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Frontiers in veterinary science2023; 10; 1109473; doi: 10.3389/fvets.2023.1109473

Distinct differences in immunological properties of equine orthobiologics revealed by functional and transcriptomic analysis using an activated macrophage readout system.

Abstract: Multiple biological therapies for orthopedic injuries are marketed to veterinarians, despite a lack of rigorous comparative biological activity data to guide informed decisions in selecting a most effective compound. Therefore, the goal of this study was to use relevant bioassay systems to directly compare the anti-inflammatory and immunomodulatory activity of three commonly used orthobiological therapies (OTs): mesenchymal stromal cells (MSC), autologous conditioned serum (ACS), and platelet rich plasma (PRP). Unassigned: Equine monocyte-derived macrophages were used as the readout system to compare therapies, including cytokine production and transcriptomic responses. Macrophages were stimulated with IL-1ß and treated 24 h with OTs, washed and cultured an additional 24 h to generate supernatants. Secreted cytokines were measured by multiplex immunoassay and ELISA. To assess global transcriptomic responses to treatments, RNA was extracted from macrophages and subjected to full RNA sequencing, using an Illumina-based platform. Data analysis included comparison of differentially expressed genes and pathway analysis in treated vs. untreated macrophages. Unassigned: All treatments reduced production of IL-1ß by macrophages. Secretion of IL-10 was highest in MSC-CM treated macrophages, while PRP lysate and ACS resulted in greater downregulation of IL-6 and IP-10. Transcriptomic analysis revealed that ACS triggered multiple inflammatory response pathways in macrophages based on GSEA, while MSC generated significant downregulation of inflammatory pathways, and PRP lysate induced a mixed immune response profile. Key downregulated genes in MSC-treated cultures included type 1 and type 2 interferon response, TNF-α and IL-6. PRP lysate cultures demonstrated downregulation of inflammation-related genes IL-1RA, SLAMF9, ENSECAG00000022247 but concurrent upregulation of TNF-α, IL-2 signaling, and Myc targets. ACS induced upregulation of inflammatory IL-2 signaling, TNFα and KRAS signaling and hypoxia, but downregulation of MTOR signaling and type 1 interferon signaling. Unassigned: These findings, representing the first comprehensive look at immune response pathways for popular equine OTs, reveal distinct differences between therapies. These studies address a critical gap in our understanding of the relative immunomodulatory properties of regenerative therapies commonly used in equine practice to treat musculoskeletal disease and will serve as a platform from which further comparisons may build.
Copyright © 2023 Pezzanite, Chow, Griffenhagen, Bass, Goodrich, Impastato and Dow.
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Publication Date: 2023-02-16 PubMed ID: 36876001PubMed Central: PMC9978772DOI: 10.3389/fvets.2023.1109473Google 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.

This research studies and compares the immunomodulatory and anti-inflammatory effects of three biological therapies commonly used in treating orthopedic injuries in horses. The three therapies are mesenchymal stromal cells (MSC), autologous conditioned serum (ACS), and platelet rich plasma (PRP). The study’s findings show distinct differences in the immunomodulatory properties among these therapies.

Research Methodology

  • The study used equine monocyte-derived macrophages as the readout system to compare the effects of the therapies in terms of cytokine production and transcriptomic responses.
  • The macrophages were stimulated with IL-1ß and treated with the therapies for 24 hours, washed and cultured for an additional 24 hours to generate supernatants.
  • The secreted cytokines were measured by multiplex immunoassay and ELISA.
  • Global transcriptomic responses to the treatments were assessed by extracting RNA from the macrophages and subjecting it to full RNA sequencing using an Illumina-based platform.

Differences Between Therapies

  • All three therapies reduced the production of IL-1ß by macrophages, however their effects varied on other components of the immune response.
  • Secretion of IL-10 was highest in MSC-treated macrophages, while PRP lysate and ACS resulted in greater downregulation of IL-6 and IP-10.
  • The transcriptomic analysis revealed that ACS triggered multiple inflammatory response pathways in macrophages based on GSEA, while MSC led to significant downregulation of inflammatory pathways, and PRP lysate induced a mixed immune response profile.

Significant Findings

  • MSC-treated cultures showed downregulation of inflammation-related genes including type 1 and type 2 interferon response, TNF-α, and IL-6.
  • PRP lysate cultures demonstrated downregulation of inflammation-related genes IL-1RA, SLAMF9, ENSECAG00000022247 but concurrent upregulation of TNF-α, IL-2 signaling, and Myc targets.
  • ACS induced upregulation of inflammatory IL-2 signaling, TNFα and KRAS signaling and hypoxia, but downregulation of MTOR signaling and type 1 interferon signaling.

Reuse and Future Studies

The study has addressed an important gap in understanding of the relative immunomodulatory properties of regenerative therapies used in equine practice. The findings may act as a platform for further comparisons and development of optimized treatments for musculoskeletal disease in horses.

Cite This Article

APA
Pezzanite LM, Chow L, Griffenhagen GM, Bass L, Goodrich LR, Impastato R, Dow S. (2023). Distinct differences in immunological properties of equine orthobiologics revealed by functional and transcriptomic analysis using an activated macrophage readout system. Front Vet Sci, 10, 1109473. https://doi.org/10.3389/fvets.2023.1109473

Publication

Frontiers in veterinary science
ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 10
Pages: 1109473
PII: 1109473

Researcher Affiliations

Pezzanite, Lynn M
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
Chow, Lyndah
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
Griffenhagen, Gregg M
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
Bass, Luke
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
Goodrich, Laurie R
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
Impastato, Renata
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
Dow, Steven
  • Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
  • Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.

Conflict of Interest Statement

LP, LG, LC, and SD acknowledge that they hold stock options in eQCell Inc. (LP, LG, and SD), Validus (SD), and ART Advanced Regenerative Therapies (LG), and have filed provisional patents covering immune activated MSC technology for treatment of musculoskeletal disease (SD, LP, LC, and LG). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Citations

This article has been cited 6 times.
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