Skip to main content
SpringerLink
Log in

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

  • Review Article
  • Published:
Journal of Cell Communication and Signaling Aims and scope

Abstract

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.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Achyut BR, Bader DA, Robles AI, Wangsa D, Harris CC, Ried T et al (2013) Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-beta signaling. PLoS Genet 9(2):e1003251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S et al (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303(5659):848–851

    Article  CAS  PubMed  Google Scholar 

  • Bissell MJ, Hines WC (2011) Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 17(3):320–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Du XY (2007) Functional properties and intracellular signaling of CCN1/Cyr61. J Cell Biochem 100(6):1337–1345

    Article  CAS  PubMed  Google Scholar 

  • Chen K, Kwon SH, Henn D, Kuehlmann BA, Tevlin R, Bonham CA et al (2021) Disrupting biological sensors of force promotes tissue regeneration in large organisms. Nat Commun 12(1):5256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheresh DA, Stupack DG (2008) Regulation of angiogenesis: apoptotic cues from the ECM. Oncogene 27(48):6285–6298

    Article  CAS  PubMed  Google Scholar 

  • Cho S, Lowe L, Hamilton TA, Fisher GJ, Voorhees JJ, Kang S (2005) Long-term treatment of photoaged human skin with topical retinoic acid improves epidermal cell atypia and thickens the collagen band in papillary dermis. J Am Acad Dermatol 53(5):769–774

    Article  PubMed  Google Scholar 

  • Cole MA, Quan T, Voorhees JJ, Fisher GJ (2018) Extracellular matrix regulation of fibroblast function: redefining our perspective on skin aging. J Cell Commun Signal 12(1):35–43

    Article  PubMed  PubMed Central  Google Scholar 

  • Cui Y, Worthen C, Haas R, Grill S, Shi M, Tsoi LC et al (2022) The phenotype of dermal fibroblasts in young vs. aged human skin: adaptation to dermal extracellular matrix deterioration and cell autonomous responses. J Investig Dermatol 142(8):S24

    Article  Google Scholar 

  • de Magalhaes JP (2013) How ageing processes influence cancer. Nat Rev Cancer 13(5):357–365

    Article  PubMed  Google Scholar 

  • Eaglstein WH (1986) Wound healing and aging. Dermatol Clin 4(3):481–484

    Article  CAS  PubMed  Google Scholar 

  • Fane M, Weeraratna AT (2020) How the ageing microenvironment influences tumour progression. Nat Rev Cancer 20(2):89–106

    Article  CAS  PubMed  Google Scholar 

  • Fisher GJ, Datta SC, Talwar HS, Wang ZQ, Varani J, Kang S et al (1996) Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature 379(6563):335–339

    Article  CAS  PubMed  Google Scholar 

  • Fisher GJ, Wang ZQ, Datta SC, Varani J, Kang S, Voorhees JJ (1997) Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med 337(20):1419–1428

    Article  CAS  PubMed  Google Scholar 

  • Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S et al (2002) Mechanisms of photoaging and chronological skin aging. Arch Dermatol 138(11):1462–1470

    Article  CAS  PubMed  Google Scholar 

  • Fisher GJ, Varani J, Voorhees JJ (2008) Looking older: fibroblast collapse and therapeutic implications. Arch Dermatol 144(5):666–672

    Article  PubMed  PubMed Central  Google Scholar 

  • Fisher GJ, Quan T, Purohit T, Shao Y, Cho MK, He T et al (2009) Collagen fragmentation promotes oxidative stress and elevates matrix metalloproteinase-1 in fibroblasts in aged human skin. Am J Pathol 174(1):101–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fisher GJ, Sachs DL, Voorhees JJ (2014) Ageing: collagenase-mediated collagen fragmentation as a rejuvenation target. Br J Dermatol 171(3):446–449

    Article  CAS  PubMed  Google Scholar 

  • Gelse K, Poschl E, Aigner T (2003) Collagens–structure, function, and biosynthesis. Adv Drug Deliv Rev 55(12):1531–1546

    Article  CAS  PubMed  Google Scholar 

  • Gordon MK, Hahn RA (2010) Collagens. Cell Tissue Res 339(1):247–257

    Article  CAS  PubMed  Google Scholar 

  • Goruppi S, Dotto GP (2013) Mesenchymal stroma: primary determinant and therapeutic target for epithelial cancer. Trends Cell Biol 23(12):593–602

    Article  CAS  PubMed  Google Scholar 

  • Griffiths CE, Russman AN, Majmudar G, Singer RS, Hamilton TA, Voorhees JJ (1993) Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). N Engl J Med 329(8):530–535

    Article  CAS  PubMed  Google Scholar 

  • Holmes DF, Lu Y, Starborg T, Kadler KE (2018) Collagen fibril assembly and function. Curr Top Dev Biol 130:107–142

    Article  CAS  PubMed  Google Scholar 

  • Holt DR, Kirk SJ, Regan MC, Hurson M, Lindblad WJ, Barbul A (1992) Effect of age on wound healing in healthy human beings. Surgery 112(2):293–297

    CAS  PubMed  Google Scholar 

  • Hu B, Castillo E, Harewood L, Ostano P, Reymond A, Dummer R et al (2012) Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling. Cell 149(6):1207–1220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jacob MP (2003) Extracellular matrix remodeling and matrix metalloproteinases in the vascular wall during aging and in pathological conditions. Biomed Pharmacother 57(5–6):195–202

    Article  CAS  PubMed  Google Scholar 

  • Jensen JM, Proksch E (2009) The skin’s barrier. G Ital Dermatol Venereol 144(6):689–700

    CAS  PubMed  Google Scholar 

  • Jonason AS, Kunala S, Price GJ, Restifo RJ, Spinelli HM, Persing JA et al (1996) Frequent clones of p53-mutated keratinocytes in normal human skin. Proc Natl Acad Sci USA 93(24):14025–14029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kafi R, Kwak HS, Schumacher WE, Cho S, Hanft VN, Hamilton TA et al (2007) Improvement of naturally aged skin with vitamin A (retinol). Arch Dermatol 143(5):606–612

    Article  CAS  PubMed  Google Scholar 

  • Kang S, Fisher GJ, Voorhees JJ (2001) Photoaging: pathogenesis, prevention, and treatment. Clin Geriatr Med 17(4):643–659

    Article  CAS  PubMed  Google Scholar 

  • Kanitakis J (2002) Anatomy, histology and immunohistochemistry of normal human skin. Eur J Dermatol 12(4):390–399

    PubMed  Google Scholar 

  • Kaufman SR (2009) Developments in age-related macular degeneration: diagnosis and treatment. Geriatrics 64(3):16–19

    PubMed  Google Scholar 

  • Kaur A, Ecker BL, Douglass SM, Kugel CH 3rd, Webster MR, Almeida FV et al (2019) Remodeling of the collagen matrix in aging skin promotes melanoma metastasis and affects immune cell motility. Cancer Discov 9(1):64–81

    Article  CAS  PubMed  Google Scholar 

  • Knox S, O’Boyle NM (2021) Skin lipids in health and disease: a review. Chem Phys Lipids 236:105055

    Article  CAS  PubMed  Google Scholar 

  • Lau LF (2011) CCN1/CYR61: the very model of a modern matricellular protein. Cell Mol Life Sci 68(19):3149–3163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liggett LA, DeGregori J (2017) Changing mutational and adaptive landscapes and the genesis of cancer. Biochim Biophys Acta Rev Cancer 1867(2):84–94

    Article  CAS  PubMed  Google Scholar 

  • Martin P, Nunan R (2015) Cellular and molecular mechanisms of repair in acute and chronic wound healing. Br J Dermatol 173(2):370–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S et al (2015) Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348(6237):880–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nelson CM, Bissell MJ (2006) Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu Rev Cell Dev Biol 22:287–309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ng MR, Brugge JS (2009) A stiff blow from the stroma: collagen crosslinking drives tumor progression. Cancer Cell 16(6):455–457

    Article  CAS  PubMed  Google Scholar 

  • Pickup M, Novitskiy S, Moses HL (2013) The roles of TGFbeta in the tumour microenvironment. Nat Rev Cancer 13(11):788–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pilkington SM, Bulfone-Paus S, Griffiths CEM, Watson REB (2021) Inflammaging and the Skin. J Invest Dermatol 141(4S):1087–1095

    Article  CAS  PubMed  Google Scholar 

  • Purohit T, He T, Qin Z, Li T, Fisher GJ, Yan Y et al (2016) Smad3-dependent regulation of type I collagen in human dermal fibroblasts: impact on human skin connective tissue aging. J Dermatol Sci 83(1):80–83

    Article  CAS  PubMed  Google Scholar 

  • Qin Z, Okubo T, Voorhees JJ, Fisher GJ, Quan T (2014a) Elevated cysteine-rich protein 61 (CCN1) promotes skin aging via upregulation of IL-1beta in chronically sun-exposed human skin. Age (dordr) 36(1):353–364

    Article  CAS  PubMed  Google Scholar 

  • Qin Z, Voorhees JJ, Fisher GJ, Quan T (2014b) Age-associated reduction of cellular spreading/mechanical force up-regulates matrix metalloproteinase-1 expression and collagen fibril fragmentation via c-Jun/AP-1 in human dermal fibroblasts. Aging Cell 13(6):1028–1037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qin Z, Balimunkwe RM, Quan T (2017) Age-related reduction of dermal fibroblast size upregulates multiple matrix metalloproteinases as observed in aged human skin in vivo. Br J Dermatol 177(5):1337–1348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qin Z, Fisher GJ, Voorhees JJ, Quan T (2018) Actin cytoskeleton assembly regulates collagen production via TGF-beta type II receptor in human skin fibroblasts. J Cell Mol Med 22(9):4085–4096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quan T, Fisher GJ (2015) Role of age-associated alterations of the dermal extracellular matrix microenvironment in human skin aging: a mini-review. Gerontology 61(5):427–434

    Article  CAS  PubMed  Google Scholar 

  • Quan T, Qin Z, Xia W, Shao Y, Voorhees JJ, Fisher GJ (2009) Matrix-degrading metalloproteinases in photoaging. J Investig Dermatol Symp Proc 14(1):20–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quan T, Qin Z, Robichaud P, Voorhees JJ, Fisher GJ (2011) CCN1 contributes to skin connective tissue aging by inducing age-associated secretory phenotype in human skin dermal fibroblasts. J Cell Commun Signal 5(3):201–207

    Article  PubMed  PubMed Central  Google Scholar 

  • Quan T, Little E, Quan H, Qin Z, Voorhees JJ, Fisher GJ (2013a) Elevated matrix metalloproteinases and collagen fragmentation in photodamaged human skin: impact of altered extracellular matrix microenvironment on dermal fibroblast function. J Invest Dermatol 133(5):1362–1366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quan T, Wang F, Shao Y, Rittie L, Xia W, Orringer JS et al (2013b) Enhancing structural support of the dermal microenvironment activates fibroblasts, endothelial cells, and keratinocytes in aged human skin in vivo. J Invest Dermatol 133(3):658–667

    Article  CAS  PubMed  Google Scholar 

  • Quan T, Xiang Y, Liu Y, Qin Z, Yang Y, Bou-Gharios G et al (2021) Dermal fibroblast CCN1 expression in mice recapitulates human skin dermal aging. J Invest Dermatol 141(4S):1007–1016

    Article  CAS  PubMed  Google Scholar 

  • Ricard-Blum S (2011) The collagen family. Cold Spring Harb Perspect Biol 3(1):a004978

    Article  PubMed  PubMed Central  Google Scholar 

  • Rockey DC, Bell PD, Hill JA (2015) Fibrosis–a common pathway to organ injury and failure. N Engl J Med 372(12):1138–1149

    Article  CAS  PubMed  Google Scholar 

  • Rogers JD, Holmes JW, Saucerman JJ, Richardson WJ (2021) Mechano-chemo signaling interactions modulate matrix production by cardiac fibroblasts. Matrix Biol plus 10:100055

    Article  CAS  PubMed  Google Scholar 

  • Rozhok AI, DeGregori J (2015) Toward an evolutionary model of cancer: considering the mechanisms that govern the fate of somatic mutations. Proc Natl Acad Sci USA 112(29):8914–8921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rutter N (2000) The dermis. Semin Neonatol 5(4):297–302

    Article  CAS  PubMed  Google Scholar 

  • Schaefer L (2018) Decoding fibrosis: mechanisms and translational aspects. Matrix Biol 68–69:1–7

    Article  PubMed  Google Scholar 

  • Shoulders MD, Raines RT (2009) Collagen structure and stability. Annu Rev Biochem 78:929–958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valencia IC, Falabella A, Kirsner RS, Eaglstein WH (2001) Chronic venous insufficiency and venous leg ulceration. J Am Acad Dermatol 44(3):401–421

    Article  CAS  PubMed  Google Scholar 

  • van der Kraan PM (2017) The changing role of TGFbeta in healthy, ageing and osteoarthritic joints. Nat Rev Rheumatol 13(3):155–163

    Article  PubMed  Google Scholar 

  • Vanharanta S, Massague J (2012) Field cancerization: something new under the sun. Cell 149(6):1179–1181

    Article  CAS  PubMed  Google Scholar 

  • Varani J, Warner RL, Gharaee-Kermani M, Phan SH, Kang S, Chung JH et al (2000) Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin. J Invest Dermatol 114(3):480–486

    Article  CAS  PubMed  Google Scholar 

  • Verzijl N, DeGroot J, Thorpe SR, Bank RA, Shaw JN, Lyons TJ et al (2000) Effect of collagen turnover on the accumulation of advanced glycation end products. J Biol Chem 275(50):39027–39031

    Article  CAS  PubMed  Google Scholar 

  • Wang F, Garza LA, Kang S, Varani J, Orringer JS, Fisher GJ et al (2007) In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol 143(2):155–163

    Article  CAS  PubMed  Google Scholar 

  • Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines. Physiol Rev 83(3):835–870

    Article  CAS  PubMed  Google Scholar 

  • Wong R, Geyer S, Weninger W, Guimberteau JC, Wong JK (2016) The dynamic anatomy and patterning of skin. Exp Dermatol 25(2):92–98

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institute of Health (AG054835 to GJ Fisher & T Quan; AG051849 to GJ Fisher & T Quan and P30AR075043 to Gudjonsson).

Author information

Authors and Affiliations

  1. Department of Dermatology, University of Michigan, Ann Arbor, MI, USA

    Gary J. Fisher, Bo Wang, Yilei Cui, Mai Shi, Yi Zhao, Taihao Quan & John J. Voorhees

  2. Department of Dermatology, Tsinghua Changgung Hospital, Tsinghua University, Beijing, China

    Gary J. Fisher, Bo Wang, Yilei Cui, Mai Shi, Yi Zhao, Taihao Quan & John J. Voorhees

Authors
  1. Gary J. Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yilei Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mai Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Taihao Quan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John J. Voorhees
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gary J. Fisher.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fisher, G.J., Wang, B., Cui, Y. et al. Skin aging from the perspective of dermal fibroblasts: the interplay between the adaptation to the extracellular matrix microenvironment and cell autonomous processes. J. Cell Commun. Signal. 17, 523–529 (2023). https://doi.org/10.1007/s12079-023-00743-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12079-023-00743-0

Keywords

Search

Navigation