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BMC veterinary research2018; 14(1); 241; doi: 10.1186/s12917-018-1556-3

Assessment of effectiveness and safety of repeat administration of proinflammatory primed allogeneic mesenchymal stem cells in an equine model of chemically induced osteoarthritis.

Abstract: This study aimed at assessing the effectiveness and safety of repeated administrations of allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) primed with tumor necrosis factor (TNF)-α and interferon-γ in an equine model of chemically-induced osteoarthritis. Arthritis was induced in both radio-carpal (RC)-joints by amphotericin-B in 18 ponies, divided into three groups depending on the treatment injected: MSC-naïve (n = 7), MSC-primed (n = 7) and control (n = 4). The study consisted of two phases and used one RC-joint of each animal in each phase, with four months time-lapse, in order to assess two end-points. Clinical, synovial, radiological and ultrasonographic follow-up was performed. At six months, animals were euthanized and both carpi were assessed by magnetic resonance imaging (MRI), gross anatomy, histopathology, histochemistry and gene expression. Results: Clinical and synovial inflammatory signs were quicker reduced in MSC-treated groups and repeated allogeneic administration did not produce adverse reactions, but MSC-primed group showed slight and transient local inflammation after second injection. Radiology and MRI did not show significant differences between treated and control groups, whereas ultrasonography suggested reduced synovial effusion in MSC-treated groups. Both MSC-treated groups showed enhanced cartilage gross appearance at two compared to six months (MSC-naïve, p < 0.05). Cartilage histopathology did not reveal differences but histochemistry suggested delayed progression of proteoglycan loss in MSC-treated groups. Synovium histopathology indicated decreased inflammation (p < 0.01) in MSC-primed and MSC-naïve at two and six months, respectively. At two months, cartilage from MSC-primed group significantly (p < 0.05) upregulated collagen type II (COL2A1) and transforming growth factor (TGF)-β1 and downregulated cyclooxygenase-2 and interleukin (IL)-1β. At six months, MSC-treatments significantly downregulated TNFα (p < 0.05), plus MSC-primed upregulated (p < 0.05) COL2A1, aggrecan, cartilage oligomeric protein, tissue inhibitor of metalloproteinases-2 and TGF-β1. In synovium, both MSC-treatments decreased (p < 0.01) matrix metalloproteinase-13 expression at two months and MSC-primed also downregulated TNFα (p < 0.05) and IL-1β (p < 0.01). Conclusions: Both MSC-treatments provided beneficial effects, mostly observed at short-term. Despite no huge differences between MSC-treatments, the findings suggested enhanced anti-inflammatory and regulatory potential of MSC-primed. While further research is needed to better understand these effects and clarify immunogenicity implications, these findings contribute to enlarge the knowledge about MSC therapeutics and how they could be influenced.
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Publication Date: 2018-08-17 PubMed ID: 30119668PubMed Central: PMC6098603DOI: 10.1186/s12917-018-1556-3Google Scholar: Lookup
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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 investigates the safety and benefits of applying twice a treatment, which is mesenchymal stem cells derived from allogeneic bone marrow and activated with tumor necrosis factor-alpha and interferon-gamma, to an osteoarthritis model that chemically induced in ponies. The study has indicated that such treatments can provide relief, particularly short-term, and the treatment with those cells that were primed has shown potential for increased inflammation control.

Methodology

  • The study involved 18 ponies in which osteoarthritis was chemically induced in their radio-carpal (RC)-joints using amphotericin-B.
  • The ponies were divided into three groups – one control group and two test groups, with one receiving naive mesenchymal stem cells (MSCs) and the other treated with MSCs that had been primed using tumor necrosis factor (TNF)-α and interferon-γ.
  • This research was delivered in two stages by researchers, with a four month gap between each stage. Each stage used one RC-joint from each pony to determine the two end points.
  • The researchers monitored the ponies through clinical, synovial, radiological, and ultrasonographic follow-ups.
  • After six months, the ponies were euthanized for further assessment with MRI and analysis of gross anatomy, histopathology, histochemistry, and gene expression.

Findings

  • Signs of inflammation were reduced more rapidly in the groups treated with MSCs.
  • Repeated treatment with allogeneic MSCs did not produce any adverse reactions. However, some temporary local inflammation was observed after the second injection of the MSC-primed group.
  • Radiology and MRIs did not indicate significant differences between the control and test groups. Ultrasonography suggested that synovial effusion was lessened in the groups receiving MSC treatments.
  • Groups treated with MSCs demonstrated improved cartilage at two months compared to six months, suggesting a delay in the progression of proteoglycan loss.
  • At two months, the group receiving MSC-primed treatment showed a significant upregulation of collagen type II (COL2A1) and transforming growth factor (TGF)-β1 and a downregulation of cyclooxygenase-2 and interleukin (IL)-1β.
  • At six months, both MSC-primed and MSC-naive treatments significantly downregulated TNFα. Additionally, the MSC-primed treatment notably upregulated COL2A1, aggrecan, tissue inhibitor of metalloproteinases-2, and TGF-β1.

Conclusion

  • Both MSC treatments produced beneficial effects, with more noticeable results appearing in the short term.
  • Despite minor differences between the MSC treatments, the research demonstrated enhanced anti-inflammatory potential for the MSC-primed treatment.
  • Further study is required to better understand the consequences and to identify the immunogenicity implications. Nevertheless, the findings provide useful knowledge regarding MSC therapeutics.

Cite This Article

APA
Barrachina L, Remacha AR, Romero A, Vitoria A, Albareda J, Prades M, Roca M, Zaragoza P, Vázquez FJ, Rodellar C. (2018). 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, 14(1), 241. https://doi.org/10.1186/s12917-018-1556-3

Publication

BMC veterinary research
ISSN: 1746-6148
NlmUniqueID: 101249759
Country: England
Language: English
Volume: 14
Issue: 1
Pages: 241
PII: 241

Researcher Affiliations

Barrachina, Laura
  • Laboratorio de Genética Bioquímica LAGENBIO - Instituto Agroalimentario de Aragón IA2 - Instituto de Investigación Sanitaria de Aragón IIS, 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.
Remacha, Ana Rosa
  • Laboratorio de Genética Bioquímica LAGENBIO - Instituto Agroalimentario de Aragón IA2 - Instituto de Investigación Sanitaria de Aragón IIS, Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
Romero, Antonio
  • Laboratorio de Genética Bioquímica LAGENBIO - Instituto Agroalimentario de Aragón IA2 - Instituto de Investigación Sanitaria de Aragón IIS, 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.
Vitoria, Arantza
  • Laboratorio de Genética Bioquímica LAGENBIO - Instituto Agroalimentario de Aragón IA2 - Instituto de Investigación Sanitaria de Aragón IIS, 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.
Albareda, Jorge
  • Laboratorio de Genética Bioquímica LAGENBIO - Instituto Agroalimentario de Aragón IA2 - Instituto de Investigación Sanitaria de Aragón IIS, 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.
Prades, Marta
  • Laboratorio de Genética Bioquímica LAGENBIO - Instituto Agroalimentario de Aragón IA2 - Instituto de Investigación Sanitaria de Aragón IIS, 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.
Roca, Mercedes
  • Clínica Doctora Roca Diagnóstico Médico, Carrera del Sábado 4, local (Edificio Europa), 50006, Zaragoza, Spain.
Zaragoza, Pilar
  • Laboratorio de Genética Bioquímica LAGENBIO - Instituto Agroalimentario de Aragón IA2 - Instituto de Investigación Sanitaria de Aragón IIS, Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain.
Vázquez, Francisco José
  • Laboratorio de Genética Bioquímica LAGENBIO - Instituto Agroalimentario de Aragón IA2 - Instituto de Investigación Sanitaria de Aragón IIS, 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.
Rodellar, Clementina
  • Laboratorio de Genética Bioquímica LAGENBIO - Instituto Agroalimentario de Aragón IA2 - Instituto de Investigación Sanitaria de Aragón IIS, Universidad de Zaragoza, C/Miguel Servet, 177, 50013, Zaragoza, Spain. rodellar@unizar.es.

MeSH Terms

  • Amphotericin B / administration & dosage
  • Animals
  • Horse Diseases / chemically induced
  • Horse Diseases / therapy
  • Horses
  • Inflammation / veterinary
  • Interferon-gamma / pharmacology
  • Male
  • Mesenchymal Stem Cell Transplantation
  • Osteoarthritis / chemically induced
  • Osteoarthritis / therapy
  • Osteoarthritis / veterinary
  • Synovial Membrane / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology

Grant Funding

  • AGL2011-28609 / Ministerio de Economu00eda y Competitividad
  • A17-LAGENBIO / Gobierno de Aragu00f3n
  • Doctoral grant / Gobierno de Aragu00f3n
  • Doctoral grant / Universidad de Zaragoza

Conflict of Interest Statement

ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All procedures were carried out under Project License (PI 31/11) approved by the Ethic Committee for Animal Experiments from the University of Zaragoza. The care and use of animals were performed in accordance with the Spanish Policy for Animal Protection RD53/2013, which meets the European Union Directive 2010/63 on the protection of animals used for scientific purposes. CONSENT FOR PUBLICATION: Not applicable COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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