Deficiency in the LIM-only protein Fhl2 impairs skin wound healing

After skin wounding, the repair process is initiated by the release of growth factors, cytokines, and bioactive lipids from injured vessels and coagulated platelets. These signal molecules induce synthesis and deposition of a provisional extracellular matrix, as well as fibroblast invasion into and contraction of the wounded area. We previously showed that sphingosine-1-phosphate (S1P) triggers a signal transduction cascade mediating nuclear translocation of the LIM-only protein Fhl2 in response to activation of the RhoA GTPase (Muller, J.M., U. Isele, E. Metzger, A. Rempel, M. Moser, A. Pscherer, T. Breyer, C. Holubarsch, R. Buettner, and R. Schule. 2000. EMBO J. 19:359–369; Muller, J.M., E. Metzger, H. Greschik, A.K. Bosserhoff, L. Mercep, R. Buettner, and R. Schule. 2002. EMBO J. 21:736–748.). We demonstrate impaired cutaneous wound healing in Fhl2-deficient mice rescued by transgenic expression of Fhl2. Furthermore, collagen contraction and cell migration are severely impaired in Fhl2-deficient cells. Consequently, we show that the expression of α-smooth muscle actin, which is regulated by Fhl2, is reduced and delayed in wounds of Fhl2-deficient mice and that the expression of p130Cas, which is essential for cell migration, is reduced in Fhl2-deficient cells. In summary, our data demonstrate a function of Fhl2 as a lipid-triggered signaling molecule in mesenchymal cells regulating their migration and contraction during cutaneous wound healing.

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Activin B Promotes BMSC-Mediated Cutaneous Wound Healing by Regulating Cell Migration via the JNK—ERK Signaling Pathway

Cell Transplantation ◽

10.3727/096368913x666999 ◽

2014 ◽

Vol 23 (9) ◽

pp. 1061-1073 ◽

Cited By ~ 30

Author(s):

Min Zhang ◽

Li Sun ◽

Xueer Wang ◽

Shixuan Chen ◽

Yanan Kong ◽

...

Keyword(s):

Wound Healing ◽

Cell Migration ◽

Signaling Pathway ◽

Erk Signaling ◽

Cutaneous Wound Healing ◽

Cutaneous Wound

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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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Zebrafish Keratocyte Explants to Study Collective Cell Migration and Reepithelialization in Cutaneous Wound Healing

Journal of Visualized Experiments ◽

10.3791/52489 ◽

2015 ◽

Cited By ~ 1

Author(s):

Jose L. Rapanan ◽

Agnes S. Pascual ◽

Chandana K. Uppalapati ◽

Kimbal E. Cooper ◽

Kathryn J. Leyva ◽

...

Keyword(s):

Wound Healing ◽

Cell Migration ◽

Collective Cell Migration ◽

Cutaneous Wound Healing ◽

Cutaneous Wound

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Activities of MSCs Derived from Transgenic Mice Seeded on ADM Scaffolds in Wound Healing and Assessment by Advanced Optical Techniques

Cellular Physiology and Biochemistry ◽

10.1159/000477872 ◽

2017 ◽

Vol 42 (2) ◽

pp. 623-639 ◽

Cited By ~ 13

Author(s):

Ning Wang ◽

Hanping Liu ◽

Xuefeng Li ◽

Qilei Zhang ◽

Maosheng Chen ◽

...

Keyword(s):

Wound Healing ◽

Transgenic Mice ◽

Second Harmonic ◽

Smooth Muscle Actin ◽

Cutaneous Wound Healing ◽

Post Transplantation ◽

Dermal Matrix ◽

Double Labeling ◽

Cutaneous Wound ◽

Cell Numbers

Background/Aims: Bone marrow Mesenchymal stem cells (MSCs) are promising for promoting cutaneous wound healing through reinforcing cellular processes. We evaluated the effect of GFP-tagged MSCs transplantation on skin regeneration in excisional wounds in mice. Methods: MSCs from GFP-labeled transgenic mice were co-cultured with acellular dermal matrix (ADM) scaffolds, and MSC-ADM scaffolds were transplanted into surgical skin wounds of BALB/c mice. After implantation, the survival and behavior of MSCs were examined by second harmonic generation and two-photon excitation fluorescence imaging, western blotting and DNA amplification and sequencing. Results: GFP-tagged MSCs were retained inside the regenerating skin until day 14 post-transplantation. Alpha-smooth muscle actin (α-SMA) and vimentin (VIM) were detected at 3, 5, 7, and 14 days post-transplantation by immunofluorescence double labeling. Although the GFP+/α-SMA+- and GFP+/VIM+-cell numbers decreased gradually with healing time, α-SMA+- and VIM+-cell numbers significantly increased, most of them were endogenous functional cells which were related to angiogenesis and collagen fiber structural remodeling. Conclusion: Therefore, in the initial stage of wound healing, transplanted MSCs differentiated into functional cells and played paracrine roles to recruit more endogenous cells for tissue remodeling. With the disappearance of exogenous cells, endogenous cells were responsible for the latter stage of cutaneous wound healing.

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Delayed Re-Epithelialization in Periostin-Deficient Mice during Cutaneous Wound Healing

PLoS ONE ◽

10.1371/journal.pone.0018410 ◽

2011 ◽

Vol 6 (4) ◽

pp. e18410 ◽

Cited By ~ 77

Author(s):

Takashi Nishiyama ◽

Isao Kii ◽

Takeshi G. Kashima ◽

Yoshinao Kikuchi ◽

Atsushi Ohazama ◽

...

Keyword(s):

Wound Healing ◽

Cutaneous Wound Healing ◽

Cutaneous Wound ◽

Deficient Mice

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Exosomes from adipose-derived mesenchymal stem cells can promote fibroblasts proliferation, migration, and collagen synthesis via activating Wnt/β-catenin signaling pathway during wound healing

10.21203/rs.3.rs-520642/v1 ◽

2021 ◽

Author(s):

Yu An ◽

Cong Li ◽

Quanchen Xu ◽

Yu Sun ◽

Zhiguo Wang

Keyword(s):

Wound Healing ◽

Signaling Pathway ◽

Western Blotting ◽

Skin Wound ◽

Dependent Manner ◽

Cutaneous Wound Healing ◽

Skin Wound Healing ◽

Cutaneous Wound ◽

Dose Dependent ◽

Western Blotting Assay

Abstract Background Differentiation, migration, proliferation of skin fibroblasts are identified as the key factors during the cutaneous wound healing. Adipose-derived mesenchymal stem cells (ADMSCs) have been recorded as possible candidates for wound treatment because of their positive effect on the regeneration of many tissues. Exosomes derived from ADMSCs (ADMSC-Exos), an important signal transduction substance secreted by ADMSCs, have a similar role to ADMSCs in wound healing. However, the effects of ADMSC‐Exos on cutaneous wound healing remain to be unclear. In this study, we tried to explore the role and mechaninsm of ADMSC‐Exos during cutaneous wound healing. Methods Human skin fibroblasts (HSF) and ADMSCs were isolated from skin and adipose tissues of healthy person. ADMSC-Exos were purified from human ADMSCs culture medium by differential ultracentrifugation and identified by Electron microscopy, Nanoparticle tracking, and Western blotting assay. Fibroblasts were treated with different concentrations of ADMSC‐Exos. The proliferation and migration abilities of fibroblasts were analyzed by CCK-8 assay and scratch method. The synthesis of collagen type I (Col-I), collagen type III (Col-III), and α-smooth muscle actin (α-SMA) in fibroblasts was assessed by real-time quantitative polymerase chain reaction and Western blotting assay. A tensional wound model on rat back was used to evaluate the effect of ADMSC-Exos on wound healing. The expression levels of Wntb2 and β-catenin were analyzed by Western blotting and immunohistochemical assay. Results ADMSC-Exos were successfully obtained. ADMSC-Exos could significantly promote the migration and proliferation ability of fibroblasts in a dose-dependent manner in vitro. Compared with the treatment without ADMSC-Exos, the expression levels of Col-I and Col-III in fibroblasts treated with ADMSC-Exos were significantly increased, while the expression level of α-SMA is decreased. Besides, the enhanced expression of Wnt2b and β-catenin proteins confirmed the activation of the Wnt/β-catenin signaling pathway. Conclusions ADMSC-Exos can promote fibroblasts proliferation, migration, and collagen synthesis in a dose-dependent manner and may play a positive role in skin wound healing through Wnt/β-catenin signaling pathway. So our study elucidates part of the mechanism of ADMSC-Exos in wound healing, which illustrates the therapeutic potential of ADMSC-Exos as a new therapeutic approach to promote skin wound healing.

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