Gary J Fisher

University of Michigan | U-M · Department of Dermatology

Skin ageing is an inevitable phenomenon with several characteristic manifestations. The genetic, molecular, and cellular factors that contribute to aged skin are becoming increasingly understood. As our knowledge of how skin ages advances, the potential therapeutic opportunities for skin rejuvenation are similarly increased and improved. In this ch...

In photoaged human skin, type I collagen fragmentation impairs dermal extracellular matrix (ECM) integrity, resulting in collapsed/contracted fibroblasts with reduced type I procollagen synthesis. Injections of cross‐linked hyaluronic acid (CL‐HA) reverse these deleterious changes. To investigate the time course and effects of biochemical changes i...

Collagen is the major structural protein in the skin. Fragmentation and disorganization of the collagen fibrils are the hallmarks of the aged human skin dermis. These age-related alterations of collagen fibrils impair skin structural integrity and make the tissue microenvironment more prone to skin disorders. As the biological function of collagen...

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...

Fragmentation, disorganization, and depletion of the collagen-rich dermal extracellular matrix (ECM) 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 propensity for carcinoma. Matrix meta...

Activation of Toll-like receptor 4 (TLR4) by its cognate damage-associated endogenous ligands (DAMPs) elicits potent profibrotic effects and myofibroblasts activation in systemic sclerosis (SSc), while genetic targeting of TLR4 or its DAMPs in mice accelerates fibrosis resolution. To prevent aberrant DAMP-TLR4 activity, a variety of negative regula...

Collagen 17A1 (COL17A1) is a transmembrane structural component of the hemidesmosome that mediate adhesion of keratinocytes to the underlying membrane. Recent work in mouse showed that COL17A1 deficiency leads to premature skin aging. Although the role COL17A1 in skin aging is becoming recognized in mouse models, its connection to human skin natura...

Background Aged human skin is primarily attributable to the loss of collagen. Hepatocyte growth factor (HGF) acts as an anti-fibrotic factor by suppression of collagen production. In aged human skin, HGF is elevated in dermal fibroblasts and thus contributes to dermal aging (thin dermis) by suppression of collagen production. Objective We aimed to...

Background Dermal injection of chemically cross-linked hyaluronic acid (CL-HA) is a common procedure to smooth wrinkles and add fullness to the face. Due to its physical properties, CL-HA both fills space and exerts mechanical forces within the dermis. Dermal fibroblasts produce the collagen-rich extracellular matrix (ECM), which comprises the bulk...

The aging process deleteriously alters the structure and function of dermal collagen. These alterations result in thinning, fragility, wrinkles, laxity, impaired wound healing, and a microenvironment conducive to cancer. However, the key factors responsible for these changes have not been fully elucidated and relevant models for the study of skin a...

Human skin is composed of the cell-rich epidermis, the extracellular matrix (ECM) rich dermis, and the hypodermis. Within the dermis, a dense network of ECM proteins provides structural support to the skin and regulates a wide variety of signaling pathways which govern cell proliferation and other critical processes. Both intrinsic aging, which occ...

Fibroblasts produce collagens and other proteins that form the bulk of the extracellular matrix (ECM) in connective tissues. Emerging data point to functional heterogeneity of fibroblasts. However, the lack of sub-type specific markers hinders our understanding of the different roles of fibroblasts in ECM biology, wound healing, diseases and aging....

Background: Exposure to the sun causes premature skin aging, known as photoaging. Clinical features of photoaging vary widely among individuals. In one form, skin appears thin with telangiectasia, and in another form, skin appears thickened with coarse wrinkles. Etiologic, clinical, and therapeutic distinctions among different forms of photoaging...

Background: Transcription factors YAP and TAZ function as the primary mediators of the Hippo pathway. Yet, crosstalk of YAP and TAZ with other signaling pathways remains relatively unexplored. We have explored the impact of YAP and TAZ levels on the TGF-β/Smad signaling pathway in human skin dermal fibroblasts. Methods: YAP and TAZ levels in der...

Fragmentation of collagen fibrils and aberrant elastic material (solar elastosis) in the dermal extracellular matrix (ECM) are among the most prominent features of photodamaged human skin. These alterations impair the structural integrity and create a dermal microenvironment prone to skin disorders. The objective of this study was to determine the...

The dermal compartment of skin is primarily composed of collagen‐rich extracellular matrix (ECM), which is produced by dermal fibroblasts. In Young skin, fibroblasts attach to the ECM through integrins. During ageing, fragmentation of the dermal ECM limits fibroblast attachment. This reduced attachment is associated with decreased collagen producti...

妊娠纹影响着50~90%的孕妇并且可能会引起情感抑郁。最初的妊娠纹略带红色,在几个月至几年后逐渐成熟,形成永久性白色条纹并带有凹陷的疤痕状外观。由于我们对妊娠纹的发展方式知之甚少,因此由美国密歇根大学开展的本项研究旨在检查早期妊娠纹中发生的分子改变,这些发现可能可以解释成熟妊娠纹的出现。为了这项研究,妊娠中期或晚期的孕妇提供了最近形成的、微红色妊娠纹腹部皮肤样本;此外,一些孕妇还在分娩后提供了皮肤样本。作者利用实验室技术分析了这些皮肤样本,以检查胶原质(为皮肤提供力量和支撑的主要蛋白质)的外观、组织和产生。他们发现,胶原质在早期妊娠纹中表现异常。特别是通常包裹紧密的胶原纤维束呈现出明显的分离状态,就好象被极限的皮肤拉伸“撕开”了一样。而皮肤则试图通过制造更多的胶原质来修复这些分离、受损的胶原...

Stretch marks affect 50‐90% of pregnant women and can cause emotional distress. Stretch marks initially appear reddish, and mature over months to years, becoming permanent white streaks with a depressed, scar‐like appearance. As little is known about how stretch marks develop, this study, from the University of Michigan in the US, aimed to examine...

The dermal extracellular matrix (ECM) comprises the bulk of skin and confers strength and resiliency. In young skin, fibroblasts produce and adhere to the dermal ECM, which is composed primarily of type I collagen fibrils. Adherence allows fibroblasts to spread and exert mechanical force on the surrounding ECM. In this state, fibroblasts display a...

Kinetics and peptide substrate concentration dependence of cleavage by MMP1-CD. Notes: To optimize assay conditions for HTS, we examined both the MMP1-CD concentration dependence and the fluorogenic peptide substrate concentration dependence on the kinetics of peptide substrate cleavage by MMP1-CD. This figure shows the peptide substrate concentrat...

Determination of Km using the Lineweaver–Burk double reciprocal plot. Notes: The Km was 11 μm.

Yong Li, John J Voorhees, Gary J FisherDepartment of Dermatology, University of Michigan, Ann Arbor, MI, USAType I collagen (COL1) is the predominant structural protein in the skin. COL1 forms densely packed fibrils which are essential for maintaining skin mechanical properties and youthful appearance.1 The enzyme matrix metalloproteinase-1 (MMP1)...

CCN proteins are vital to a variety of biological processes that contribute to the normal development and function of skin. Quantitative real-time reverse transcriptase PCR (qPCR) quantifies mRNA levels of these key genes. Immunostaining localizes CCN proteins within skin tissue, and provides semiquantitative information regarding relative levels o...

Polyacrylamide hydrogels can be used to culture cells in a range of stiffness that can closer mimic physiological environments. Changes in environmental stiffness have been documented in conditions such as fibrosis, cancer, and aging. In this chapter, we describe a method in which we pour gels directly into multiwell plates using a plastic support...

Background: Striae gravidarum (SG), or stretch marks of pregnancy, begin as erythematous streaks, and mature into hypopigmented atrophic bands. Objectives: To investigate molecular alterations that may promote atrophy of SG, we investigated dermal type I collagen fibrils, which provide human skin with support. Methods: We obtained skin samples...

Altering the fatty acid (FA) composition in the skin by dietary fish oil could provide therapeutic benefits. Although it has been shown that fish oil supplementation enhances EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) abundance in the skin, comprehensive skin FA profiling is needed. We established a gas chromatography-mass spectrome...

Skin ageing results from both the passage of time and from extrinsic forces, predominantly solar ultraviolet irradiation. Intrinsic ageing is characterized by fine wrinkling and homogenous colour on sun‐protected sites whereas extrinsic ageing is characterized by fine and coarse wrinkling, erythema and dyspigmentation on sun‐exposed sites. Two dist...

Video S2 Animated version for Fig. 2A–C (H.264 encoding). Revolving reconstructions of PSU and ESG stained with Ki67. The video shows, successively, i) (starts at 1 s, or frame 1) anagen PSU from aged individual 5 days post‐wounding; scale bar (500 μm‐long) was positioned at the forwardmost plan of the taller hair follicle, ii) (starts at 25 s, or...

Video S1 Animated version for Fig. 1A–D (H.264 encoding). Revolving reconstructions of wounded skin samples of young and aged individuals taken 5 and 7 days post‐wounding (starting at 1 s or frame 1 and 20 s or frame 415, respectively), as labeled in the video.

Production of type I collagen (COL1), the major structural protein of the skin, declines during aging, leading to skin thinning and becoming fragile, which increases the risk of bruising and wound healing disorders in the elderly. Topical treatments that can restore COL1 synthesis and ultimately COL1 content in aged skin hold promise to improve ski...

Objective: Retinoic acid has been shown to improve the aged-appearing skin. However, less is known about the anti-aging effects of retinol (ROL, vitamin A), a precursor of retinoic acid, in aged human skin in vivo. This study aimed to investigate the molecular basis of retinol anti-aging properties in naturally aged human skin in vivo. Methods:...

Human skin heals more slowly in aged vs. young adults, but the mechanism for this delay is unclear. In humans, eccrine sweat glands (ESGs) and hair follicles underlying wounds generate cohesive keratinocyte outgrowths that expand to form the new epidermis. Here, we compared the re-epithelialization of partial-thickness wounds created on the forearm...

Alterations of the collagen, the major structural protein in skin, contribute significantly to human skin connective tissue aging. As aged-appearing skin is more common in diabetes, here we investigated the molecular basis of aged-appearing skin in diabetes. Among all known human matrix metalloproteinases (MMPs), diabetic skin shows elevated levels...

Fig. S1 Reduced cell size/mechanical force inhibits ECM production. Fig. S2 Reduced fibroblast size/mechanical force does not change mRNA expression of TGF‐β ligands or Smad2/3/4/7. Fig. S3 Specificity of the TβRII adn TβRI antibodies.

Blue nevi may display significant atypia or undergo malignant transformation. Morphologic diagnosis of this spectrum of lesions is notoriously difficult, and molecular tools are increasingly used to improve diagnostic accuracy. We studied copy number aberrations in a cohort of cellular blue nevi, atypical cellular blue nevi, and melanomas ex blue n...

Background All-trans retinol, a precursor of retinoic acid, is an effective anti-aging treatment widely used in skin care products. In comparison, topical retinoic acid is believed to provide even greater anti-aging effects; however, there is limited research directly comparing the effects of retinol and retinoic acid on skin. Objectives In this st...

The complex pathogenesis of psoriasis is still not fully understood. The study by Sun et al. (2015) suggests that CYR61 (now named CCN1), a secreted matricellular protein, has a role in the pathogenesis of psoriasis, and thus targeting CCN1 represents a potential therapeutic strategy in its treatment.

The structural integrity of human skin is largely dependent on the quality of the dermal extracellular matrix (ECM), which is produced, organized, and maintained by dermal fibroblasts. Normally, fibroblasts attach to the ECM and thereby achieve stretched, elongated morphology. A prominent characteristic of dermal fibroblasts in aged skin is reduced...

Striae gravidarum (SG), or "stretch marks" of pregnancy, begin as erythematous streaks, and mature over months to years to become permanent scar-like bands that may be hypopigmented, atrophic, and lax. To investigate early molecular alterations that may promote laxity of mature SG, we investigated the dermal elastic fiber network, which provides hu...

Production of type I collagen declines during aging, leading to skin thinning and impaired function. Prostaglandin E2 (PGE2) is a pleiotropic lipid mediator that is synthesized from arachidonic acid by the sequential actions of cyclooxygenases (COX) and PGE synthases (PTGES). PGE2 inhibits collagen production by fibroblasts in vitro. We report that...

Facial erythema and telangiectasia are commonly associated with the erythematotelangiectatic subtype of rosacea (ETR). It is important for clinicians to recognize that these findings can also be associated with a subtype of photoaging, which we term telangiectatic photoaging (TP). To demonstrate that ETR and TP are distinct dermatologic disorders....

Human skin is largely composed of a collagen-rich connective tissue, which provides structural and functional support. The collagen-rich connective tissue is produced, organized, and maintained by dermal fibroblasts. During aging, dermal collagen fibrils undergo progressive loss and fragmentation, leading to thin and structurally weakened skin. Age...

Receptor protein tyrosine phosphatase-kappa (PTPRK) specifically and directly dephosphorylates epidermal growth factor receptor (EGFR), thereby limiting EGFR function in primary human keratinocytes. PTPRK expression is increased by the TGF-β/Smad3 pathway and cell-cell contact. Since the Notch receptor pathway is responsive to cell-cell contact and...

With worldwide expansion of the aging population, research on age-related pathologies is receiving growing interest. In this review, we discuss current knowledge regarding the decline of skin structure and function induced by the passage of time (chronological aging) and chronic exposure to solar UV irradiation (photoaging). Nearly every aspect of...

Human skin is a primary target of oxidative stress from reactive oxygen species (ROS) generated from both extrinsic and intrinsic sources. Oxidative stress inhibits the production of collagen, the most abundant protein in skin, and thus contributes to connective tissue aging. Here we report that cysteine-rich protein 61 (CCN1), a negative regulator...

Transforming growth factor-β (TGF-β) is a major regulator of collagen gene expression in human skin fibroblasts. Cellular responses to TGF-β are mediated primarily through its cell surface type I (TβRI) and type II (TβRII) receptors. Ultraviolet (UV) irradiation impairs TGF-β signalling largely due to reduced TβRII gene expression, thereby decreasi...

The dermal compartment of human skin is largely composed of dense collagen-rich fibrils, which provide structural and mechanical support. Skin dermal fibroblasts, the major collagen-producing cells, are interact with collagen fibrils to maintain cell spreading and mechanical force for function. A characteristic feature of aged human skin is fragmen...

Exposure to oxidants results in cellular alterations that are implicated in aging and age-associated diseases. Here, we report that brief, low-level oxidative exposure leads to long-term elevation of cellular reactive oxygen species (ROS) levels and oxidative damage in human skin fibroblasts. Elevated ROS impairs the transforming growth factor-β (T...

Yes-associated protein (YAP) is a transcriptional co-activator of hippo signaling pathway, which plays an important role in organ size control and tumorigenesis. Here we report that YAP and its downstream transcriptional targets CCN1 and CCN2 are markedly elevated in keratinocytes in human skin basal cell carcinoma tumor islands. In human keratinoc...

Importance Solar UV irradiation causes photoaging, characterized by fragmentation and reduced production of type I collagen fibrils that provide strength to skin. Exposure to UV-B irradiation (280-320 nm) causes these changes by inducing matrix metalloproteinase 1 and suppressing type I collagen synthesis. The role of UV-A irradiation (320-400 nm)...

Head and neck cancer is the sixth most common type of cancer worldwide. Despite advances in aggressive multidisciplinary treatments, the 5-year survival rate for this dreadful disease is only 50%, mostly due to high rate of recurrence and early involvement of regional lymph nodes and subsequent metastasis. Understanding the molecular mechanisms res...

Exposure of human skin to solar ultraviolet (UV) irradiation induces matrix metalloproteinase-1 (MMP-1) activity, which degrades type I collagen fibrils. Type I collagen is the most abundant protein in skin and constitutes the majority of skin connective tissue (dermis). Degradation of collagen fibrils impairs the structure and function of skin tha...

Proteoglycans, a family of glycosaminoglycan (GAG) conjugated proteins, are important constituents of human skin connective tissue (dermis) and are essential for maintaining mechanical strength of the skin. Age-related alterations of dermal proteoglycans have not been fully elucidated. We quantified transcripts of 20 known interstitial proteoglycan...

Supplemental Figure 1 & 2

Chronic exposure of human skin to solar ultraviolet (UV) irradiation causes premature skin aging, which is characterized by reduced type I collagen production and increased fragmentation of the dermal collagenous extracellular matrix. This imbalance of collagen homeostasis is mediated, in part, by elevated expression of the matricellular protein cy...

Increased expression of matrix metalloproteinase-1 (MMP-1) and reduced production of type I collagen by dermal fibroblasts are prominent features of aged human skin. We have proposed that MMP-1-mediated collagen fibril fragmentation is a key driver of age-related decline of skin function. To investigate this hypothesis, we constructed, characterize...

Human skin is largely comprised of collagenous extracellular matrix. The hallmark of skin aging is fragmentation of collagen fibrils. Matrix metalloproteinases (MMPs) are largely responsible for collagen degradation. MMP-1, principally derived from dermal fibroblasts is the major protease capable of initiating degradation of native fibrillar collag...

Abbreviations: ECM, extracellular matrix; MMPs, matrix metalloproteinase family; 3D, three dimensional; TIMP, tissue inhibitor of metalloproteinases

Eccrine sweat glands are skin-associated epithelial structures (appendages) that are unique to some primates including humans and are absent in the skin of most laboratory animals including rodents, rabbits, and pigs. On the basis of the known importance of other skin appendages (hair follicles, apocrine glands, and sebaceous glands) for wound repa...

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and has a high rate of mortality. Emerging evidence indicates that hepatocyte growth factor receptor (or Met) pathway plays a pivotal role in HNSCC metastasis and resistance to chemotherapy. Met function is dependent on tyrosine phosphorylation that is under direct contro...

The dermal extracellular matrix (ECM) provides strength and resiliency to skin. The ECM consists mostly of type I collagen fibrils, which are produced by fibroblasts. Binding of fibroblasts to collagen fibrils generates mechanical forces, which regulate cellular morphology and function. With aging, collagen fragmentation reduces fibroblast-ECM bind...

Dermal fibroblasts produce a collagen-rich extracellular matrix, which confers mechanical strength and resiliency to human skin. During aging, collagen production is reduced and collagen fragmentation is increased, which is initiated by matrix metalloproteinase-1 (MMP-1). This aberrant collagen homeostasis results in net collagen deficiency, which...

Protein tyrosine phosphorylation is a fundamental regulatory mechanism controlling cell proliferation, differentiation, communication, and adhesion. Disruption of this key regulatory mechanism contributes to a variety of human diseases including cancer, diabetes, and auto-immune diseases. Net protein tyrosine phosphorylation is determined by the dy...

Fractionated ablative laser resurfacing has become a widely used treatment modality. Its clinical results are often found to approach those of traditional fully ablative laser resurfacing. To directly compare the molecular changes that result from fractionated and fully ablative carbon dioxide (CO(2) ) laser resurfacing in photodamaged human skin....

We recently show that CCN3 is a counter-regulatory molecule for the pro-fibrotic protein CCN2, and a potentially novel fibrosis therapy. The goal of this study was to assess the role of CCN3 in fibroproliferative/fibrotic responses in human dermal fibroblasts exposed to Omniscan, one of the gadolinium-based contrast agents associated with developme...

Psoriasis is a Th17/Th1-mediated skin disease that often responds to antitumour necrosis factor (TNF)-α therapies, such as etanercept. To better define mechanisms by which etanercept improves psoriasis and to gain insight into disease pathogenesis. We investigated the early biochemical and cellular effects of etanercept on skin lesions in responder...