Comment on “Topically Applied Connective Tissue Growth Factor/CCN2 Improves Diabetic Preclinical Cutaneous Wound Healing: Potential Role for CTGF in Human Diabetic Foot Ulcer Healing”

A recent paper in this journal, presented a novel method by topical application of growth factors in stimulating diabetic cutaneous wound healing that caught our attention. We believe that the experimental method in the article is efficient and creative, but it also has some controversies and shortcomings to be discussed. We noted that the authors used “Tegaderm” as a semiocclusive dressing film and stated that it exerted a “splinting effect” on the wound margins and controlled contraction. Indeed, the “Tegaderm” itself can serve as a dressing film to isolate the wound bed with outside environments while the “splinting effect” is mainly achieved by adding silicone splints around the wound. Considering the unique properties of silicone splints and “Tegaderm,” our experimental group propose an alternative method named “combined-suturing” technique that is not only suturing the silicone splints but also securing the “Tegaderm” around the wound. The specific reasons and operative procedures are explained in detail in this letter.

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Exosomes from adipose-derived stem cells overexpressing Nrf2 accelerate cutaneous wound healing by promoting vascularization in a diabetic foot ulcer rat model

Experimental & Molecular Medicine ◽

10.1038/s12276-018-0058-5 ◽

2018 ◽

Vol 50 (4) ◽

Cited By ~ 65

Author(s):

Xue Li ◽

Xiaoyun Xie ◽

Weishuai Lian ◽

Rongfeng Shi ◽

Shilong Han ◽

...

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Rat Model ◽

Diabetic Foot ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Adipose Derived Stem Cells ◽

Cutaneous Wound Healing ◽

Cutaneous Wound

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Endothelial cell-derived small extracellular vesicles suppress cutaneous wound healing through regulating fibroblasts autophagy

Clinical Science ◽

10.1042/cs20190008 ◽

2019 ◽

Vol 133 (9) ◽

Cited By ~ 2

Author(s):

Tingting Zeng ◽

Xiaoyi Wang ◽

Wei Wang ◽

Qiling Feng ◽

Guojuan Lao ◽

...

Keyword(s):

Wound Healing ◽

Endothelial Cell ◽

Extracellular Vesicles ◽

Diabetic Foot ◽

Collagen Synthesis ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Skin Fibroblasts ◽

Cutaneous Wound Healing ◽

Cutaneous Wound

Abstract Diabetic foot ulcer is a life-threatening clinical problem in diabetic patients. Endothelial cell-derived small extracellular vesicles (sEVs) are important mediators of intercellular communication in the pathogenesis of several diseases. However, the exact mechanisms of wound healing mediated by endothelial cell-derived sEVs remain unclear. sEVs were isolated from human umbilical vein endothelial cells (HUVECs) pretreated with or without advanced glycation end products (AGEs). The roles of HUVEC-derived sEVs on the biological characteristics of skin fibroblasts were investigated both in vitro and in vivo. We demonstrate that sEVs derived from AGEs-pretreated HUVECs (AGEs-sEVs) could inhibit collagen synthesis by activating autophagy of human skin fibroblasts. Additionally, treatment with AGEs-sEVs could delay the wound healing process in Sprague–Dawley (SD) rats. Further analysis indicated that miR-106b-5p was up-regulated in AGEs-sEVs and importantly, in exudate-derived sEVs from patients with diabetic foot ulcer. Consequently, sEV-mediated uptake of miR-106b-5p in recipient fibroblasts reduces expression of extracellular signal-regulated kinase 1/2 (ERK1/2), resulting in fibroblasts autophagy activation and subsequent collagen degradation. Collectively, our data demonstrate that miR-106b-5p could be enriched in AGEs-sEVs, then decreases collagen synthesis and delays cutaneous wound healing by triggering fibroblasts autophagy through reducing ERK1/2 expression.

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M2-Polarized Macrophages Mediate Wound Healing by Regulating Connective Tissue Growth Factor via AKT, ERK 1/2, and STAT 3 Signaling Pathways

10.21203/rs.3.rs-624342/v1 ◽

2021 ◽

Author(s):

Si-Min Zhang ◽

Chuan-Yuan Wei ◽

Qiang Wang ◽

Lu Wang ◽

Lu Lu ◽

...

Keyword(s):

Wound Healing ◽

Tissue Growth ◽

Cutaneous Wound Healing ◽

M2 Macrophages ◽

Cutaneous Wound ◽

Stat3 Signaling ◽

M2 Polarization ◽

Stat3 Signaling Pathway ◽

And Migration ◽

Proliferation And Migration

Abstract Background: Timely and sufficient recruitment of M1 macrophages and M2 polarization are necessary for fibrous repair during cutaneous wound healing. The inherent mechanism of how M2 polarization mediate wound healing is worth exploring and illustrating. Abnormally up-regulated connective tissue growth factor (CTGF) is closely related with multiple organ fibrosis, including cardiac, pulmonary, hepatic, renal, and cutaneous fibrosis. Previous studies have reported that M2-polarized macrophages contribute to hepatic and renal fibrosis by secreting CTGF. It is worth discussing if M2 macrophages regulate fibrosis through secreting CTGF in cutaneous wound healing.Methods: We established the murine full-thickness excisional wound model and inhibited macrophages during proliferation phase (mainly M2 and M1-M2 polarization) with clodronate liposomes to analyze how M2 macrophages mediate wound healing rates, collagen deposition, collagen 1/3 expression, and Ki67 expression in vivo. Furthermore, M2 polarization was induced by IL-4 and in vitro. F4/80+CD206+ M2 macrophages were measured by flow cytometry. The morphological characteristics were observed. Secretion of IL-6, TNF-α, IL-10, TGF-β1, and CTGF was tested by ELISA. CTGF gene of M2 was blocked using siCTGF. Effects of M2 on proliferation and migration of fibroblasts were detected by CCK8 and cellular wound healing assay. Protein level of AKT, ERK1/2, and STAT3 pathway were assessed by western blotting.Results: Depletion of macrophages at proliferation phase (mainly M2 and M1-M2 polarization) resulted in delayed cutaneous wound closure and down-regulation of wound healing rates, collagen deposition, collagen 1/3 expression, and Ki67 expression. M2 polarization was induced, which producing more CTGF, TGF-β1, and IL-6, as well as less TNF-α and IL-10. Blockade of CTGF in M2 macrophages deactivated fibroblast proliferation and migration. Addition of recombinant CTGF restored the promotional effects of M2 macrophages on fibroblast proliferation and migration. Blockade of CTGF in M2 mediate fibroblasts via down-regulating AKT, ERK1/2, and STAT3 signaling pathway.Conclusion: Our research, for the first time, indicated that M2-polarized macrophages promoted cutaneous wound healing by secreting CTGF, which further mediating proliferation and migration of fibroblasts via AKT, ERK1/2, and STAT3 signaling pathway.

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Gypenoside LXXV Promotes Cutaneous Wound Healing In Vivo by Enhancing Connective Tissue Growth Factor Levels Via the Glucocorticoid Receptor Pathway

Molecules ◽

10.3390/molecules24081595 ◽

2019 ◽

Vol 24 (8) ◽

pp. 1595 ◽

Cited By ~ 7

Author(s):

Sungjoo Park ◽

Eunsu Ko ◽

Jun Hyoung Lee ◽

Yoseb Song ◽

Chang-Hao Cui ◽

...

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Connective Tissue ◽

Wound Closure ◽

Tissue Growth ◽

Cutaneous Wound Healing ◽

Cutaneous Wound ◽

And Migration ◽

Proliferation And Migration

Cutaneous wound healing is a well-orchestrated event in which many types of cells and growth factors are involved in restoring the barrier function of skin. In order to identify whether ginsenosides, the main active components of Panax ginseng, promote wound healing, the proliferation and migration activities of 15 different ginsenosides were tested by MTT assay and scratched wound closure assay. Among ginsenosides, gypenoside LXXV (G75) showed the most potent wound healing effects. Thus, this study aimed to investigate the effects of G75 on wound healing in vivo and characterize associated molecular changes. G75 significantly increased proliferation and migration of keratinocytes and fibroblasts, and promoted wound closure in an excision wound mouse model compared with madecassoside (MA), which has been used to treat wounds. Additionally, RNA sequencing data revealed G75-mediated significant upregulation of connective tissue growth factor (CTGF), which is known to be produced via the glucocorticoid receptor (GR) pathway. Consistently, the increase in production of CTGF was confirmed by western blot and ELISA. In addition, GR-competitive binding assay and GR translocation assay results demonstrated that G75 can be bound to GR and translocated into the nucleus. These results demonstrated that G75 is a newly identified effective component in wound healing.

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Dracorhodin Perchlorate Accelerates Cutaneous Wound Healing in Wistar Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/8950516 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Xiao-wen Jiang ◽

Lu Qiao ◽

Lin Liu ◽

Bin-qing Zhang ◽

Xue-wei Wang ◽

...

Keyword(s):

Wound Healing ◽

Wistar Rats ◽

Inflammatory Responses ◽

Tissue Growth ◽

Control Treatment ◽

Cutaneous Wound Healing ◽

Cutaneous Wound ◽

Dragon’S Blood ◽

Biochemical Analyses ◽

Dracorhodin Perchlorate

Dracorhodin perchlorate (DP) is extracted from Dragon’s blood, which is widely used in traditional Chinese medicine, especially in wound healing. The aim of this paper is to investigate the influence of DP ointment, which contained DP dissolved in DMSO and mixed with Vaseline, on cutaneous wound healing in Wistar rats. Forty Wistar rats were divided into two groups: control and DP groups. The skin on the back of each rat was punched with two full-thickness wounds and then treated with the corresponding drug. After 3, 7, 10, 14, and 21 days, four rats were sacrificed for immunological, biochemical, and histological analyses. Compared with the control treatment, DP could significantly promote wound closure. Histological and biochemical analyses of the skin biopsies also showed that DP regulated the expression of inflammatory responses by TNF-α and IL-β and by supporting wound tissue growth and collagen deposition. Western blot revealed that DP could also facilitate the expression of EGF and VEGF proteins. In conclusion, DP promotes wound healing.

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Study on the Effect of Cerium Oxide Nanocubes on Full-Thickness Cutaneous Wound Healing of Type 2 Diabetic Rats

Diabetes ◽

10.2337/db18-643-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 643-P ◽

Cited By ~ 2

Author(s):

YANFEI HAN ◽

LINDONG LI ◽

YANJUN LIU ◽

YOU WANG ◽

CHUNHUA YAN ◽

...

Keyword(s):

Wound Healing ◽

Cerium Oxide ◽

Diabetic Rats ◽

Cutaneous Wound Healing ◽

Full Thickness ◽

Cutaneous Wound ◽

Type 2 Diabetic

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Faculty Opinions recommendation of The role of neuromediators and innervation in cutaneous wound healing.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726019673.793517674 ◽

2016 ◽

Author(s):

Rayaz Malik

Keyword(s):

Wound Healing ◽

Cutaneous Wound Healing ◽

Cutaneous Wound

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Short Report: The Moisture Balance with Aloe Vera Gel in Diabetic Wound Healing

International Journal of Nursing and Health Services (IJNHS) ◽

10.35654/ijnhs.v1i1.9 ◽

2018 ◽

Vol 1 (1) ◽

pp. 21-23

Author(s):

Fahrianto Selamet ◽

Andi Mayasari Usman ◽

Rian Adi Pamungkas

Keyword(s):

Diabetes Mellitus ◽

Wound Healing ◽

Wound Care ◽

Aloe Vera ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Short Report ◽

Bacterial Reduction ◽

Moisture Balance ◽

Patients With Diabetes

Diabetic foot ulcer (DF) is a chronic complication of diabetes mellitus (DM), which impact on the morbidity, mortality and quality of patients’ lives.Of those patients with diabetes mellitus, approximately 15% to 25% developed to the foot ulcer. Beside has the infection and debridement of devitalized tissue downloading; the moisture imbalance becomes the factors of recalcitrant to healing. Moist wound healing is often contraindicated to the non-healable wounds. While wound care involves the debridement, bacterial reduction, and moisture balance in order to achieve the good granulation of the tissue development and adequate blood supply.

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