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Abstract: SA-PO546

Exploring Monocyte Trafficking: Unveiling MicroRNA (miRNA) Contributions with Organ-on-Chip Vessel Models

Session Information

  • Bioengineering
    October 26, 2024 | Location: Exhibit Hall, Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Bioengineering

  • 400 Bioengineering

Authors

  • Hueso, Miguel, Hospital Universitari de Bellvitge Servei de Nefrologia, L'Hospitalet de Llobregat, Catalunya, Spain
  • Mallén Bareas, Adrián, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain
  • Navarro, Estanis, Fundacio Institut d'Investigacio en Ciencies de la Salut Germans Trias i Pujol, Badalona, Catalunya, Spain
  • Bover, Jordi, Hospital Universitari Germans Trias i Pujol, Badalona, Catalunya, Spain
Background

Monocytes play pivotal roles in numerous inflammatory disorders, including vascular and renal diseases. Environmental signals at site of inflammation mediate rapid monocyte migration and dictate differentiation programs. However, the molecular mechanisms of the migration of monocytes remain poorly understood. Since, proinflammatory activation of monocyte-derived macrophages were associated with a concomitant increase in miR-125b we will study if miR-125b contribute to the regulation of the traffic of monocytes using in vivo and in vitro models.

Methods

In the ApoE-/- mice model fed with a high fat diet for 14 weeks, we inhibited miR-125b using an antagomir over a 4-week period. We explored the mechanism using a Vessel-on-Chip adhesion assay, constructed with Human Aortic Endothelial Cells (HAoEC) stimulated with TNFα, along with Transwell studies.

Results

We observed a significant reduction in infiltration of F4/80 macrophages and attenuation of NF-κB+ activation in vascular lesions. We observed an impairment in the trafficking of miR-125b transfected THP-1 monocytes, accompanied by the downregulation of the CD11b/CD18 integrin and the CCR7 receptor. Furthermore, we demonstrated a direct regulation of the CCR7 receptor by miR-125b using a reporter plasmid construct (p_CCR7.WT) containing the 3’UTR region of CCR7 gene fused with a luciferase coding sequence. In addition, miR-125b transfected monocytes inhibited CCR7 cell migration induced by the CCL21 ligand but did not affect migration induced by others ligands such as MCP1. Finally, we confirmed the downregulation of CCR7 in coronary plaques in both ApoE-/- mice and patients with coronary artery disease.

Conclusion

Organs-on-chip, engineered to mimic the complexity of organs and replicate specific microenvironments are valuable models for studying biological mechanisms. In our study, we demonstrated that miR-125b contributes to monocyte trafficking by downregulating the CD11b/CD18 integrin and the CCR7 receptor. Thus, miR-125b could be a potential therapeutic target in renal or vascular inflammatory disorders.

Funding

  • Government Support – Non-U.S.