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Indirubin-pregnane X receptor-JNK axis accelerates skin wound healing.

ABSTRACT: Indirubin is a potent anti-inflammatory phytochemical derived from indigo naturalis. It is also endogenously produced in the intestine and detected in the circulation in mammals. Indirubin exerts its biological functions via two xenobiotic receptor systems: aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR); however, its effects on wound healing remain elusive. To investigate whether indirubin promotes wound healing, we utilized an in vitro scratch injury assay and in vivo full-thickness mouse skin ulcer model and assessed wound closure. Indirubin significantly accelerated wound closure in both the scratch assay and the skin ulcer model. Using inhibitors of cell proliferation or migration, indirubin was found to upregulate the migratory but not the proliferative capacity of keratinocytes. Activation of AHR/PXR by indirubin was confirmed by their nuclear translocation and subsequent upregulation of CYP1A1 (AHR), or UGT1A1 mRNA (PXR) and also by luciferase reporter assay (PXR). Although both AHR and PXR were activated by indirubin, its pro-migratory capacity was canceled by PXR inhibition but not by AHR inhibition and was dependent on the JNK pathway. Moreover, activated PXR was detected in the nuclei of re-epithelialized keratinocytes in human skin ulcers. In conclusion, this study shows that the indirubin-PXR-JNK pathway promotes skin wound healing.

SUBMITTER: Tanaka Y

PROVIDER: S-EPMC6890704 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Indirubin-pregnane X receptor-JNK axis accelerates skin wound healing.

Tanaka Yuka Y Uchi Hiroshi H Ito Takamichi T Furue Masutaka M

Scientific reports 20191203 1

Indirubin is a potent anti-inflammatory phytochemical derived from indigo naturalis. It is also endogenously produced in the intestine and detected in the circulation in mammals. Indirubin exerts its biological functions via two xenobiotic receptor systems: aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR); however, its effects on wound healing remain elusive. To investigate whether indirubin promotes wound healing, we utilized an in vitro scratch injury assay and in vivo full-thickn ...[more]

PMID: 31796845

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Project description:BackgroundThe secretomes of mesenchymal stem cells (MSCs) have great therapeutic potential and thereby their efficient delivery into the target site is of particular interest. Here, we propose a new strategy of hMSCs-derived secretomes delivery for advanced wound healing upon harnessing the working principle of extracellular matrix (ECM)-growth factors interaction in vivo.MethodsWe prepared an alginate hydrogel based wound patch, where it contains both human MSC-derived secretomes and ECM. The ECM was obtained from the decellularization of in vitro cultured human lung fibroblasts. The alginate solution was blended with ECM suspension, crosslinked, air-dried, then rehydrated with the secretomes contained in the concentrated conditioned media (CCM) as a highly saturated form of conditioned media (CM). We tested four different groups, with or without the ECM to investigate not only the role of ECM but the therapeutic effect of secretomes.ResultsThe secretomes reserved many, diverse bioactive factors, such as VEGF, HGF, IGFBPs, IL-6, and IL-8. Alginate/ECM/CCM (AEC) patch could hold significantly larger amount of secretomes and release them longer than the other groups. Our AEC patch was the most effective in stimulating not only cell migration and proliferation but the collagen synthesis of dermal fibroblasts in vitro. Moreover, the AEC patch-treated full-thickness skin wounds disclosed significantly better wound healing indications: cell recruitment, neovascularization, epidermis thickness, keratinocyte migration, and mature collagen deposition, as assessed via histology (H&E, Herovici staining) and immunofluorescence, respectively. In particular, our AEC patch enabled a phenotype shift of myofibroblast into fibroblast over time and led to mature blood vessel formation at 14 day.ConclusionsWe believe that ECM certainly contributed to generate a secretomes-enriched milieu via ECM-secretomes interactions and thereby such secretomes could be delivered more efficiently, exerting significant therapeutic impact either individually or collectively during wound healing process.

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Indirubin-pregnane X receptor-JNK axis accelerates skin wound healing.

Publications

Indirubin-pregnane X receptor-JNK axis accelerates skin wound healing.

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