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

AbstractIndirubin 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.

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Overexpression of the Oral Mucosa-Specific microRNA-31 Promotes Skin Wound Closure

International Journal of Molecular Sciences ◽

10.3390/ijms20153679 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3679 ◽

Cited By ~ 3

Author(s):

Lin Chen ◽

Alyne Simões ◽

Zujian Chen ◽

Yan Zhao ◽

Xinming Wu ◽

...

Keyword(s):

Wound Healing ◽

Oral Mucosa ◽

Wound Closure ◽

Expression Patterns ◽

Skin Wound ◽

Skin Wound Healing ◽

Specific Expression ◽

Keratinocyte Proliferation

Wounds within the oral mucosa are known to heal more rapidly than skin wounds. Recent studies suggest that differences in the microRNAome profiles may underlie the exceptional healing that occurs in oral mucosa. Here, we test whether skin wound-healing can be accelerating by increasing the levels of oral mucosa-specific microRNAs. A panel of 57 differentially expressed high expresser microRNAs were identified based on our previously published miR-seq dataset of paired skin and oral mucosal wound-healing [Sci. Rep. (2019) 9:7160]. These microRNAs were further grouped into 5 clusters based on their expression patterns, and their differential expression was confirmed by TaqMan-based quantification of LCM-captured epithelial cells from the wound edges. Of these 5 clusters, Cluster IV (consisting of 8 microRNAs, including miR-31) is most intriguing due to its tissue-specific expression pattern and temporal changes during wound-healing. The in vitro functional assays show that ectopic transfection of miR-31 consistently enhanced keratinocyte proliferation and migration. In vivo, miR-31 mimic treatment led to a statistically significant acceleration of wound closure. Our results demonstrate that wound-healing can be enhanced in skin through the overexpression of microRNAs that are highly expressed in the privileged healing response of the oral mucosa.

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Carbonic Anhydrase VI in Skin Wound Healing Study on Car6 Knockout Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21145092 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5092

Author(s):

Toini Pemmari ◽

Jaakko Laakso ◽

Maarit S. Patrikainen ◽

Seppo Parkkila ◽

Tero A. H. Järvinen

Keyword(s):

Wound Healing ◽

Knockout Mice ◽

Wound Closure ◽

Skin Wound ◽

Carbonic Anhydrases ◽

Skin Wound Healing ◽

Tumor Cell Migration ◽

Treatment Groups ◽

Thickness Skin ◽

Carbonic Anhydrase Vi

Carbonic anhydrases (CAs) contribute to tumor cell migration by generating an acidic environment through the conversion of carbon dioxide to bicarbonate and a proton. CA VI is secreted to milk and saliva, and it could contribute to wound closure, as a potential trophic factor, in animals that typically lick their wounds. Our aim was to investigate whether human CA VI improves skin-wound healing in full-thickness skin-wound models. The effect was studied in Car6 −/− knockout mice and wild type littermates. Half of both mice strains were given topically administered, milk-derived CA VI after wounding and eight hours later. The amount of topically given CA VI exceeded the predicted amount of natural saliva-delivered CA VI. The healing was followed for seven days and studied from photographs and histological sections. Our results showed no significant differences between the treatment groups in wound closure, re-epithelization, or granulation tissue formation, nor did the Car6 genotype affect the healing. Our results demonstrate that CA VI does not play a major role in skin-wound healing and also suggest that saliva-derived CA VI is not responsible for the licking-associated improved wound healing in animals.

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In vivo Optical Coherence Tomography of Mouse Skin Wound Healing

10.1364/biomed.2008.pdpbtug2 ◽

2008 ◽

Author(s):

Zhijia Yuan ◽

Julia Zakehaleva ◽

Hugang Ren ◽

Weiliam Chen ◽

Yingtian Pan

Keyword(s):

Wound Healing ◽

Optical Coherence Tomography ◽

Mouse Skin ◽

Skin Wound ◽

Optical Coherence ◽

Skin Wound Healing

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Effect of Combining Low Temperature Plasma, Negative Pressure Wound Therapy, and Bone Marrow Mesenchymal Stem Cells on an Acute Skin Wound Healing Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms21103675 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3675 ◽

Cited By ~ 1

Author(s):

Hui Song Cui ◽

So Young Joo ◽

Yoon Soo Cho ◽

Ji Heon Park ◽

June-Bum Kim ◽

...

Keyword(s):

Wound Healing ◽

Combination Therapy ◽

Wound Closure ◽

Negative Pressure Wound Therapy ◽

Skin Wound ◽

Low Temperature Plasma ◽

Wound Therapy ◽

Skin Wound Healing ◽

Temperature Plasma ◽

Marrow Mesenchymal Stem Cells

Low-temperature plasma (LTP; 3 min/day), negative pressure wound therapy (NPWT; 4 h/day), and bone marrow mesenchymal stem cells (MSCs; 1 × 106 cells/day) were used as mono- and combination therapy in an acute excisional skin wound-healing ICR mouse model. These therapies have been beneficial in treating wounds. We investigated the effectiveness of monotherapy with LTP, NPWT, and MSC and combination therapy with LTP + MSC, LTP + NPWT, NPWT + MSC, and LTP + NPWT + MSC on skin wounds in mice for seven consecutive days. Gene expression, protein expression, and epithelial thickness were analyzed using real time polymerase chain reaction (RT-qPCR), western blotting, and hematoxylin and eosin staining (H&E), respectively. Wound closure was also evaluated. Wound closure was significantly accelerated in monotherapy groups, whereas more accelerated in combination therapy groups. Tumor necrosis factor-α (TNF-α) expression was increased in the LTP monotherapy group but decreased in the NPWT, MSC, and combination therapy groups. Expressions of vascular endothelial growth factor (VEGF), α-smooth muscle actin (α-SMA), and type I collagen were increased in the combination therapy groups. Re-epithelialization was also considerably accelerated in combination therapy groups. Our findings suggest that combination therapy with LPT, NPWT, and MSC exert a synergistic effect on wound healing, representing a promising strategy for the treatment of acute wounds.

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SOCS3 Negatively Regulates the gp130–STAT3 Pathway in Mouse Skin Wound Healing

Journal of Investigative Dermatology ◽

10.1038/sj.jid.5701224 ◽

2008 ◽

Vol 128 (7) ◽

pp. 1821-1829 ◽

Cited By ~ 38

Author(s):

Bing-Mei Zhu ◽

Yuko Ishida ◽

Gertraud W. Robinson ◽

Margit Pacher-Zavisin ◽

Akihiko Yoshimura ◽

...

Keyword(s):

Wound Healing ◽

Mouse Skin ◽

Skin Wound ◽

Skin Wound Healing ◽

Stat3 Pathway

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The Phytochemical Shikonin Stimulates Epithelial-Mesenchymal Transition (EMT) in Skin Wound Healing

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/262796 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 19

Author(s):

Shu-Yi Yin ◽

An-Ping Peng ◽

Li-Ting Huang ◽

Ya-Ting Wang ◽

Chun-Wen Lan ◽

...

Keyword(s):

Wound Healing ◽

Topical Treatment ◽

Immune Modulation ◽

Epithelial Mesenchymal Transition ◽

Mouse Skin ◽

Molecular Data ◽

Skin Wound ◽

Skin Wound Healing ◽

Mesenchymal Transition

Although various pharmacological activities of the shikonins have been documented, understanding the hierarchical regulation of these diverse bioactivities at the genome level is unsubstantiated. In this study, through cross examination between transcriptome and microRNA array analyses, we predicted that topical treatment of shikoninin vivoaffects epithelial-mesenchymal transition (EMT) and the expression of related microRNAs, including 200a, 200b, 200c, 141, 205, and 429 microRNAs, in mouse skin tissues.In situimmunohistological analyses further demonstrated that specific EMT regulatory molecules are enhanced in shikonin-treated epidermal tissues. RT-PCR analyses subsequently confirmed that shikonin treatment downregulated expression of microRNA-205 and other members of the 200 family microRNAs. Further, expression of two RNA targets of the 200 family microRNAs in EMT regulation, Sip1 (Zeb2) and Tcf8 (Zeb1), was consistently upregulated by shikonin treatment. Enhancement of these EMT activities was also detected in shikonin-treated wounds, which repaired faster than controls. These results suggest that topical treatment with shikonin can confer a potent stimulatory effect on EMT and suppress the expression of the associated microRNAs in skin wound healing. Collectively, these cellular and molecular data provide further evidence in support of our previous findings on the specific pharmacological effects of shikonin in wound healing and immune modulation.

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Bioinspired mechanically active adhesive dressings to accelerate wound closure

Science Advances ◽

10.1126/sciadv.aaw3963 ◽

2019 ◽

Vol 5 (7) ◽

pp. eaaw3963 ◽

Cited By ~ 61

Author(s):

S. O. Blacklow ◽

J. Li ◽

B. R. Freedman ◽

M. Zeidi ◽

C. Chen ◽

...

Keyword(s):

Wound Healing ◽

Wound Closure ◽

Healing Process ◽

Skin Wound ◽

Wound Management ◽

In Vivo Studies ◽

Skin Wound Healing ◽

Accelerate Wound Healing

Inspired by embryonic wound closure, we present mechanically active dressings to accelerate wound healing. Conventional dressings passively aid healing by maintaining moisture at wound sites. Recent developments have focused on drug and cell delivery to drive a healing process, but these methods are often complicated by drug side effects, sophisticated fabrication, and high cost. Here, we present novel active adhesive dressings consisting of thermoresponsive tough adhesive hydrogels that combine high stretchability, toughness, tissue adhesion, and antimicrobial function. They adhere strongly to the skin and actively contract wounds, in response to exposure to the skin temperature. In vitro and in vivo studies demonstrate their efficacy in accelerating and supporting skin wound healing. Finite element models validate and refine the wound contraction process enabled by these active adhesive dressings. This mechanobiological approach opens new avenues for wound management and may find broad utility in applications ranging from regenerative medicine to soft robotics.

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Apoptotic bodies derived from mesenchymal stem cells promote cutaneous wound healing via regulating the functions of macrophages

Stem Cell Research & Therapy ◽

10.1186/s13287-020-02014-w ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Jin Liu ◽

Xinyu Qiu ◽

Yajie Lv ◽

Chenxi Zheng ◽

Yan Dong ◽

...

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Mesenchymal Stem Cells ◽

Mouse Skin ◽

Skin Wound ◽

Therapeutic Effects ◽

Cutaneous Wound Healing ◽

Apoptotic Bodies ◽

Skin Wound Healing ◽

Cutaneous Wound

Abstract Background As the major interface between the body and the external environment, the skin is liable to various injuries. Skin injuries often lead to severe disability, and the exploration of promising therapeutic strategies is of great importance. Exogenous mesenchymal stem cell (MSC)-based therapy is a potential strategy due to the apparent therapeutic effects, while the underlying mechanism is still elusive. Interestingly, we observed the extensive apoptosis of exogenous bone marrow mesenchymal stem cells (BMMSCs) in a short time after transplantation in mouse skin wound healing models. Considering the roles of extracellular vesicles (EVs) in intercellular communication, we hypothesized that the numerous apoptotic bodies (ABs) released during apoptosis may partially contribute to the therapeutic effects. Methods ABs derived from MSCs were extracted, characterized, and applied in mouse skin wound healing models, and the therapeutic effects were evaluated. Then, the target cells of ABs were explored, and the effects of ABs on macrophages were investigated in vitro. Results We found ABs derived from MSCs promoted cutaneous wound healing via triggering the polarization of macrophages towards M2 phenotype. In addition, the functional converted macrophages further enhanced the migration and proliferation abilities of fibroblasts, which together facilitated the wound healing process. Conclusions Collectively, our study demonstrated that transplanted MSCs promoted cutaneous wound healing partially through releasing apoptotic bodies which could convert the macrophages towards an anti-inflammatory phenotype that plays a crucial role in the tissue repair process.

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Sphingosine-1-Phosphate Facilitates Skin Wound Healing by Increasing Angiogenesis and Inflammatory Cell Recruitment with Less Scar Formation

International Journal of Molecular Sciences ◽

10.3390/ijms20143381 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3381 ◽

Cited By ~ 10

Author(s):

Masayo Aoki ◽

Hiroaki Aoki ◽

Partha Mukhopadhyay ◽

Takuya Tsuge ◽

Hirofumi Yamamoto ◽

...

Keyword(s):

Wound Healing ◽

Wound Closure ◽

Inflammatory Cell ◽

Skin Wound ◽

Sphingosine Kinase 1 ◽

Related Factors ◽

Skin Wound Healing ◽

Cell Recruitment ◽

Sphingosine 1 Phosphate ◽

Inflammatory Cell Recruitment

Wound healing starts with the recruitment of inflammatory cells that secrete wound-related factors. This step is followed by fibroblast activation and tissue construction. Sphingosine-1-phosphate (S1P) is a lipid mediator that promotes angiogenesis, cell proliferation, and attracts immune cells. We investigated the roles of S1P in skin wound healing by altering the expression of its biogenic enzyme, sphingosine kinase-1 (SphK1). The murine excisional wound splinting model was used. Sphingosine kinase-1 (SphK1) was highly expressed in murine wounds and that SphK1−/− mice exhibit delayed wound closure along with less angiogenesis and inflammatory cell recruitment. Nanoparticle-mediated topical SphK1 overexpression accelerated wound closure, which associated with increased angiogenesis, inflammatory cell recruitment, and various wound-related factors. The SphK1 overexpression also led to less scarring, and the interaction between transforming growth factor (TGF)-β1 and S1P receptor-2 (S1PR2) signaling is likely to play a key role. In summary, SphK1 play important roles to strengthen immunity, and contributes early wound healing with suppressed scarring. S1P can be a novel therapeutic molecule with anti-scarring effect in surgical, trauma, and chronic wound management.

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