title: Immunomodulation by mesenchymal stem cells combats the foreign body response to cell-laden synthetic hydrogels.
abstract: The implantation of non-biological materials, including scaffolds for tissue engineering, ubiquitously leads to a foreign body response (FBR). We recently reported that this response negatively impacts fibroblasts encapsulated within a synthetic hydrogel and in turn leads to a more severe FBR, suggesting a cross-talk between encapsulated cells and inflammatory cells. Given the promise of mesenchymal stem cells (MSCs) in tissue engineering and recent evidence of their immunomodulatory properties, we hypothesized that MSCs encapsulated within poly(ethylene glycol) (PEG) hydrogels will attenuate the FBR. In vitro, murine MSCs encapsulated within PEG hydrogels attenuated classically activated primary murine macrophages by reducing gene expression and protein secretion of pro-inflammatory cytokines, most notably tumor necrosis factor-α. Using a COX2 inhibitor, prostaglandin E2 (PGE2) was identified as a mediator of MSC immunomodulation of macrophages. In vivo, hydrogels laden with MSCs, osteogenically differentiating MSCs, or no cells were implanted subcutaneously into C57BL/6 mice for 28 days to assess the impact of MSCs on the fibrotic response of the FBR. The presence of encapsulated MSCs reduced fibrous capsule thickness compared to acellular hydrogels, but this effect diminished with osteogenic differentiation. The use of MSCs prior to differentiation in tissue engineering may therefore serve as a dynamic approach, through continuous cross-talk between MSCs and the inflammatory cells, to modulate macrophage activation and attenuate the FBR to implanted synthetic scaffolds thus improving the long-term tissue engineering outcome.
authors.affiliation: Department of Chemical & Biological Engineering, University of Colorado, Boulder, CO 80309, USA; Biofrontiers Institute, University of Colorado, Boulder, CO 80309, USA. Electronic address: Mark.Swartzlander@colorado.edu.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Swartzlander
authors.affiliation: Department of Chemical & Biological Engineering, University of Colorado, Boulder, CO 80309, USA. Electronic address: Blakney@uw.edu.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Blakney
authors.affiliation: Department of Chemical & Biological Engineering, University of Colorado, Boulder, CO 80309, USA; Biofrontiers Institute, University of Colorado, Boulder, CO 80309, USA. Electronic address: Luke.Amer@colorado.edu.
authors.forename: Luke D
authors.initials: LD
authors.lastname: Amer
authors.affiliation: Department of Small Animal Clinical Science, School of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA; Department of Physiology, Colleges of Natural Sciences and Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA. Electronic address: kdhank@msu.edu.
authors.forename: Kurt D
authors.initials: KD
authors.lastname: Hankenson
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06509, USA. Electronic address: Themis.Kyriakides@yale.edu.
authors.forename: Themis R
authors.initials: TR
authors.lastname: Kyriakides
authors.affiliation: Department of Chemical & Biological Engineering, University of Colorado, Boulder, CO 80309, USA; Biofrontiers Institute, University of Colorado, Boulder, CO 80309, USA; Material Science and Engineering Program, University of Colorado, Boulder, CO 80309, USA. Electronic address: Stephanie.Bryant@colorado.edu.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Bryant
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D018914:Cells, Immobilized / Q000166:cytology / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D005549:Foreign-Body Reaction / Q000139:chemically induced* / Q000276:immunology*; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000009:adverse effects*; D056747:Immunomodulation / Q000187:drug effects*; D042541:Intracellular Space / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000276:immunology*; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D015232:Dinoprostone
keywords: Foreign body response; Hydrogel; Immunomodulation; Macrophage; Mesenchymal stem cell; Poly(ethylene glycol)