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Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice.

ABSTRACT: Impaired wound healing is a major source of morbidity in diabetic patients. Poor outcome has, in part, been related to increased inflammation, poor angiogenesis, and deficiencies in extracellular matrix components. Despite the enormous impact of these chronic wounds, effective therapies are lacking. Here, we showed that the topical application of recombinant matricellular protein angiopoietin-like 4 (ANGPTL4) accelerated wound reepithelialization in diabetic mice, in part, by improving angiogenesis. ANGPTL4 expression is markedly elevated upon normal wound injury. In contrast, ANGPTL4 expression remains low throughout the healing period in diabetic wounds. Exogenous ANGPTL4 modulated several regulatory networks involved in cell migration, angiogenesis, and inflammation, as evidenced by an altered gene expression signature. ANGPTL4 influenced the expression profile of endothelial-specific CD31 in diabetic wounds, returning its profile to that observed in wild-type wounds. We showed ANGPTL4-induced nitric oxide production through an integrin/JAK/STAT3-mediated upregulation of inducible nitric oxide synthase (iNOS) expression in wound epithelia, thus revealing a hitherto unknown mechanism by which ANGPTL4 regulated angiogenesis via keratinocyte-to-endothelial-cell communication. These data show that the replacement of ANGPTL4 may be an effective adjunctive or new therapeutic avenue for treating poor healing wounds. The present finding also confirms that therapeutic angiogenesis remains an attractive treatment modality for diabetic wound healing.

SUBMITTER: Chong HC

PROVIDER: S-EPMC4435481 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice.

Chong Han Chung HC Chan Jeremy Soon Kiat JS Goh Chi Qin CQ Gounko Natalia V NV Luo Baiwen B Wang Xiaoling X Foo Selin S Wong Marcus Thien Chong MT Choong Cleo C Kersten Sander S Tan Nguan Soon NS

Molecular therapy : the journal of the American Society of Gene Therapy 20140606 9

Impaired wound healing is a major source of morbidity in diabetic patients. Poor outcome has, in part, been related to increased inflammation, poor angiogenesis, and deficiencies in extracellular matrix components. Despite the enormous impact of these chronic wounds, effective therapies are lacking. Here, we showed that the topical application of recombinant matricellular protein angiopoietin-like 4 (ANGPTL4) accelerated wound reepithelialization in diabetic mice, in part, by improving angiogene ...[more]

PMID: 24903577

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Project description:BackgroundReactive oxygen species (ROS) are increased in diabetic conditions and play a causal role in diabetic foot ulcers (DFU). We previously showed that ROS up-regulate miR-200c expression, that in turns causes apoptosis, senescence, ROS upregulation and nitric oxide decrease, leading to endothelial disfunction.MethodsThe aim of this study is to dissect miR-200c role in DFU and to explore the potential role of anti-miR-200c and antioxidant catalase (CAT) in promoting wound healing (WH). miR-200c inhibition and CAT treatment were performed either in immortalized keratinocytes (HaCaT) or in primary fibroblasts (FBs) and keratinocytes (KCs) deriving from diabetic patients (pts) undergoing amputations. Primary cells deriving from pts undergoing saphenectomies were used as controls. The miR-200c blockade was performed either via lentiviral particles bearing an anti-miR-200c sequence or locked nucleic acid (LNA) anti-miR-200c oligos. Equine CAT was administered on cell medium. The WH assay was performed in vivo on diabetic (db/db) mice by a topical treatment with CAT and LNA anti-miR-200c on wounds dissolved in a Pluronic gel mixture, administered every three days.ResultsWe found that miR-200c levels were increased by different stimuli known to induce ROS, such as ultraviolet radiation (UV), hydrogen peroxide (H2O2), and high glucose in HaCaT. miR-200c was also upregulated in skin biopsies, in FBs and KCs isolated from pts with DFU vs controls. Forced miR-200c expression induced ROS in both FBs and KCs, and CAT reduced it. miR-200c inhibition improved WH in HaCaT, both under basal conditions and after UV and H2O2 treatment, and the simultaneous treatment with CAT accelerated it. miR-200c inhibition accelerated WH in KCs of DFU pts, increasing its protein targets: sirtuin 1 (SIRT1), the transcription factors FOXO1 and ZEB1 and decreasing p66Shc phosphorylation at Ser-36, that is induced by ROS, and the co-treatment with CAT showed synergistic effects in reducing ROS and cytotoxicity. Interestingly, CAT treatment decreased miR-200c expression in FBs and KCs of DFU pts. Topical administration of anti-miR-200c and CAT in a WH model of diabetic mice accelerated closure.ConclusionsAnti-miR-200c and CAT could be considered a novel treatment for DFU and, possibly, for other types of non-diabetic skin ulcers.

Project description:BackgroundPlatelet-rich plasma (PRP), which is prepared by concentrating platelets in autologous blood, shows efficacy in chronic skin wounds via multiple growth factors. However, it exhibits heterogeneity across patients, leading to unstable therapeutic efficacy. Human induced pluripotent stem cell (iPSC)-derived megakaryocytes and platelets (iMPs) are capable of providing a stable supply, holding promise as materials for novel platelet concentrate-based therapies. In this context, we evaluated the effect of iMPs on wound healing and validated lyophilization for clinical applications.MethodsThe growth factors released by activated iMPs were measured. The effect of the administration of iMPs on human fibroblasts and human umbilical vein endothelial cells (HUVECs) was investigated in vitro. iMPs were applied to dorsal skin defects of diabetic mice to assess the wound closure rate and quantify collagen deposition and angiogenesis. Following the storage of freeze-dried iMPs (FD-iMPs) for three months, the stability of growth factors and their efficacy in animal models were determined.ResultMultiple growth factors that promote wound healing were detected in activated iMPs. iMPs specifically released FGF2 and exhibited a superior enhancement of HUVEC proliferation compared to PRP. Moreover, an RNA-seq analysis revealed that iMPs induce polarization to stalk cells and enhance ANGPTL4 gene expression in HUVECs. Animal studies demonstrated that iMPs promoted wound closure and angiogenesis in chronic wounds caused by diabetes. We also confirmed the long-term stability of growth factors in FD-iMPs and their comparable effects to those of original iMPs in the animal model.ConclusionOur study demonstrates that iMPs promote angiogenesis and wound healing through the activation of vascular endothelial cells. iMPs exhibited more effectiveness than PRP, an effect attributed to the exclusive presence of specific factors including FGF2. Lyophilization enabled the long-term maintenance of the composition of the growth factors and efficacy of the iMPs, therefore contributing to stable supply for clinical application. These findings suggest that iMPs provide a novel treatment for chronic wounds.

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Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice.

Publications

Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice.

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