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      The Usefulness of Mesenchymal Stem Cells beyond the Musculoskeletal System in Horses

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          Abstract

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          The main target of mesenchymal stem cell therapy in horses has long been the locomotor system, because these athletic animals commonly suffer from tendon and joint lesions. Originally, mesenchymal stem cells were thought to act by just differentiating into the cells of the injured tissue. However, these cells are also able to regulate and stimulate the body’s own repair mechanisms, opening the door to many applications in inflammatory and immune-mediated disorders in both animals and humans. In horses, beyond their traditional application in the musculoskeletal system, these cells have been studied for ophthalmologic pathologies such as corneal ulcers or immune-mediated processes, and for reproductive disorders such as endometritis/endometrosis. Their potential has been explored for equine pathologies very similar to those affecting people, such as asthma, metabolic syndrome, aberrant wound healing, or endotoxemia, as well as for equine-specific pathologies such as laminitis. Current evidence is still preliminary, and further research is needed to clarify different aspects, although research performed so far shows the promising potential of mesenchymal stem cells to treat a wide variety of equine pathologies, some of which are analogous to human disorders. Therefore, advancements in this path will be beneficial for both animals and people.

          Abstract

          The differentiation ability of mesenchymal stem cells (MSCs) initially raised interest for treating musculoskeletal injuries in horses, but MSC paracrine activity has widened their scope for inflammatory and immune-mediated pathologies in both equine and human medicine. Furthermore, the similar etiopathogenesis of some diseases in both species has advanced the concept of “One Medicine, One Health”. This article reviews the current knowledge on the use of MSCs for equine pathologies beyond the locomotor system, highlighting the value of the horse as translational model. Ophthalmologic and reproductive disorders are among the most studied for MSC application. Equine asthma, equine metabolic syndrome, and endotoxemia have been less explored but offer an interesting scenario for human translation. The use of MSCs in wounds also provides a potential model for humans because of the healing particularities in both species. High-burden equine-specific pathologies such as laminitis have been suggested to benefit from MSC-therapy, and MSC application in challenging disorders such as neurologic conditions has been proposed. The available data are preliminary, however, and require further development to translate results into the clinic. Nevertheless, current evidence indicates a significant potential of equine MSCs to enlarge their range of application, with particular interest in pathologies analogous to human conditions.

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          Most cited references142

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          Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.

          The considerable therapeutic potential of human multipotent mesenchymal stromal cells (MSC) has generated markedly increasing interest in a wide variety of biomedical disciplines. However, investigators report studies of MSC using different methods of isolation and expansion, and different approaches to characterizing the cells. Thus it is increasingly difficult to compare and contrast study outcomes, which hinders progress in the field. To begin to address this issue, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC. First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules. Third, MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro. While these criteria will probably require modification as new knowledge unfolds, we believe this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators.
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            Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice.

            We tested the hypothesis that multipotent stromal cells from human bone marrow (hMSCs) can provide a potential therapy for human diabetes mellitus. Severe but nonlethal hyperglycemia was produced in NOD/scid mice with daily low doses of streptozotocin on days 1-4, and hMSCs were delivered via intracardiac infusion on days 10 and 17. The hMSCs lowered blood glucose levels in the diabetic mice on day 32 relative to untreated controls (18.34 mM +/- 1.12 SE vs. 27.78 mM +/- 2.45 SE, P = 0.0019). ELISAs demonstrated that blood levels of mouse insulin were higher in the hMSC-treated as compared with untreated diabetic mice, but human insulin was not detected. PCR assays detected human Alu sequences in DNA in pancreas and kidney on day 17 or 32 but not in other tissues, except heart, into which the cells were infused. In the hMSC-treated diabetic mice, there was an increase in pancreatic islets and beta cells producing mouse insulin. Rare islets contained human cells that colabeled for human insulin or PDX-1. Most of the beta cells in the islets were mouse cells that expressed mouse insulin. In kidneys of hMSC-treated diabetic mice, human cells were found in the glomeruli. There was a decrease in mesangial thickening and a decrease in macrophage infiltration. A few of the human cells appeared to differentiate into glomerular endothelial cells. Therefore, the results raised the possibility that hMSCs may be useful in enhancing insulin secretion and perhaps improving the renal lesions that develop in patients with diabetes mellitus.
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              Mechanisms involved in the therapeutic properties of mesenchymal stem cells.

              Mesenchymal stem cells (MSCs) have been described as being able to give rise to several quite different mesenchymal cell phenotypes. However, the ability to differentiate is not the only characteristic that makes these cells attractive for therapeutic purposes. The secretion of a broad range of bioactive molecules by MSCs, such as growth factors, cytokines and chemokines, constitutes their most biologically significant role under injury conditions. Understanding this intricate secretory activity as well as the properties of MSCs in vivo is central to harnessing their clinical potential. Herein, we identify some of the molecules involved in the paracrine effects of MSCs with a perspective that these cells intrinsically belong to a perivascular niche in vivo, and discuss how this knowledge could be advantageously used in clinical applications.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Animals (Basel)
                Animals (Basel)
                animals
                Animals : an Open Access Journal from MDPI
                MDPI
                2076-2615
                25 March 2021
                April 2021
                : 11
                : 4
                : 931
                Affiliations
                [1 ]Laboratorio de Genética Bioquímica LAGENBIO—Instituto de Investigación Sanitaria de Aragón (IIS)—Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; alinacs@ 123456unizar.es (A.C.); rodellar@ 123456unizar.es (C.R.)
                [2 ]Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; cap141297@ 123456gmail.com
                Author notes
                [* ]Correspondence: lbarrach@ 123456unizar.es
                [†]

                These authors equally contributed to this article.

                Article
                animals-11-00931
                10.3390/ani11040931
                8064371
                33805967
                00598aa0-42c7-4610-a379-8f82a08c8e20
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 09 March 2021
                : 22 March 2021
                Categories
                Review

                one medicine,mesenchymal stem cells,immune-mediated disorders,ophthalmology,reproduction,equine asthma,equine metabolic syndrome,wounds,laminitis,neurologic disorders

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