Agrin-Matrix Metalloproteinase-12 axis confers a mechanically competent microenvironment in skin wound healing

Chakraborty, Sanjoy; Sampath, Divyaleka; Lin, Melissa; Bilton, Matthew; Huang, Cheng-Kuang; Nai, Mui Hoon; Njah, Kizito; Goy, Pierre-Alexis; Wang, Cheng-Chun; Guccione, Ernesto; Lim, Chin Tat; Hong, Wanjin

doi:10.1038/s41467-021-26717-7

Cited by 32 publications

(18 citation statements)

References 75 publications

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“…The emergence of regenerated hair follicles and dermal papilla in the center of the wound area (Fig. 4C–l ) may suggest that ADSCs embedded in the DA-MeHA hydrogel significantly accelerated skin remodeling [ 16 ]. ADSCs encapsulated by the DA-MeHA hydrogel may differentiate into primary mesenchymal cells, accelerate the regeneration of surrounding hair follicles, and simultaneously induce new blood vessel generation.…”

Section: Discussionmentioning

confidence: 99%

“…Cells probe the stiffness of their niche using mechanotransduction to interact with the ECM and surrounding cells, sense mechanical perturbations, and transmit environmental pressure to modulate their behaviors [ 15 ]. In addition to functions of cell scaffolding, the ECM serves as a dynamic communicative plane to its circumambient cells in the tissue to maintain tissue integrity [ 16 ]. Hydrogels are characterized by unique hydrated networks and physicochemical properties and have been widely used as scaffolds for cell therapies based on their ability to mimic the ECM [ 13 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

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A dopamine-methacrylated hyaluronic acid hydrogel as an effective carrier for stem cells in skin regeneration therapy

Gong

Yan

et al. 2022

Cell Death Dis

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Adipose-derived stem cells (ADSCs) show potential in skin regeneration research. A previous study reported the failure of full-thickness skin self-repair in an injury area exceeding 4 cm in diameter. Stem cell therapies have shown promise in accelerating skin regeneration; however, the low survival rate of transplanted cells due to the lack of protection during and after transplantation leads to low efficacy. Hence, effective biomaterials for the delivery and retention of ADSCs are urgently needed for skin regeneration purposes. Here, we covalently crosslinked hyaluronic acid with methacrylic anhydride and then covalently crosslinked the product with dopamine to engineer dopamine-methacrylated hyaluronic acid (DA-MeHA). Our experiments suggested that the DA-MeHA hydrogel firmly adhered to the skin wound defect and promoted cell proliferation in vitro and skin defect regeneration in vivo. Mechanistic analyses revealed that the beneficial effect of the DA-MeHA hydrogel combined with ADSCs on skin defect repair may be closely related to the Notch signaling pathway. The ADSCs from the DA-MeHA hydrogel secrete high levels of growth factors and are thus highly efficacious for promoting skin wound healing. This DA-MeHA hydrogel may be used as an effective potential carrier for stem cells as it enhances the efficacy of ADSCs in skin regeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A dopamine-methacrylated hyaluronic acid hydrogel as an effective carrier for stem cells in skin regeneration therapy

Gong

Yan

et al. 2022

Cell Death Dis

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“…Apart from MMP1 and MMP3 , MMP12 and MMP9 were upregulated. MMP-12 appears to play a key role in cytoskeletal rearrangements in migrating keratinocytes [ 35 ]. MMP-9 protein increases during suction blister wound healing [ 7 , 11 ].…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Linked to Reepithelialization of Human Skin Wounds

Ågren

Litman

Eriksen

et al. 2022

IJMS

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Our understanding of the regulatory processes of reepithelialization during wound healing is incomplete. In an attempt to map the genes involved in epidermal regeneration and differentiation, we measured gene expression in formalin-fixed, paraffin-embedded standardized epidermal wounds induced by the suction-blister technique with associated nonwounded skin using NanoString technology. The transcripts of 139 selected genes involved in clotting, immune response to tissue injury, signaling pathways, cell adhesion and proliferation, extracellular matrix remodeling, zinc transport and keratinocyte differentiation were evaluated. We identified 22 upregulated differentially expressed genes (DEGs) in descending order of fold change (MMP1, MMP3, IL6, CXCL8, SERPINE1, IL1B, PTGS2, HBEGF, CXCL5, CXCL2, TIMP1, CYR61, CXCL1, MMP12, MMP9, HGF, CTGF, ITGB3, MT2A, FGF7, COL4A1 and PLAUR). The expression of the most upregulated gene, MMP1, correlated strongly with MMP3 followed by IL6 and IL1B. rhIL-1β, but not rhIL-6, exposure of cultured normal human epidermal keratinocytes and normal human dermal fibroblasts increased both MMP1 mRNA and MMP-1 protein levels, as well as TIMP1 mRNA levels. The increased TIMP1 in wounds was validated by immunohistochemistry. The six downregulated DEGs (COL7A1, MMP28, SLC39A2, FLG1, KRT10 and FLG2) were associated with epidermal maturation. KLK8 showed the strongest correlation with MKI67 mRNA levels and is a potential biomarker for keratinocyte proliferation. The observed gene expression changes correlate well with the current knowledge of physiological reepithelialization. Thus, the gene expression panel described in this paper could be used in patients with impaired healing to identify possible therapeutic targets.

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“…MMP-7 is responsible for stimulating the process of re-epithelialization ( Letra et al, 2013 ). MMP-12 is induced by Agrin and mediates collective migration due to enhanced local inflammation ( Aristorena et al, 2019 ; Chakraborty et al, 2021 ). Although chronic cutaneous wounds in humans have not been extensively studied, these MMPs play a key part in wound healing because of their ability to influence variety of cellular processes and activate other MMPs.…”

Section: Mmps In Dfusmentioning

confidence: 99%

Role of matrix metalloproteinases in diabetic foot ulcers: Potential therapeutic targets

Zheng

Chen

et al. 2022

Front. Pharmacol.

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Diabetic foot ulcers (DFUs) are pathological states of tissue destruction of the foot or lower extremity in diabetic patients and are one of the serious chronic complications of diabetes mellitus. Matrix metalloproteinases (MMPs) serve crucial roles in both pathogenesis and wound healing. The primary functions of MMPs are degradation, which involves removing the disrupted extracellular matrix (ECM) during the inflammatory phase, facilitating angiogenesis and cell migration during the proliferation phase, and contracting and rebuilding the tissue during the remodeling phase. Overexpression of MMPs is a feature of DFUs. The upregulated MMPs in DFUs can cause excessive tissue degradation and impaired wound healing. Regulation of MMP levels in wounds could promote wound healing in DFUs. In this review, we talk about the roles of MMPs in DFUs and list potential methods to prevent MMPs from behaving in a manner detrimental to wound healing in DFUs.

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Agrin-Matrix Metalloproteinase-12 axis confers a mechanically competent microenvironment in skin wound healing

Cited by 32 publications

References 75 publications

A dopamine-methacrylated hyaluronic acid hydrogel as an effective carrier for stem cells in skin regeneration therapy

A dopamine-methacrylated hyaluronic acid hydrogel as an effective carrier for stem cells in skin regeneration therapy

Gene Expression Linked to Reepithelialization of Human Skin Wounds

Role of matrix metalloproteinases in diabetic foot ulcers: Potential therapeutic targets

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