Porous Precision-Templated 40 μm Pore Scaffolds Promote Healing through Synergy in Macrophage Receptor with Collagenous Structure and Toll-Like Receptor Signaling.

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  • Additional Information
    • Source:
      Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 101466659 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1937-335X (Electronic) Linking ISSN: 19373341 NLM ISO Abbreviation: Tissue Eng Part A Subsets: MEDLINE
    • Publication Information:
      Original Publication: New Rochelle, NY : Mary Ann Liebert, Inc.
    • Subject Terms:
      Myeloid Differentiation Factor 88*/metabolism ; Toll-Like Receptors*/metabolism; Humans ; Porosity ; Signal Transduction ; Macrophages/metabolism ; NF-kappa B/metabolism ; Foreign-Body Reaction/pathology ; Fibrosis ; Wound Healing
    • Abstract:
      Porous precision-templated scaffolds (PTS) with uniform, interconnected, 40 μm pores have shown favorable healing outcomes and a reduced foreign body reaction (FBR). Macrophage receptor with collagenous structure (MARCO) and toll-like receptors (TLRs) have been identified as key surface receptors in the initial inflammatory phase of wound healing. However, the role of MARCO and TLRs in modulating monocyte and macrophage phenotypes within PTS remains uncharacterized. In this study, we demonstrate a synergetic relationship between MARCO and TLR signaling in cells inhabiting PTS, where induction with TLR3 or TLR4 agonists to 40 μm scaffold-resident cells upregulates the transcription of MARCO. Upon deletion of MARCO, the prohealing phenotype within 40 μm PTS polarizes to a proinflammatory and profibrotic phenotype. Analysis of downstream TLR signaling shows that MARCO is required to attenuate nuclear factor kappa B (NF-κB) inflammation in 40 μm PTS by regulating the transcription of inhibitory NFKB inhibitor alpha ( NFKBIA ) and interleukin-1 receptor-associated kinase 3 ( IRAK-M ), primarily through a MyD88 -dependent signaling pathway. Investigation of implant outcome in the absence of MARCO demonstrates an increase in collagen deposition within the scaffold and the development of tissue fibrosis. Overall, these results further our understanding of the molecular mechanisms underlying MARCO and TLR signaling within PTS. Impact statement Monocyte and macrophage phenotypes in the foreign body reaction (FBR) are essential for the development of a proinflammatory, prohealing, or profibrotic response to implanted biomaterials. Identification of key surface receptors and signaling mechanisms that give rise to these phenotypes remain to be elucidated. In this study, we report a synergistic relationship between macrophage receptor with collagenous structure (MARCO) and toll-like receptor (TLR) signaling in scaffold-resident cells inhabiting porous precision-templated 40 μm pore scaffolds through a MyD88 -dependent pathway that promotes healing. These findings advance our understanding of the FBR and provide further evidence that suggests MARCO, TLRs, and fibrosis may be interconnected.
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    • Grant Information:
      R01 DE018701 United States DE NIDCR NIH HHS; R01 GM128991 United States GM NIGMS NIH HHS
    • Contributed Indexing:
      Keywords: MyD88; biomaterial scaffolds; cell phenotype; fibrosis; foreign body response; macrophage polarization
    • Accession Number:
      0 (Myeloid Differentiation Factor 88)
      0 (Toll-Like Receptors)
      0 (NF-kappa B)
    • Publication Date:
      Date Created: 20240111 Date Completed: 20240417 Latest Revision: 20240426
    • Publication Date:
      20240426
    • Accession Number:
      PMC11040183
    • Accession Number:
      10.1089/ten.TEA.2023.0144
    • Accession Number:
      38205652