Systemic Administration of Rejuvenated Adipose-Derived Mesenchymal Stem Cells Improves Liver Metabolism in Equine Metabolic Syndrome (EMS)- New Approach in Veterinary Regenerative Medicine.
Abstract: Equine metabolic syndrome (EMS) is characterized by adiposity, insulin dysregulation and increased risk for laminitis. Increased levels of specific liver enzymes in the peripheral blood are typical findings in horses diagnosed with EMS. Current management of EMS is based on caloric restriction and increased physical activity. However, new potential treatment options are arising such as the transplantation of autologous adipose stem cells (ASC). However, cytophysiological properties of ASC derived from EMS horses are impaired which strongly limits their therapeutic potential. We hypothesized, that in vitro pharmacotherapy of those cells with 5-azacytidine (AZA) and resveratrol (RES) before their clinical application can reverse the aged phenotype of those cells and improve clinical outcome of autologous therapy. A 9 year old Dutch Warmblood Horse used for driving, was presented with severe obesity, insulin resistance. After EMS diagnosis, the animal received three intravenous injections of autologous, AZA/RES treated ASCs at weekly intervals. The therapeutic effect was assessed by the analysis of liver specific enzymes in the blood. ASC-transplantation reduced levels of glutamate dehydrogenase (GLDH), gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH) and aspartate transaminase (AST). This case report demonstrates the therapeutic potential of this intervention for EMS as well as apt utility of autologous, rejuvenated ASC injections.
Publication Date: 2019-10-18 PubMed ID: 31620992PubMed Central: PMC6925066DOI: 10.1007/s12015-019-09913-3Google 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.
- 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 impact of using rejuvenated adipose-derived mesenchymal stem cells to improve liver function and metabolic health in horses with equine metabolic syndrome (EMS), offering a new potential treatment option in veterinary regenerative medicine.
Introduction and Background
- The research document is about the equine metabolic syndrome (EMS), a condition prevalent in horses, characterized by insulin dysregulation, obesity, and the risk for laminitis (a severe disease affecting a horse’s hooves). An increase in certain liver enzymes in a horse’s peripheral blood is a typical identifier of EMS.
- Presently, the management of EMS is based on reducing caloric intake and increasing physical activities. However, researchers are exploring new potential treatment options, such as autologous adipose stem cell (ASC) transplantation.
- The stem cells, ASC, derived from EMS-affected horses have impaired physiological properties, which limit their therapeutic potential.
Research Hypothesis and Method
- The researchers hypothesized that treating these impaired stem cells with 5-azacytidine (AZA) and resveratrol (RES) in vitro before clinical application could rejuvenate these cells, reversing their aged phenotype and improving the outcome of autologous therapy.
- To test their hypothesis, they applied this method on a 9-year-old Dutch Warmblood Horse with severe EMS symptoms, including obesity and insulin resistance. They administered three intravenous injections of autologous, AZA/RES-treated ASCs to the subject at weekly intervals.
Results and Conclusion
- The researchers assessed the treatment’s efficacy by analyzing the levels of liver-specific enzymes in the horse’s blood post-transplantation. The results showed a reduction in the levels of glutamate dehydrogenase (GLDH), gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH), and aspartate transaminase (AST).
- This indicated that ASC transplantation improved the metabolic functionality of the liver.
- The authors concluded that this single case study demonstrated potentially significant therapeutic potential by using this method for treating EMS. Autologous, rejuvenated stem cell injections could be a promising therapeutic and intervention strategy.
Cite This Article
APA
Marycz K, Szłapka-Kosarzewska J, Geburek F, Kornicka-Garbowska K.
(2019).
Systemic Administration of Rejuvenated Adipose-Derived Mesenchymal Stem Cells Improves Liver Metabolism in Equine Metabolic Syndrome (EMS)- New Approach in Veterinary Regenerative Medicine.
Stem Cell Rev Rep, 15(6), 842-850.
https://doi.org/10.1007/s12015-019-09913-3 Publication
Researcher Affiliations
- International Institute of Translational Medicine, Malin, Jesionowa 11 street, 55-114, Wisznia Mała, Poland. krzysztof.marycz@upwr.edu.pl.
- Department of Experimental Biology, The Faculty of Biology and Animal Science, University of Environmental and Life Sciences Wroclaw, Wroclaw, Poland. krzysztof.marycz@upwr.edu.pl.
- Faculty of Veterinary Medicine, Clinic for Horses - Department for Surgery, Justus-Liebig-University, Gießen, Germany. krzysztof.marycz@upwr.edu.pl.
- Faculty of Veterinary Medicine, Clinic for Horses - Department for Surgery, Justus-Liebig-University, Gießen, Germany.
- International Institute of Translational Medicine, Malin, Jesionowa 11 street, 55-114, Wisznia Mała, Poland.
- Department of Experimental Biology, The Faculty of Biology and Animal Science, University of Environmental and Life Sciences Wroclaw, Wroclaw, Poland.
MeSH Terms
- Animals
- Antimetabolites, Antineoplastic / pharmacology
- Azacitidine / pharmacology
- Horses
- Insulin Resistance
- Liver / drug effects
- Liver / metabolism
- Liver / pathology
- Mesenchymal Stem Cell Transplantation / veterinary
- Mesenchymal Stem Cells / cytology
- Metabolic Syndrome / etiology
- Metabolic Syndrome / pathology
- Metabolic Syndrome / therapy
- Obesity / complications
- Regenerative Medicine
Conflict of Interest Statement
Authors declare that there is no conflict of interest.
References
This article includes 51 references
- Frank N. Equine metabolic syndrome.. Journal of Equine Veterinary Science 2009;29(5):259–267.
- Wyse CA, McNie KA, Tannahill VJ, Tannahil VJ, Murray JK, Love S. Prevalence of obesity in riding horses in Scotland.. The Veterinary Record 2008;162(18):590–591.
- Stephenson HM, Green MJ, Freeman SL. Prevalence of obesity in a population of horses in the UK.. The Veterinary Record 2011;168(5):131.
- Marycz K, Grzesiak J, Wrzeszcz K, Golonka P. Adipose stem cell combined with plasma-based implant bone tissue differentiation in vitro and in a horse with a phalanx digitalis distalis fracture: A case report.. Veterinarni Medicina (Czech Republic) 2012;57(11):610–617.
- Powell DM, Reedy SE, Sessions DR, Fitzgerald BP. Effect of short-term exercise training on insulin sensitivity in obese and lean mares.. Equine Veterinary Journal 2002;34(Supplement):81–84.
- Hustace JL, Firshman AM, Mata JE. Pharmacokinetics and bioavailability of metformin in horses.. American Journal of Veterinary Research 2009;70(5):665–668.
- Wearn JMG, Crisman MV, Davis JL, Geor RJ, Hodgson DR, Suagee JK. Pharmacokinetics of pioglitazone after multiple oral dose administration in horses.. Journal of Veterinary Pharmacology and Therapeutics 2011;34(3):252–258.
- Marycz Krzysztof, Mierzejewska Katarzyna, Śmieszek Agnieszka, Suszynska Ewa, Malicka Iwona, Kucia Magda, Ratajczak Mariusz Z. Endurance Exercise Mobilizes Developmentally Early Stem Cells into Peripheral Blood and Increases Their Number in Bone Marrow: Implications for Tissue Regeneration.. Stem Cells International 2016;2016:1–10.
- Oreffo ROC, Cooper C, Mason C, Clements M. Mesenchymal stem cells.. Stem Cell Reviews 2005;1(2):169–178.
- Holan V, Hermankova B, Bohacova P, Kossl J, Chudickova M, Hajkova M, Javorkova E. Distinct Immunoregulatory mechanisms in mesenchymal stem cells: Role of the cytokine environment.. Stem Cell Reviews and Reports 2016;12(6):654–663.
- Abumaree M, Al Jumah M, Pace RA, Kalionis B. Immunosuppressive properties of mesenchymal stem cells.. Stem Cell Reviews and Reports 2012;8(2):375–392.
- Cislo-Pakuluk A, Marycz K. A promising tool in retina regeneration: Current perspectives and challenges when using mesenchymal progenitor stem cells in veterinary and human ophthalmological applications.. Stem Cell Reviews 2017;13(5):598–602.
- Wang H, Zhang H, Huang B, Miao G, Yan X, Gao G, Yang L. Mesenchymal stem cells reverse high-fat diet-induced non-alcoholic fatty liver disease through suppression of CD4+ T lymphocytes in mice.. Molecular Medicine Reports 2018;17(3):3769–3774.
- Tsuchiya A, Kojima Y, Ikarashi S, Seino S, Watanabe Y, Kawata Y, Terai S. Clinical trials using mesenchymal stem cells in liver diseases and inflammatory bowel diseases.. Inflammation and Regeneration 2017;37:16.
- Marycz K, Michalak I, Kornicka K. Advanced nutritional and stem cells approaches to prevent equine metabolic syndrome.. Research in Veterinary Science 2018;118:115–125.
- da Justa Pinheiro CH, de Queiroz JCF, Guimarães-Ferreira L, Vitzel KF, Nachbar RT, de Sousa LGO, Curi R. Local injections of adipose-derived mesenchymal stem cells modulate inflammation and increase angiogenesis ameliorating the dystrophic phenotype in dystrophin-deficient skeletal muscle.. Stem Cell Reviews and Reports 2012;8(2):363–374.
- Fiore EJ, Mazzolini G, Aquino JB. Mesenchymal stem/stromal cells in liver fibrosis: Recent findings, old/new caveats and future perspectives.. Stem Cell Reviews and Reports 2015;11(4):586–597.
- Marycz K, Kornicka K, Marędziak M, Golonka P, Nicpoń J. Equine metabolic syndrome impairs adipose stem cells osteogenic differentiation by predominance of autophagy over selective mitophagy.. Journal of Cellular and Molecular Medicine 2016;20(12):2384–2404.
- Marycz K, Kornicka K, Basinska K, Czyrek A. Equine metabolic syndrome affects viability, senescence, and stress factors of equine adipose-derived mesenchymal stromal stem cells: New insight into EqASCs Isolated from EMS horses in the context of their aging.. Oxidative Medicine and Cellular Longevity 2016;2016:1–17.
- Kornicka Katarzyna, Houston Jenny, Marycz Krzysztof. Dysfunction of Mesenchymal Stem Cells Isolated from Metabolic Syndrome and Type 2 Diabetic Patients as Result of Oxidative Stress and Autophagy may Limit Their Potential Therapeutic Use.. Stem Cell Reviews and Reports 2018;14(3):337–345.
- Pezzanite LM, Fortier LA, Antczak DF, Cassano JM, Brosnahan MM, Miller D, Schnabel LV. Equine allogeneic bone marrow-derived mesenchymal stromal cells elicit antibody responses in vivo.. Stem Cell Research & Therapy 2015;6:54.
- Owens SD, Kol A, Walker NJ, Borjesson DL. Allogeneic mesenchymal stem cell treatment induces specific alloantibodies in horses.. Stem Cells International 2016;2016:1–8.
- Kornicka K, Marycz K, Marędziak M, Tomaszewski KA, Nicpoń J. The effects of the DNA methyltranfserases inhibitor 5-Azacitidine on ageing, oxidative stress and DNA methylation of adipose derived stem cells.. Journal of Cellular and Molecular Medicine 2017;21(2):387–401.
- Yan X, Ehnert S, Culmes M, Bachmann A, Seeliger C, Schyschka L, Nussler AK. 5-azacytidine improves the osteogenic differentiation potential of aged human adipose-derived mesenchymal stem cells by DNA demethylation.. PLoS One 2014;9(6):e90846.
- Švajger U, Jeras M. Anti-inflammatory effects of resveratrol and its potential use in therapy of immune-mediated diseases.. International Reviews of Immunology 2012;31(3):202–222.
- Gülçin İ. Antioxidant properties of resveratrol: A structure–activity insight.. Innovative Food Science & Emerging Technologies 2010;11(1):210–218.
- Aguirre L, Fernández-Quintela A, Arias N, Portillo MP. Resveratrol: Anti-obesity mechanisms of action.. Molecules (Basel, Switzerland) 2014;19(11):18632–18655.
- Bhullar KS, Hubbard BP. Lifespan and healthspan extension by resveratrol.. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2015;1852(6):1209–1218.
- Kornicka K, Szłapka-Kosarzewska J, Śmieszek A, Marycz K. 5-Azacytydine and resveratrol reverse senescence and ageing of adipose stem cells via modulation of mitochondrial dynamics and autophagy.. Journal of Cellular and Molecular Medicine 2019;23(1):237–259.
- Kornicka Katarzyna, Śmieszek Agnieszka, Węgrzyn Agnieszka, Röcken Michael, Marycz Krzysztof. Immunomodulatory Properties of Adipose-Derived Stem Cells Treated with 5-Azacytydine and Resveratrol on Peripheral Blood Mononuclear Cells and Macrophages in Metabolic Syndrome Animals.. Journal of Clinical Medicine 2018;7(11):383.
- Kosolofski HR, Gow SP, Robinson KA. Prevalence of obesity in the equine population of Saskatoon and surrounding area.. The Canadian Veterinary Journal 2017;58(9):967.
- Carter RA, Geor RJ, Burton Staniar W, Cubitt TA, Harris PA. Apparent adiposity assessed by standardised scoring systems and morphometric measurements in horses and ponies.. Veterinary Journal 2009;179(2):204–210.
- Frank N, Walsh DM. Repeatability of Oral sugar test results, glucagon-like Peptide-1 measurements, and serum high-molecular-weight adiponectin concentrations in horses.. Journal of Veterinary Internal Medicine 2017;31(4):1178–1187.
- Marędziak M, Marycz K, Lewandowski D, Siudzińska A, Śmieszek A. Static magnetic field enhances synthesis and secretion of membrane-derived microvesicles (MVs) rich in VEGF and BMP-2 in equine adipose-derived stromal cells (EqASCs)-a new approach in veterinary regenerative medicine.. In Vitro Cellular & Developmental Biology Animal 2015;51(3):230–240.
- Marycz K, Kornicka K, Irwin-Houston JM, Weiss C. Combination of resveratrol and 5-azacytydine improves osteogenesis of metabolic syndrome mesenchymal stem cells.. Journal of Cellular and Molecular Medicine 2018;22(10):4771–4793.
- Si Y, Zhao Y, Hao H, Liu J, Guo Y, Mu Y, Han W. Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats: Identification of a novel role in improving insulin sensitivity.. Diabetes 2012;61(6):1616–1625.
- Shree N, Bhonde RR. Conditioned media from adipose tissue derived mesenchymal stem cells reverse insulin resistance in cellular models.. Journal of Cellular Biochemistry 2017;118(8):2037–2043.
- Xie Z, Hao H, Tong C, Cheng Y, Liu J, Pang Y, Han W. Human umbilical cord-derived mesenchymal stem cells elicit macrophages into an anti-inflammatory phenotype to alleviate insulin resistance in type 2 diabetic rats.. Stem Cells (Dayton, Ohio) 2016;34(3):627–639.
- Melief SM, Schrama E, Brugman MH, Tiemessen MM, Hoogduijn MJ, Fibbe WE, Roelofs H. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages.. Stem Cells (Dayton, Ohio) 2013;31(9):1980–1991.
- Madrigal M, Rao KS, Riordan NH. A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods.. Journal of Translational Medicine 2014;12:260.
- Zheng S, Yang J, Yang J, Tang Y, Shao Q, Guo L, Liu Q. Transplantation of umbilical cord mesenchymal stem cells via different routes in rats with acute liver failure.. International Journal of Clinical and Experimental Pathology 2015;8(12):15854–15862.
- Huang B, Cheng X, Wang H, Huang W, la Ga Hu Z, Wang D, Zhang R. Mesenchymal stem cells and their secreted molecules predominantly ameliorate fulminant hepatic failure and chronic liver fibrosis in mice respectively.. Journal of Translational Medicine 2016;14:45.
- Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, Prockop DJ. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6.. Cell Stem Cell 2009;5(1):54–63.
- Eggenhofer E, Benseler V, Kroemer A, Popp FC, Geissler EK, Schlitt HJ, Hoogduijn MJ. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion.. Frontiers in Immunology 2012;3:297.
- Kim G, Eom YW, Baik SK, Shin Y, Lim YL, Kim MY, Chang SJ. Therapeutic effects of mesenchymal stem cells for patients with chronic liver diseases: Systematic review and meta-analysis.. Journal of Korean Medical Science 2015;30(10):1405–1415.
- Wang L, Li J, Liu H, Li Y, Fu J, Sun Y, Wang F-S. Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis.. Journal of Gastroenterology and Hepatology 2013;28(Suppl 1):85–92.
- Nam A, Han S-M, Go D-M, Kim D-Y, Seo K-W, Youn H-Y. Long-Term Management with Adipose Tissue-Derived Mesenchymal Stem Cells and Conventional Treatment in a Dog with Hepatocutaneous Syndrome.. Journal of Veterinary Internal Medicine 2017;31(5):1514–1519.
- Liu Z, Meng F, Li C, Zhou X, Zeng X, He Y, Li T. Human umbilical cord mesenchymal stromal cells rescue mice from acetaminophen-induced acute liver failure.. Cytotherapy 2014;16(9):1207–1219.
- Lindroos B, Suuronen R, Miettinen S. The potential of adipose stem cells in regenerative medicine.. Stem Cell Reviews 2011;7(2):269–291.
- Bourebaba L, Röcken M, Marycz K. Osteochondritis dissecans (OCD) in horses – Molecular background of its pathogenesis and perspectives for progenitor stem cell therapy.. Stem Cell Reviews and Reports 2019;15:374–390.
- Piryaei A, Valojerdi MR, Shahsavani M, Baharvand H. Differentiation of bone marrow-derived mesenchymal stem cells into hepatocyte-like cells on nanofibers and their transplantation into a carbon tetrachloride-induced liver fibrosis model.. Stem Cell Reviews and Reports 2011;7(1):103–118.
Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists