title: Alternative strategies to manipulate fibrocyte involvement in the fibrotic tissue response: pharmacokinetic inhibition and the feasibility of directed-adipogenic differentiation.
abstract: Fibrocytes have previously been identified as important mediators in several inflammatory and fibrotic diseases. However, there is no effective treatment thus far to reduce fibrotic tissue responses without affecting wound healing reactions. Here we investigate two strategies to alleviate fibrocyte interactions at the biomaterial interface, reducing collagen production and scar tissue formation. First, in an indirect approach, TGF-β inhibitor-SB431542 and IL-1β/TNF-α inhibitor SB203580 were locally released from scaffold implants to block their respective signaling pathways. We show that the inhibition of IL-1β/TNF-α has no influence on overall fibrotic tissue reactions to the implants. However, the reduction of localized TGF-β significantly decreases the fibrocyte accumulation and myofibroblast activation while reducing the fibrotic tissue formation. Since fibrocytes can be differentiated into non-fibrotic cell types, such as adipocytes, we further sought a more direct approach to reduce fibrocyte responses by directing fibrocyte differentiation into adipocytes. Interestingly, by initiating fibrocyte-to-adipocyte differentiation through sustained differentiation cocktail release, we find that adipogenic differentiation forces incoming fibrocytes away from the traditional myofibroblast lineage, leading to a substantial reduction in the collagen formation and fibrotic response. Our results support a novel and effective strategy to improve implant safety by reducing implant-associated fibrotic tissue reactions via directing non-fibrotic differentiation of fibrocytes.
authors.affiliation: Bioengineering Department, University of Texas at Arlington, Arlington, TX 76019-0138, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Baker
authors.affiliation: Bioengineering Department, University of Texas at Arlington, Arlington, TX 76019-0138, USA.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Tsai
authors.affiliation: Bioengineering Department, University of Texas at Arlington, Arlington, TX 76019-0138, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Weng
authors.affiliation: Bioengineering Department, University of Texas at Arlington, Arlington, TX 76019-0138, USA; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: ltang@uta.edu.
authors.forename: Liping
authors.initials: L
authors.lastname: Tang
mesh_terms: D000273:Adipose Tissue / Q000166:cytology* / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002454:Cell Differentiation; D004149:Dioxoles / Q000494:pharmacology; D005240:Feasibility Studies; D005347:Fibroblasts / Q000166:cytology; D005355:Fibrosis; D051379:Mice; D008807:Mice, Inbred BALB C; D010599:Pharmacokinetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D016212:Transforming Growth Factor beta
keywords: Adipocyte; Differentiation; Fibrocyte; Fibrosis; Foreign body response