title: Enhancing structural support of the dermal microenvironment activates fibroblasts, endothelial cells, and keratinocytes in aged human skin in vivo.
abstract: 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 binding and mechanical forces, resulting in fibroblast shrinkage and reduced function, including collagen production. Here, we report that these age-related alterations are largely reversed by enhancing the structural support of the ECM. Injection of dermal filler, cross-linked hyaluronic acid, into the skin of individuals over 70 years of age stimulates fibroblasts to produce type I collagen. This stimulation is associated with localized increase in mechanical forces, indicated by fibroblast elongation/spreading, and mediated by upregulation of type II TGF-β receptor and connective tissue growth factor. Interestingly, enhanced mechanical support of the ECM also stimulates fibroblast proliferation, expands vasculature, and increases epidermal thickness. Consistent with our observations in human skin, injection of filler into dermal equivalent cultures causes elongation of fibroblasts, coupled with type I collagen synthesis, which is dependent on the TGF-β signaling pathway. Thus, fibroblasts in aged human skin retain their capacity for functional activation, which is restored by enhancing structural support of the ECM.
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Taihao
authors.initials: T
authors.lastname: Quan
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Laure
authors.initials: L
authors.lastname: Rittié
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xia
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Orringer
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: dianemch@med.umich.edu.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Fisher
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology* / Q000502:physiology; D001696:Biomechanical Phenomena; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000502:physiology*; D024042:Collagen Type I / Q000378:metabolism; D042783:Endothelial Cells / Q000473:pathology*; D005109:Extracellular Matrix / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology; D015603:Keratinocytes / Q000473:pathology*; D008297:Male; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D016212:Transforming Growth Factor beta; D006820:Hyaluronic Acid