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International journal of molecular sciences2026; 27(9); 4006; doi: 10.3390/ijms27094006

Allogeneic Platelet-Rich Gel Supernatant Reprograms the Cytokine and Growth Factor Microenvironment in an Equine In Vitro Inflammatory Tendon System.

Abstract: Tendinopathy involves a dysregulated inflammatory microenvironment in which cytokines, growth factors (GF) and extracellular matrix components interact dynamically. Platelet-rich plasma (PRP) is widely used as a regenerative therapy, but its mechanisms of action in inflamed tendon remain unclear. This study evaluated whether platelet-rich gel supernatant (PRGS) reprograms the inflammatory-anabolic mediator network in an equine in vitro tendon explant system stimulated with lipopolysaccharide (LPS). Tendon explants were cultured under six experimental conditions, including non-stimulated control, LPS-stimulated control, and LPS combined with 25% or 50% PRGS or platelet-poor gel supernatant (PPGS). Cytokines, GF, and hyaluronic acid (HA) were quantified at 1 h and 48 h and analyzed using linear mixed-effects models, mediator ratios, correlation networks, and principal component analysis. PRGS contained higher concentrations of PDGF-BB (2044 pg/mL, 95% CI 1382-2706) and IL-1ra (1196 pg/mL, 95% CI 424-1967) compared with PPGS. In LPS-stimulated explants, PRGS significantly increased IL-1ra and PDGF-BB, while IL-1β and HA exhibited significant time-dependent changes (F = 8.675 and F = 10.752, respectively). The PDGF-BB:HA ratio remained consistently higher in PRGS-treated groups (F = 46.100, p < 0.001). Multivariate analysis showed that the first two principal components explained 62% of the total variance and revealed coordinated shifts in mediator organization over time. These findings indicate that PRGS does not simply suppress inflammation but actively reprograms the tendon microenvironment toward a regulatory and reparative phenotype within this experimental system.
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Publication Date: 2026-04-29 PubMed ID: 42123585PubMed Central: PMC13164241DOI: 10.3390/ijms27094006Google 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 study tested whether the cell-free supernatant released from allogeneic platelet-rich gels can shift an LPS-induced inflammatory tendon environment toward a more balanced, repair-supportive state. In equine tendon explants, platelet-rich gel supernatant increased anti-inflammatory and pro-repair mediators and reorganized the overall mediator network rather than simply suppressing inflammation.

What problem the study addresses

  • Tendinopathy is driven by a misbalanced milieu of cytokines, growth factors, and extracellular matrix signals that perpetuate inflammation and impair repair.
  • Platelet-rich plasma (PRP) is commonly used to treat tendon injuries, but its mechanisms in inflamed tendon tissue remain unclear and variable.
  • This work asks whether the soluble factors released from platelet-rich gels (platelet-rich gel supernatant, PRGS) can actively “reprogram” the inflammatory-anabolic network in an in vitro tendon inflammation model, rather than merely dampening inflammation.

Model and experimental design

  • System: Equine tendon explants subjected to lipopolysaccharide (LPS) to model acute inflammatory activation.
  • Groups: Six conditions—non-stimulated control; LPS-stimulated control; LPS + 25% or 50% PRGS; and LPS + 25% or 50% platelet-poor gel supernatant (PPGS) as a comparator lacking platelet-derived factors.
  • Timing: Mediators measured at 1 hour (early response) and 48 hours (evolving response).
  • Readouts: Concentrations of cytokines (e.g., IL-1β, IL-1 receptor antagonist [IL-1ra]), growth factors (e.g., PDGF-BB), and hyaluronic acid (HA, an extracellular matrix component linked to inflammation and remodeling).
  • Statistics and systems analysis:
    • Linear mixed-effects models to account for repeated measurements and biological variability.
    • Mediator ratios (e.g., PDGF-BB:HA) to capture balance between pro-repair and matrix/inflammatory signals.
    • Correlation networks to visualize coordinated mediator behavior.
    • Principal component analysis (PCA) to summarize multivariate shifts over time and treatment.

Key composition differences between PRGS and PPGS

  • PRGS contained higher PDGF-BB (approx. 2044 pg/mL; 95% CI 1382–2706) than PPGS, indicating greater pro-repair growth factor content.
  • PRGS also had higher IL-1ra (approx. 1196 pg/mL; 95% CI 424–1967) than PPGS, supplying an endogenous antagonist to IL-1 signaling.
  • These differences support the premise that platelet-derived releasate (PRGS) delivers both anabolic and regulatory signals not present at comparable levels in platelet-poor preparations.

Main findings in LPS-stimulated tendon explants

  • PRGS upregulated IL-1ra and PDGF-BB in the inflamed explants, aligning with a shift toward regulation (via IL-1 pathway antagonism) and repair (via PDGF-driven cell activity).
  • IL-1β and HA changed significantly over time (reported F = 8.675 and F = 10.752, respectively), indicating dynamic remodeling of both inflammatory signaling and matrix-associated components across 1–48 hours.
  • The PDGF-BB:HA ratio was consistently higher with PRGS treatment than in controls (F = 46.100; p < 0.001), suggesting a sustained tilt toward growth factor–dominant, repair-supportive conditions relative to HA-associated matrix/inflammatory signaling.
  • Multivariate structure: The first two principal components captured 62% of total variance and showed coordinated mediator reorganization over time, consistent with active microenvironment “reprogramming.”

How to interpret the mediator shifts

  • IL-1ra increase:
    • IL-1ra competitively blocks IL-1 receptor signaling, countering IL-1β–driven inflammation.
    • Higher IL-1ra with PRGS implies a built-in regulatory check on inflammatory cascades without fully silencing them.
  • PDGF-BB increase:
    • PDGF-BB promotes tenocyte chemotaxis, proliferation, and matrix synthesis—core components of early tendon repair.
    • Elevated PDGF-BB supports an anabolic, reparative shift.
  • HA dynamics:
    • HA levels reflect extracellular matrix turnover and can be linked to inflammation, edema, and remodeling; changes over time indicate evolving tissue responses.
    • The consistently higher PDGF-BB:HA ratio with PRGS indicates a mediator balance favoring repair signals over matrix-associated inflammatory cues.
  • Network and PCA findings:
    • Correlated mediator clusters and principal components shifting under PRGS indicate system-level reorganization, not just single-mediator suppression.
    • This supports the conclusion that PRGS “reprograms” the microenvironment toward a regulatory–reparative phenotype.

Why PRGS (platelet releasate) matters relative to PRP or PPGS

  • PRGS is the supernatant collected after platelet activation/gelation, enriched in soluble platelet-derived factors and largely devoid of intact cells.
  • Compared to PPGS, PRGS provides higher concentrations of key mediators (e.g., PDGF-BB, IL-1ra), which likely drive the observed effects.
  • Compared to whole PRP, PRGS reduces variability and removes cellular components (e.g., leukocytes) that can add pro-inflammatory signals, potentially offering a more controlled biologic input.
  • Allogeneic sourcing (from donor animals) raises the prospect of standardized, off-the-shelf preparations, though immunogenicity and regulatory aspects require evaluation beyond this in vitro model.

Strengths of the study

  • Uses a relevant species (equine) and tendon explant system that preserves native extracellular matrix context.
  • Combines targeted mediator quantification with systems-level analytics (ratios, networks, PCA) to capture complex microenvironment behavior.
  • Compares PRGS with a platelet-poor counterpart, helping attribute effects to platelet-derived factors.
  • Assesses both very early (1 h) and later (48 h) responses to capture dynamics rather than static snapshots.

Limitations to keep in mind

  • In vitro explants lack vascular, immune cell trafficking, and mechanical loading present in vivo; translation to injured tendons in animals or humans is not guaranteed.
  • LPS models acute innate immune activation and may not fully replicate multifactorial tendinopathy.
  • Only two timepoints were assessed; intermediary dynamics and longer-term remodeling remain unknown.
  • The mediator panel, while informative, does not capture all relevant repair pathways (e.g., collagen deposition quality, matrix metalloproteinase activity, biomechanical outcomes).
  • Allogeneic product safety, standardization, and batch-to-batch variability were not addressed in this experiment.

Clinical and translational implications

  • PRGS may offer a way to steer an inflamed tendon environment toward regulation and repair rather than bluntly suppressing inflammation.
  • The higher PDGF-BB:HA ratio under PRGS suggests a quantifiable metric that could be explored as a quality attribute for therapeutic preparations.
  • Both 25% and 50% PRGS concentrations were tested; sustained effects on ratios across doses hint at a potentially flexible dosing window, though optimal dosing needs in vivo validation.
  • Findings support the rationale for cell-free, platelet-derived therapeutics as candidates for standardized, off-the-shelf biologics in tendon care.

Future directions

  • Extend to in vivo tendon injury models to evaluate functional healing, re-injury rates, and biomechanical properties.
  • Profile additional mediators (e.g., MMPs/TIMPs, TGF-β isoforms, SDF-1, prostaglandins) and extracellular matrix quality markers (e.g., collagen I/III ratios).
  • Examine the molecular weight distribution of HA to distinguish inflammatory (low-MW) from homeostatic (high-MW) forms.
  • Assess immunogenicity and safety of allogeneic PRGS, along with manufacturing controls and potency assays.
  • Compare PRGS with leukocyte-rich and leukocyte-poor PRP formulations to delineate cell-dependent versus releasate-driven effects.

Bottom line

  • In an equine LPS-stimulated tendon explant model, allogeneic PRGS increased regulatory (IL-1ra) and reparative (PDGF-BB) signals, maintained a higher PDGF-BB:HA balance, and reorganized mediator networks over time.
  • These data support a mechanism of active microenvironment reprogramming toward a regulatory–reparative phenotype, positioning PRGS as a promising, potentially more controllable alternative to conventional PRP for inflamed tendon tissues.

Cite This Article

APA
Carmona JU, López C. (2026). Allogeneic Platelet-Rich Gel Supernatant Reprograms the Cytokine and Growth Factor Microenvironment in an Equine In Vitro Inflammatory Tendon System. Int J Mol Sci, 27(9), 4006. https://doi.org/10.3390/ijms27094006

Publication

International journal of molecular sciences
ISSN: 1422-0067
NlmUniqueID: 101092791
Country: Switzerland
Language: English
Volume: 27
Issue: 9
PII: 4006

Researcher Affiliations

Carmona, Jorge U
  • Grupo de Investigación Terapia Regenerativa, Departamento de Salud Animal, Universidad de Caldas, Calle 65 No 26-10, Manizales 170004, Colombia.
López, Catalina
  • Grupo de Investigación Patología Clínica Veterinaria, Departamento de Salud Animal, Universidad de Caldas, Calle 65 No 26-10, Manizales 170004, Colombia.

MeSH Terms

  • Animals
  • Horses
  • Tendons / metabolism
  • Tendons / pathology
  • Tendons / drug effects
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Platelet-Rich Plasma / metabolism
  • Cytokines / metabolism
  • Lipopolysaccharides / pharmacology
  • Inflammation / metabolism
  • Cellular Microenvironment
  • Gels
  • Blood Platelets / metabolism
  • Tendinopathy / metabolism
  • Hyaluronic Acid / metabolism
  • Becaplermin / metabolism

Grant Funding

  • 0425915 / University of Caldas

Conflict of Interest Statement

The authors declare no conflicts of interest.

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