Dermal Extracellular Matrix Research Articles

Understanding skin aging: Exploring anti-aging modalities

With ever-improving life expectancy, skin aging has become the first casualty of exuberant health. People are progressively seeking remedies for their age-related skin problems. Understanding the aging process is unfolding newer realms in the molecular biology of the skin, giving us new insights to combat senescence more effectively. Epidermal dysfunction, compromised permeability homeostasis, elevated skin pH, diminished stratum corneum hydration, and dermal extracellular matrix aberrations with changes in its cellular composition are now well understood. Thus, a more scientific approach can be utilized while evolving various specific anti-aging therapies. The present communication attempts to address both the process of skin aging and various therapies to combat it in a concise yet succinct way.

Decellularized human dermal extracellular matrix-derived scaffolds: compositional, mechanical, and in vitro biological characterizations

Currently, there is a growing demand for in vitro skin models. In search of a more realistic approximation of the tissue microenvironment, here, we present an optimized protocol for extracting and characterizing hydrogels obtained from decellularized dermal extracellular matrix from human skin to generate scaffolds for subsequent use in 3D skin models.

CCN1 is predominantly elevated in human skin dermis by solar-simulated ultraviolet irradiation and accumulated in dermal extracellular matrix.

Skin primarily comprises a collagen-rich extracellular matrix (ECM) that provides structural and functional support to the skin. Aging causes progressive loss and fragmentation of dermal collagen fibrils, leading to thin and weakened skin (Dermal aging). We previously reported that CCN1 is elevated in naturally aged human skin, photoaged human skin, and acute UV-irradiated human skin dermal fibroblasts in vivo. Elevated CCN1 alters the expression of numerous secreted proteins that have deleterious effects on the dermal microenvironment, impairing the structural integrity and function of the skin. Here we show that CCN1 is predominantly elevated in the human skin dermis by UV irradiation and accumulated in the dermal extracellular matrix. Laser capture microdissection indicated that CCN1 is predominantly induced in the dermis, not in the epidermis, by acute UV irradiation in human skin in vivo. Interestingly, while UV-induced CCN1 in the dermal fibroblasts and in the medium is transient, secreted CCN1 accumulates in the ECM. We explored the functionality of the matrix-bound CCN1 by culturing dermal fibroblasts on an acellular matrix plate that was enriched with a high concentration of CCN1. We observed that matrix-bound CCN1 activates integrin outside-in signaling resulting in the activation of FAK and its downstream target paxillin and ERK, as well as elevated MMP-1 and inhibition of collagen, in human dermal fibroblasts. These data suggest that accumulation of CCN1 in the dermal ECM is expected to progressively promote the aging of the dermis and thereby negatively impact the function of the dermis.

Dermal Fibroblasts as the Main Target for Skin Anti-Age Correction Using a Combination of Regenerative Medicine Methods

This article includes the data from current studies regarding the pathophysiological mechanisms of skin aging and the regenerative processes occurring in the epidermis and dermis at the molecular and cellular level, mainly, the key role of dermal fibroblasts in skin regeneration. Analyzing these data, the authors proposed the concept of skin anti-age therapy that is based on the correction of age-related skin changes by stimulating regenerative processes at the molecular and cellular level. The main target of the skin anti-age therapy is dermal fibroblasts (DFs). A variant of the cosmetological anti-age program using the combination of laser and cellular methods of regenerative medicine is presented in the paper. The program includes three stages of implementation and defines the tasks and methods of each stage. Thus, laser technologies allow one to remodel the collagen matrix and create favorable conditions for DFs functions, whereas the cultivated autologous dermal fibroblasts replenish the pool of mature DFs decreasing with age and are responsible for the synthesis of components of the dermal extracellular matrix. Finally, the use of autological platelet-rich plasma (PRP) enables to maintenance of the achieved results by stimulating DF function. It has been shown that growth factors/cytokines contained in α-granules of platelets injected into the skin bind to the corresponding transmembrane receptors on the surface of DFs and stimulate their synthetic activity. Thus, the consecutive, step-by-step application of the described methods of regenerative medicine amplifies the effect on the molecular and cellular aging processes and thereby allows one to optimize and prolong the clinical results of skin rejuvenation.

Development of bovine elastin/tannic acid bioactive conjugate: physicochemical, morphological, and wound healing properties

Elastin is a functional protein of the dermal extracellular matrix and a critical component of skin wound healing. In severe wounds, skin cells do not produce enough elastin; therefore, the ability to transfer elastin to tissue is highly advantageous. This study aims to develop and characterize the bovine elastin/tannic acid (E/T) conjugate for wound healing applications. A simple conjugation method between the extracted bovine elastin (E) and tannic acid (T) was applied herein. The developed E/T conjugate showed the best binding efficiency besides controlled delivery of T content up to 7 days in acidic, alkaline, and aqueous media. The E/T conjugate exhibited great T content stability when stored at 40 °C for 60 days. The incorporation of T into E significantly improved the moisture, swelling, and solubility properties of the E/T conjugate. The micro-morphological study of the E/T conjugate confirmed the deposition of T on E fibers, whereas FTIR spectra of the E/T conjugate demonstrated the interaction between E and T functional groups. Markedly improved thermal stability was demonstrated for E/T conjugate over native E via thermogravimetric analysis. In vivo studies on Wistar rats demonstrated that the E/T conjugate considerably impacts the wound closure rate, scar disappearance, and acceleration of the wound healing process compared to the native E. According to these findings, the newly developed E/T conjugate can be used as a potential biomedical product in wound healing applications.

Skin aging from the perspective of dermal fibroblasts: the interplay between the adaptation to the extracellular matrix microenvironment and cell autonomous processes.

This article summarizes important molecular mechanisms that drive aging in human skin from the perspective of dermal fibroblasts. The dermis comprises the bulk of the skin and is largely composed of a collagen-rich extracellular matrix (ECM). The dermal ECM provides mechanical strength, resiliency, and an environment that supports the functions of ibroblasts and other types of dermal cells. Fibroblasts produce the dermal ECM and maintain its homeostasis. Fibroblasts attach to the ECM and this attachment controls their morphology and function. During aging, the ECM undergoes gradual degradation that is nitiated by matrix metalloproteinases (MMPs). This degradation alters mechanical forces within the dermal ECM and disrupts he interactions between fibroblasts and the ECM thereby generating an aged fibroblast phenotype. This aged fibroblast phenotype is characterized by collapsed morphology, altered mechanosignaling, induction of CCN1, and activation of transcription factor AP-1, with consequent upregulation of target genes including MMPs and pro-inflammatory mediators. The TGF-beta pathway coordinately regulates ECM production and turnover. Altered mechanical forces, due to ECM fragmentation, down-regulate the type II TGF-beta receptor, thereby reducing ECM production and further increasing ECM breakdown. Thus, dermal aging involves a feed-forward process that reinforces the aged dermal fibroblast phenotype and promotes age-related dermal ECM deterioration. As discussed in the article, the expression of the aged dermal fibroblast phenotype involves both adaptive and cell-autonomous mechanisms.

1004 Dermal extracellular matrix inhibits mast cell activation to skin commensal bacteria

1004 Dermal extracellular matrix inhibits mast cell activation to skin commensal bacteria

1541 Co-transcription factors YAP and TAZ regulate dermal extracellular matrix homeostasis and scar formation in mouse skin

1541 Co-transcription factors YAP and TAZ regulate dermal extracellular matrix homeostasis and scar formation in mouse skin

A novel collagenase from Vibrio Alginolyticus: experimental study for Dupuytren's disease.

Dupuytren contracture (DC) is a highly prevalent hand affection in which contracted fingers compromise hand function. It is a benign fibroproliferative condition affecting the hand palmar fascia with a deposition of excess matrix proteins in the extracellular space of the palmar aponeurosis. In particular type III over type I collagen V. Alginolyticus collagenase (CVA), is a new enzyme that is fully active on the collagen filaments and inactive on other components of the dermal extracellular matrix. The aim of this study is to evaluate the safety and effectiveness of an intra-lesional injection of CVA on an animal model of subcutaneous fibrosis mimicking the pathological anatomy of the cord of Dupuytren's disease. We performed an in vivo study on 27 rats that were randomized into four groups, and we evaluated macroscopic and microscopic analysis examining the inflamed cell population and the extracellular matrix. In all cases, no skin necrosis, skin tears or wound dehiscence were recorded, demonstrating the safety of the CVA in contrast to group D which had full-thickness skin necrosis, and this is confirmed by the microscopic analysis of the samples treated with CVA, where no hematomas are found around the fibrotic area with the absence of leukocyte infiltrates and macrophages. CVA is confirmed to be selective for collagens I and III, reducing the risk of vascular lesions or skin ulcerations.

Human dermal fibroblast-derived extracellular matrix reduces postinflammatory hyperpigmentation after fractional carbon dioxide laser facial resurfacing in Asians.

Extracellular matrix (ECM) components promote the development of skin wounds by providing biological scaffolds and regenerative microenvironments. To evaluate the beneficial effects of human dermal fibroblast-derived ECM after fractional carbon dioxide laser resurfacing in Asians. In this double-blind, randomized, vehicle-controlled, split-face study, 15 participants with features of facial skin aging were treated with a single session of fractional carbon dioxide laser, followed by the application of either ECM (ECM group) or placebo (control group). In vivo skin parameters were measured at baseline and after 4 and 12 weeks of treatment using the Antera 3D®, Cutometer® MPA580, Dermascan®, and Tewameter®. A total of 14 participants (mean age 45.1± 9.7 years) completed the study. The change in melanin level was significantly lower in the ECM group than in the control group at week 12 (p< 0.05). Transient increase in erythema level was observed at week 4 in the control group, and the change in the erythema level was greater in the control group than in the ECM group (p= 0.014). Though the ECM group showed improvements in the dermal density, texture, transepidermal water loss, marionette lines (volume, maximum depth, and average depth), and nasolabial folds (volume, maximum depth, and length), no significant differences were found between the two groups. Treatment-related adverse events were not reported. We suggest that human dermal fibroblast-derived ECM may be used as adjunctive therapy after fractional carbon dioxide resurfacing to prevent postinflammatory hyperpigmentation in Asians.

Matrix Metalloproteinase-1 Expression in Fibroblasts Accelerates Dermal Aging and Promotes Papilloma Development in Mouse Skin

Fragmentation, disorganization, and depletion of the collagen-rich dermal extracellular matrix are hallmarks of aged human skin. These deleterious alterations are thought to critically mediate many of the prominent clinical attributes of aged skin, including thinning, fragility, impaired wound healing, and a propensity for carcinoma. Matrix metalloproteinase-1 (MMP1) initiates the cleavage of collagen fibrils and is significantly increased in dermal fibroblasts in aged human skin. To investigate the role of elevated MMP1 in skin aging, we generated a conditional bitransgenic mouse (type I collagen alpha chain 2; human MMP1 [Col1a2;hMMP1]) that expresses full-length, catalytically active hMMP1 in dermal fibroblasts. hMMP1 expression is activated by a tamoxifen-inducible Cre recombinase that is driven by the Col1a2 promoter and upstream enhancer. Tamoxifen induced hMMP1 expression and activity throughout the dermis Col1a2:hMMP1 mice. At 6 months of age, Col1a2;hMMP1 mice displayed loss and fragmentation of dermal collagen fibrils, which was accompanied by many of the features of aged human skin, such as contracted fibroblast morphology, reduced collagen production, increased expression of multiple endogenous MMPs, and proinflammatory mediators. Interestingly, Col1a2;hMMP1 mice displayed substantially increased susceptibility to skin papilloma development. These data demonstrate that fibroblast expression of hMMP1 is a critical mediator of dermal aging and creates a dermal microenvironment that promotes keratinocyte tumor development.

A fragment of type VI collagen alpha-6 chain is elevated in serum from patients with atopic dermatitis, psoriasis, hidradenitis suppurativa, systemic lupus erythematosus and melanoma

Extracellular matrix (ECM) remodeling of the skin is a continuous process necessary for maintaining tissue homeostasis. Type VI collagen (COL6) is characterized as a beaded filament, located in the dermal ECM, where COL6-α6-chain has been demonstrated upregulated in atopic dermatitis. The aim of this study was to develop and validate a competitive ELISA, targeting the N-terminal of COL6-α6-chain, named C6A6, and evaluate its associations with the dermatological condition’s atopic dermatitis, psoriasis, hidradenitis suppurativa, systemic lupus erythematosus, systemic sclerosis, urticaria, vitiligo, and cutaneous malignant melanoma in comparison, to healthy controls. A monoclonal antibody was raised and employed in an ELISA assay. The assay was developed, technically validated, and evaluated in two independent patient cohorts. Cohort 1 showed C6A6 was significantly elevated in patients with atopic dermatitis (p < 0.0001), psoriasis (p < 0.0001), hidradenitis suppurativa (p = 0.0095), systemic lupus erythematosus (p = 0.0032) and melanoma (p < 0.0001) compared to healthy donors. Cohort 2 confirmed C6A6 being upregulated in atopic dermatitis compared to healthy controls (p < 0.0001), but also associated with disease severity (SCORAD, p = 0.046) and lowered in patients receiving calcineurin inhibitors (p = 0.014). These findings are hypothesis generating, and the utility of the C6A6 biomarker for disease severity and treatment response needs to be validated in larger cohorts and longitudinal studies.

Loss of RhoE Function in Dermatofibroma Promotes Disorganized Dermal Fibroblast Extracellular Matrix and Increased Integrin Activation

Dermatofibromas are common, benign fibrous skin tumors that can occur at any skin site. In most cases, dermatofibromas are solitary and sporadic, but a few are multiple and familial, and the mechanisms leading to these lesions are currently unclear. Using exome sequencing, we have identified a heterozygous variant in a pedigree with autosomal dominant multiple familial dermatofibromas within RND3 (c.692C>T,p.T231M) that encodes for the small GTPase RhoE, a regulator of the actin cytoskeleton. Expression of T231M-RhoE or RhoE depletion using CRISPR in human dermal fibroblasts increased proliferation, adhesion to extracellular matrix via enhanced β1 integrin activation and more disorganized matrix. The enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) was identified as a binding partner for RhoE and formation of this complex was disrupted by T231M-RhoE. PLOD2 promotes collagen crosslinking and activation of β1 integrins, and depleting PLOD2 in T231M-RhoE expressing cells reduced T231M-RhoE-mediated β1 integrin activation and led to increased matrix alignment. Immunohistochemical analysis revealed reduced expression of RhoE but increased expression of PLOD2 in the dermis of dermatofibroma skin samples compared to controls. Our data show loss of RhoE function leads to increased PLOD2 activation, enhancing integrin activation and leading to disorganized extracellular matrix, contributing to dermatofibroma.

Engineering edgeless human skin with enhanced biomechanical properties.

Despite the advancements in skin bioengineering, 3D skin constructs are still produced as flat tissues with open edges, disregarding the fully enclosed geometry of human skin. Therefore, they do not effectively cover anatomically complex body sites, e.g., hands. Here, we challenge the prevailing paradigm by engineering the skin as a fully enclosed 3D tissue that can be shaped after a body part and seamlessly transplanted as a biological clothing. Our wearable edgeless skin constructs (WESCs) show enhanced dermal extracellular matrix (ECM) deposition and mechanical properties compared to conventional constructs. WESCs display region-specific cell/ECM alignment, as well as physiologic anisotropic mechanical properties. WESCs replace the skin in full-thickness wounds of challenging body sites (e.g., mouse hindlimbs) with minimal suturing and shorter surgery time. This study provides a compelling technology that may substantially improve wound care and suggests that the recapitulation of the tissue macroanatomy can lead to enhanced biological function.

Biocompatible and bioactive hydrogels of recombinant fusion elastin with low transition temperature for improved healing of UV-irradiated skin.

Prolonged exposure to UV radiation can cause severe photodamage to the skin, leading to abnormal fragmentation of elastin fibers. As one of the main protein components of the dermal extracellular matrix, elastin plays a critical role in the mechanical behavior and physiological function of the skin. Animal-derived elastin has attracted extensive attention in tissue engineering, however it suffers from severe drawbacks such as a risk of virus transmission, ready degradation, and challenging quality control. Herein, we have for the first time developed a novel recombinant fusion elastin (RFE) and its cross-linked hydrogel for improved healing efficacy for UV-irradiated skin. RFE showed temperature-sensitive aggregation behavior similar to natural elastin. Compared with recombinant elastin without the fusion V-foldon domain, RFE showed a much more ordered secondary structure and lower transition temperature. Furthermore, Native-PAGE results indicated that the addition of the V-foldon domain triggered the formation of remarkable oligomers in RFE, which may result in a more ordered conformation. Tetrakis Hydroxymethyl Phosphonium Chloride (THPC) cross-linking of RFE led to the production of a fibrous hydrogel with uniform three-dimensional porous nanostructures and excellent mechanical strength. The RFE hydrogel showed superior cellular activity, significantly promoting the survival and proliferation of human foreskin fibroblast-1 (HFF-1). Studies of mice models of UV-irradiated skin demonstrated that the RFE hydrogel pronouncedly accelerated their healing process by inhibiting epidermal hyperplasia as well as boosting the regeneration of collagen and elastin fibers. The highly biocompatible and bioactive recombinant fusion elastin and its cross-linked hydrogel provide a potent treatment for photodamaged skin, which may have promising applications in dermatology and tissue engineering.

Thermal injury healing in the context of neocollagenogenesis induction: preclinical randomized experimental study

Background. The healing of skin wounds having various etiologies is known to involve a multistep process characterized by certain intercellular interactions affecting dermal cells, their attachment, migration, and differentiation. Here, recovery is interpreted as the return of dermis to its original state. The fact is, however, that the dermal extracellular matrix (ECM) is structurally impaired, which suppresses the regulatory and repository functions of the dermis, leading to the formation of a scar that inhibits several biological functions in the affected area and causes aesthetic problems associated with mobility.Objectives. To evaluate the structural features of dermis during wound healing using a calcium-containing biodegradable implant.Methods. The study used 60 rats that were inflicted with a third-degree burn injury (partially damaged dermis). The selected animals were divided into two groups: experimental and control. On post-burn day 14, a calcium-containing biodegradable implant was administered to rats from the experimental group, while a sterile saline solution was used in the control group. Material was sampled at two months (74 days) and four months (134 days). In order to assess the morphological state of the burn area, its sections were stained with hematoxylin and eosin, according to Mallory and Van-Gieson. For the selective detection of collagens, immunohistochemical tests using antibodies to collagen types I and III (Abcam, England) were employed. To characterize dermal cells, the authors used antibodies to vimentin (LabVision, USA), as well as to СD-68 (cluster of differentiation 68), α-SMA (alpha-smooth muscle actin), CD-105 (cluster of differentiation 105), and VEGF (vascular endothelial growth factor) receptors (Abcam, England). The obtained results were processed using the Statistica 6 software (StatSoft, USA).Results. The administration of a calcium-containing biodegradable filler during the burn healing process was found to ensure local fibroblast activation with the formation of collagen types I and III. When the implant residence time was prolonged up to four months, an increase in the number of macrophages expressing CD-68 receptors was observed. Of note is that these cells retained their localization, while α-SMA-expressing cells were localized in both the superficial and deep dermal compartments. The number of cells expressing CD-105 and VEGF rose as well.Conclusion. The use of the biodegradable filler is found to be promising in terms of post-burn dermal regeneration, as well as providing a dermal ECM, whose collagen network composition and assembly are similar to the original. Here, macrophages act as the primary synthesis regulators of the dermal ECM and stimulate fibroblasts, which ensures re-epithelialization and angiogenesis of the inflicted area.

256 Enlarged pore reduction by targeting parakeratosis and reinforcing dermal extracellular matrix

Enlarged pores is a common anesthetic skin issue mainly driven by excessive parakeratosis, loss of mature collagen and poor extracellular matrix (ECM) renewal. These events conduct to premature ageing with hyperdifferentiation and fragile and coarse dermis. A combination including amino acids, copper, mannose-6-phosphate and lactic acid was designed to counteract the main causes of pores formation. Impact on parakeratosis was evaluated in vitro with genes expression analysis on keratinocytes and using a model of RHE with morphological staining and involucrin immunostaining.

Targeting Multiple Hallmarks of Skin Aging: Preclinical and Clinical Efficacy of a Novel Growth Factor-Based Skin Care Serum.

The aging process involves numerous biological mechanisms that have been characterized and proposed as the "hallmarks of aging." Targeting the processes and pathways related to these hallmarks of aging that cause and promote skin aging could provide anti-aging benefits. A novel topical growth factor-based skin care serum (A+) was developed using human fibroblast conditioned media. This study aimed to assess the effects of A+ on four hallmarks of aging and its clinical efficacy in skin rejuvenation in subjects with moderate to severe overall facial photodamage. Preclinical studies included immunohistochemistry in human exvivo skin, and gene expression analysis in human 3D skin models. A 24-week, vehicle placebo-controlled study, including FaceQ patient-reported outcomes and skin biopsy analysis, was performed to assess clinical efficacy and tolerability. Treatment with A+ resulted in reduced expression of cell senescence biomarker H2A.J and upregulation of genes associated with proteasome, autophagy, stemness, and intercellular communication. Clinical assessments showed A+ provided significantly greater reductions in sagging, coarse lines/wrinkles, fine lines/wrinkles, overall photodamage, and overall hyperpigmentation compared with placebo. Subjects felt they appeared younger-looking, reporting a median decrease in self-perceived age of 6years after 12weeks of use. Decreased levels of H2A.J and increased expression of key dermal extracellular matrix and epidermal barrier components, including collagen and elastin, were observed in skin biopsy samples. The present study shows for the first time the potential effects of a topical growth factor-based cosmeceutical on cellular processes related to four hallmarks of aging (cellular senescence, loss of proteostasis, stem cell exhaustion, and altered intercellular communication) to help delay the aging process and restore aged skin. A+ targets the biological mechanisms underlying the aging process itself and stimulates skin regeneration, resulting in rapid and significant clinical improvements.

Abstract 11746: Decellularized Dermis Extracellular Matrix Alloderm Mechanically Strengthens Biological Engineered Tunica Adventitia-Based Blood Vessels

Introduction: Of the three layers of a mammalian artery, the tunica adventitia provides the most strength to prevent rupture of blood vessels under high pressures. The structural network of this outermost layer mainly consists of fibroblasts and collagen. Many groups have improved strength of their tissue engineered (TE) vessels by conditioning with pulsatile flow in bioreactors. Conditioning stimulates cellular collagen production; however, it is time-consuming ranging from 3-8 weeks. Dermis is comprised primarily of collagen providing skin with considerable strength. Hypothesis: We hypothesized inclusion of decellularized dermis, Alloderm, into TE vessels can increase the strength and thus decrease production time. Methods: To generate a TE adventitia vessel, we adapted our lab’s ring stacking method which creates tissue rings that are stacked to form a tubular, vascular constructs. Human dermal fibroblasts (HDFs) were used to form a cellular fibrin hydrogel in a petri dished with a central post. Alloderm was cut into a donut shape and placed on top of the hydrogel around the central post (Figure 1). Additional HDFs were placed on top of the hydrogel and Alloderm. Over 14 days the HDF monolayer rolled around the post into a ring. These Alloderm rings were stacked and adhered using fibrin glue to create a TE vessel. Results: TE vessel tensile strength was significantly higher with Alloderm than without: 1500 ± 262 kPa (n = 5) versus 67.9 ± 9.78 kPa (n = 5). Histology indicated Alloderm significantly increased total collagen content and fiber maturity compared to TE vessels without. Mechanical integrity of Alloderm rings was maintained for 4 weeks: tensile strength 2760 ± 1130 kPa. In comparison, native adventitia strength is 1430 ± 604 kPa. Conclusions: This work shows that decellularized dermis can successfully be incorporated into TE vessels. Additionally, inclusion of Alloderm significantly increases tissue strength and collagen content that is maintained over time.

NRF2 Shortage in Human Skin Fibroblasts Dysregulates Matrisome Gene Expression and Affects Collagen Fibrillogenesis

NRF2 is a master regulator of the antioxidative response that was recently proposed as a potential regulator of extracellular matrix (ECM) gene expression. Fibroblasts are major ECM producers in all connective tissues, including the dermis. A better understanding of NRF2-mediated ECM regulation in skin fibroblasts is thus of great interest for skin homeostasis maintenance and aging protection. In this study, we investigate the impact of NRF2 downregulation on matrisome gene expression and ECM deposits in human primary dermal fibroblasts. RNA-sequencing‒based transcriptome analysis of NRF2 silenced dermal fibroblasts shows that ECM genes are the most regulated gene sets, highlighting the relevance of the NRF2-mediated matrisome program in these cells. Using complementary light and electron microscopy methods, we show that NRF2 deprivation in dermal fibroblasts results in reduced collagen I biosynthesis and impacts collagen fibril deposition. Moreover, we identify ZNF469, a putative transcriptional regulator of collagen biosynthesis, as a target of NRF2. Both ZNF469 silenced fibroblasts and fibroblasts derived from Brittle Corneal Syndrome patients carrying variants in ZNF469 gene show reduced collagen I gene expression. Our study shows that NRF2 orchestrates matrisome expression in human skin fibroblasts through direct or indirect transcriptional mechanisms that could be prioritized to target dermal ECM homeostasis in health and disease.