.
Vet J, 2015 Nov 04; 206(3). PMID: 26526522
Humoral immune responses against gut bacteria in dogs with inflammatory bowel disease.
Sirikul Soontararak, Lyndah Chow, +4 authors, Steven Dow.
PLoS One, 2019 Aug 02; 14(8). PMID: 31369623    Free PMC article.
Mesenchymal stem cells and acellular products attenuate murine induced colitis.
Yan Li, Jessica Altemus, Amy L Lightner.
Stem Cell Res Ther, 2020 Dec 02; 11(1). PMID: 33256827    Free PMC article.
Amnion-Derived Mesenchymal Stem Cell Exosomes-Mediated Autophagy Promotes the Survival of Trophoblasts Under Hypoxia Through mTOR Pathway by the Downregulation of EZH2.
Yijing Chu, Weiping Chen, +17 authors, Yuanhua Ye.
Front Cell Dev Biol, 2020 Dec 12; 8. PMID: 33304896    Free PMC article.
Ultrashort Wave Combined with Human Umbilical Cord Mesenchymal Stem Cell (HUC-MSC) Transplantation Inhibits NLRP3 Inflammasome and Improves Spinal Cord Injury via MK2/TTP Signalling Pathway.
Li Na, Shuai Wang, Tongtong Liu, Lixin Zhang.
Biomed Res Int, 2020 Dec 31; 2020. PMID: 33376718    Free PMC article.
Immunological Insights in Equine Recurrent Uveitis.
Roxane L Degroote, Cornelia A Deeg.
Front Immunol, 2021 Jan 26; 11. PMID: 33488614    Free PMC article.
Review.
Osteoclastic effects of mBMMSCs under compressive pressure during orthodontic tooth movement.
Jing Wang, Delong Jiao, Xiaofeng Huang, Yuxing Bai.
Stem Cell Res Ther, 2021 Feb 27; 12(1). PMID: 33632323    Free PMC article.
Translational Animal Models Provide Insight Into Mesenchymal Stromal Cell (MSC) Secretome Therapy.
Rebecca M Harman, Charlotte Marx, Gerlinde R Van de Walle.
Front Cell Dev Biol, 2021 Apr 20; 9. PMID: 33869217    Free PMC article.
Review.
Impact of Three Different Serum Sources on Functional Properties of Equine Mesenchymal Stromal Cells.
Lynn Pezzanite, Lyndah Chow, +2 authors, Laurie Goodrich.
Front Vet Sci, 2021 May 18; 8. PMID: 33996964    Free PMC article.
Effects of Normal Synovial Fluid and Interferon Gamma on Chondrogenic Capability and Immunomodulatory Potential Respectively on Equine Mesenchymal Stem Cells.
Mohammed Zayed, Steve Adair, Madhu Dhar.
Int J Mol Sci, 2021 Jul 03; 22(12). PMID: 34203758    Free PMC article.
DNA Damage-Induced Inflammatory Microenvironment and Adult Stem Cell Response.
Davide Cinat, Robert P Coppes, Lara Barazzuol.
Front Cell Dev Biol, 2021 Oct 26; 9. PMID: 34692684    Free PMC article.
Review.
Immunomodulatory effects of mesenchymal stem cell-conditioned media on lipopolysaccharide of Vibrio cholerae as a vaccine candidate.
Mahboube Bahroudi, Bita Bakhshi, Sara Soudi, Shahin Najar-Peerayeh.
Stem Cell Res Ther, 2021 Nov 05; 12(1). PMID: 34732259    Free PMC article.
Forskolin-Loaded Halloysite Nanotubes as Osteoconductive Additive for the Biopolymer Tissue Engineering Scaffolds.
Ekaterina Naumenko, Ivan Guryanov, Elena Zakirova, Rawil Fakhrullin.
Polymers (Basel), 2021 Nov 28; 13(22). PMID: 34833247    Free PMC article.