Angiopoietin-like 4 Interacts with Matrix Proteins to Modulate Wound Healing*

Abstract

A dynamic cell-matrix interaction is crucial for a rapid cellular response to changes in the environment. Appropriate cell behavior in response to the changing wound environment is required for efficient wound closure. However, the way in which wound keratinocytes modify the wound environment to coordinate with such cellular responses remains less studied. We demonstrated that angiopoietin-like 4 (ANGPTL4) produced by wound keratinocytes coordinates cell-matrix communication. ANGPTL4 interacts with vitronectin and fibronectin in the wound bed, delaying their proteolytic degradation by metalloproteinases. This interaction does not interfere with integrinmatrix protein recognition and directly affects cell-matrix communication by altering the availability of intact matrix proteins. These interactions stimulate integrin-focal adhesion kinase, 14-3-3, and PKC-mediated signaling pathways essential for effective wound healing. The deficiency of ANGPTL4 in mice delays wound re-epithelialization. Further analysis revealed that cell migration was impaired in the ANGPTL4-deficient keratinocytes. Altogether, the findings provide molecular insight into a novel control of wound healing via ANGPTL4-dependent regulation of cell-matrix communication. Given the known role of ANGPTL4 in glucose and lipid homeostasis, it is a prime therapeutic candidate for the treatment of diabetic wounds. It also underscores the importance of cell-matrix communication during angiogenesis and cancer metastasis.Skin repair after an injury proceeds via a finely tuned pattern of integrated biological events aimed at restoration of the epithelial barrier. The inflammatory stage of repair is followed by the proliferation and migration of keratinocytes, a process called re-epithelialization (1). These events are regulated spatiotemporally by several classical growth factors and cytokines, the effects of which have been well documented (2). Less studied are extracellular factors such as matricellular proteins and adipocytokines, both shown to have a profound local impact during wound repair (3, 4). Effective directed cell migration requires constant cellular interaction with the extracellular matrix (ECM) 3 in response to the changing wound environment. Although the importance of such cell-matrix communication in wound healing is well recognized, the mechanism that modifies the external wound microenvironment for coordinated keratinocyte behavior remains unclear.Integrins on the cell surface often function as biosensors to constantly interrogate the wound environment and modulate cell responses accordingly. Binding of integrins to their cognate matrix proteins activates intracellular signaling pathways that modulate a broad range of cellular processes, including cell migration (5). Integrin-mediated signaling requires that integrins bind substrate-anchored matrix proteins. This interaction provides mechanical resistance that permits tensional forces to be generated via the actomyosin system (6). In contrast, small soluble matrix protein fragments gene...

Gene expression changes in bioceramic paste-treated human dental pulp cells

“…TCF7L2 plays a key role in the Wnt signaling pathway and is involved in glucose homeostasis (20). Impaired glucose homeostasis is one of the factors that negatively affect wound healing (21). In the present study, ANGPTL4 and TCF7L2 transcript levels exhibited statistically significant increases and decreases after 24 h of incubation, respectively.…”

Involvement of Angiopoietin-like 4 in Matrix Remodeling during Chondrogenic Differentiation of Mesenchymal Stem Cells

“…The amount of soluble endogenous ANGPTL4 released by differentiating MSCs reached ϳ 94 nM, a value similar to or above reported affinities for integrin subunits ␤1 and ␤5 (24,25). Importantly, the total amount of ANGPTL4 produced by MSCs is likely to be even greater than that found in the supernatant alone because this protein was shown to be also retained in the extracellular matrix in a biologically active form bound to heparan sulfate proteoglycans, vitronectin, or fibronectin (28,29). This may explain why we obtained only a partial effect or no detectable effect on some parameters with the recombinant ANGPTL4 at 100 nM.…”

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“…Since ANGPTL4 alters the migratory capacity of several cell types [13,21], we examined if ANGPTL4 over-expressing melanoma cells would manifest an altered ability to migrate through collagen coated transwells. Cutaneous ANGPTL4 hi cells migrated more efficiently than the corresponding CON pQC cells (P < 0.05) ( Figure 2D, 2E).…”

“…Angiopoietin-like proteins take part in endothelial cell survival, adhesion and paradoxically, stimulation or inhibition of angiogenesis and vascular leakiness [12,13].…”