Local expression of indoleamine 2,3-dioxygenase suppresses T-cell-mediated rejection of an engineered bilayer skin substitute

Forouzandeh, Farshad; Jalili, Reza B.; Hartwell, Ryan; Allan, Sarah; Boyce, Steven T.; Supp, Dorothy M.; Ghahary, Aziz

doi:10.1111/j.1524-475x.2010.00635.x

Cited by 17 publications

(19 citation statements)

References 38 publications

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“…Reduced collagen deposition was confirmed by down-regulation of type-I collagen and up-regulation of MMP1 expression in KynA or Kyn treated wounds. Results from our in vivo experiments were further supported by our previous studies [11], [44], [45] showing that wound treatment with IDO-expressing skin substitute not only accelerates the wound healing process, as a skin substitute, but also decreases the inflammation and scar formation. In addition to evaluating the effect of KynA treatment on collagenase and collagen expression it was found that KynA and Kyn suppress the expression of fibronectin in vitro and in vivo , and further, that KynA is more effective in reducing the fibronectin mRNA.…”

Section: Discussionsupporting

confidence: 85%

Anti-Scarring Properties of Different Tryptophan Derivatives

et al. 2014

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Hypertrophic scars are associated with prolonged extracellular matrix (ECM) production, aberrant ECM degradation and high tissue cellularity. Routinely used antifibrotic strategies aim to reduce ECM deposition and enhance matrix remodeling. Our previous study investigating the antifibrotic effects of indoleamine2, 3 dioxygenase (IDO) led to the identification of kynurenine (Kyn) as an antiscarring agent. A topical antifibrogenic therapy using Kyn is very attractive; however, it is well established that Kyn passes the blood brain barrier (BBB) which causes complications including excitatory neuronal death. Here we investigated the antiscarring properties of kynurenic acid (KynA), a downstream end product of Kyn that is unlikely to pass the BBB, as an effective and safe replacement for Kyn. Our results indicated that while not having any adverse effect on dermal cell viability, KynA significantly increases the expression of matrix metalloproteinases (MMP1 and MMP3) and suppresses the production of type-I collagen and fibronectin by fibroblasts. Topical application of cream containing KynA in fibrotic rabbit ear significantly decreased scar elevation index (1.13±0.13 vs. 1.61±0.12) and tissue cellularity (221.38±21.7 vs. 314.56±8.66 cells/hpf) in KynA treated wounds compared to controls. KynA treated wounds exhibited lower levels of collagen deposition which is accompanied with a significant decrease in type-I collagen and fibronectin expression, as well as an increase in MMP1 expression compared to untreated wounds or wounds treated with cream only. The results of this study provided evidence for the first time that KynA is promising candidate antifibrogenic agent to improve healing outcome in patients at risk of hypertrophic scarring.

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Section: Discussionsupporting

confidence: 85%

Anti-Scarring Properties of Different Tryptophan Derivatives

et al. 2014

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“…Interestingly, the IDO expressing skin substitute also demonstrated anti-fibrotic activity by increasing MMP-1 expression in the host fibroblasts. In yet another animal model, the same group demonstrated that the IDO-expressing skin substitute accelerated wound closure and increased neovascularization in the wounded site compared to the control non IDO-expressing bio-construct [34]. This is in accordance with several lines of evidence suggesting that depleting one or more inflammatory cell types can actually have a positive outcome on the wound closure [35], [36].…”

Section: Discussionsupporting

confidence: 69%

Fetal Fibroblasts and Keratinocytes with Immunosuppressive Properties for Allogeneic Cell-Based Wound Therapy

et al. 2013

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Fetal skin heals rapidly without scar formation early in gestation, conferring to fetal skin cells a high and unique potential for tissue regeneration and scar management. In this study, we investigated the possibility of using fetal fibroblasts and keratinocytes to stimulate wound repair and regeneration for further allogeneic cell-based therapy development. From a single fetal skin sample, two clinical batches of keratinocytes and fibroblasts were manufactured and characterized. Tolerogenic properties of the fetal cells were investigated by allogeneic PBMC proliferation tests. In addition, the potential advantage of fibroblasts/keratinocytes co-application for wound healing stimulation has been examined in co-culture experiments with in vitro scratch assays and a multiplex cytokines array system. Based on keratin 14 and prolyl-4-hydroxylase expression analyses, purity of both clinical batches was found to be above 98% and neither melanocytes nor Langerhans cells could be detected. Both cell types demonstrated strong immunosuppressive properties as shown by the dramatic decrease in allogeneic PBMC proliferation when co-cultured with fibroblasts and/or keratinocytes. We further showed that the indoleamine 2,3 dioxygenase (IDO) activity is required for the immunoregulatory activity of fetal skin cells. Co-cultures experiments have also revealed that fibroblasts-keratinocytes interactions strongly enhanced fetal cells secretion of HGF, GM-CSF, IL-8 and to a lesser extent VEGF-A. Accordingly, in the in vitro scratch assays the fetal fibroblasts and keratinocytes co-culture accelerated the scratch closure compared to fibroblast or keratinocyte mono-cultures. In conclusion, our data suggest that the combination of fetal keratinocytes and fibroblasts could be of particular interest for the development of a new allogeneic skin substitute with immunomodulatory activity, acting as a reservoir for wound healing growth factors.

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“…Primary human keratinocytes were cultured to 60% confluence in KSFM containing bovine pituitary extract (BPE), epidermal growth factor (EGF) and 1% antibiotic (Gibco Ò , Invitrogen). After 48 h keratinocytes (1 Â 10 6 cells) were seeded on top of the cultured gel scaffolds and the medium was changed to 49% DMEM, 49% KSFM with 1% FBS, and 1% antibiotic (50/50 medium) as previously described [25]. The medium was changed after 24 h and after 36 h the gels were raised to the liquid air interface in order to differentiate keratinocytes.…”

Section: Bi-layered Skin Substitutementioning

confidence: 99%