Internalization and processing of epidermal growth factor in aging human fibroblasts in culture

Matrisian, Lynn M.; Davis, Diana E.; Magun, Bruce E.

doi:10.1016/0531-5565(87)90043-x

Cited by 12 publications

(3 citation statements)

References 20 publications

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“…43 Beyond the effects of aging on cellular migration and proliferation, a loss of responsiveness to a variety of cytokines has been reported after in vitro and in vivo aging in human fibroblasts. 44,45 The regulation of cellular phenotype and differentiation during tissue injury is an important determinant of woundhealing outcomes. In this context TGF-␤1 is a key regulator of the wound-healing process as it is a key regulator of the fibroblast-myofibroblast phenotype.…”

Section: Discussionmentioning

confidence: 99%

Age-Related Changes in Pericellular Hyaluronan Organization Leads to Impaired Dermal Fibroblast to Myofibroblast Differentiation

Simpson

Meran

Thomas

et al. 2009

The American Journal of Pathology

107

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We have previously demonstrated that transforming growth factor-beta1 (TGF-beta1)-mediated fibroblast-myofibroblast differentiation is associated with accumulation of a hyaluronan (HA) pericellular coat. The current study demonstrates failure of fibroblast-myofibroblast differentiation associated with in vitro aging. This is associated with attenuation of numerous TGF-beta1-dependent responses, including HA synthesis and induction of the HA synthase enzyme HAS2 and the hyaladherin tumor necrosis factor-alpha-stimulated gene 6 (TSG-6), which led to an age-related defect in pericellular HA coat assembly. Inhibition of HAS2-dependent HA synthesis by gene silencing, removal of the HA coat by hyaluronidase digestion, or gene silencing of TSG-6 or cell surface receptor CD44 led to abrogation of TGF-beta1-dependent induction of alpha-smooth muscle actin in "young" cells. This result supports the importance of HAS2-dependent HA synthesis and the HA coat during phenotypic activation. Interleukin-1beta stimulation, however, failed to promote phenotypic conversion despite coat formation. A return to basal levels of HA synthesis in aged cells by HAS2 overexpression restored TGF-beta1-dependent induction of TSG-6 and pericellular HA coat assembly. However, this did not lead to the acquisition of a myofibroblast phenotype. Coordinated induction of HAS2 and TSG-6 facilitation of pericellular HA coat assembly is necessary for TGF-beta1-dependent activation of fibroblasts, and both components of this response are impaired with in vitro aging. In conclusion, the HA pericellular coat is integral but not sufficient to correct for the age-dependent defect in phenotypic conversion.

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Section: Discussionmentioning

confidence: 99%

Age-Related Changes in Pericellular Hyaluronan Organization Leads to Impaired Dermal Fibroblast to Myofibroblast Differentiation

Simpson

Meran

Thomas

et al. 2009

The American Journal of Pathology

107

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“…Irreversible growth arrest of senescent cells is suggested to be strongly related to the attenuated response to growth factors (3,4). However, in the case of the epidermal growth factor (EGF), the kinetics for binding in senescent cells still remains active as in early-passaged presenescent cells (5,6). Recently, we reported that up-regulation of caveolin in the senescent cells is partly responsible for the attenuated response to growth factors through the regulation of the downstream signal pathway (7).…”

mentioning

confidence: 99%

Down‐regulation of amphiphysin‐1 is responsible for reduced receptor‐mediated endocytosis in the senescent cells

Park

Cho

et al. 2001

FASEB j.

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Senescent cells have been generally characterized to have improper responsiveness to external stimuli and inefficient uptake of materials compared with presenescent cells, probably by downregulation of receptor-mediated endocytosis. Using transferrin-uptake assay and Western blot of endocytosis-related proteins, we found that a significant decrease of amphiphysin-1 is strongly related to the reduction of receptor-mediated endocytosis in both human diploid fibroblasts of multipassages and hydrogen peroxide-induced premature senescence. We reconfirmed the pivotal role of amphiphysin-1 in senescence by showing that transfection of dominant negative amphiphysin-1 reduces transferrin uptake in presenescent cells and that microinjection of wildtype amphiphysin-1 into senescent cells restores the ability of the transferrin uptake nearly up to that of the presenescent cell. We conclude that the loss of endocytotic activity of senescent cells is directly related to the down-regulation of amphiphysin-1, and its functional restorability can be induced by simple microinjection of amphiphysin-1 gene in the senescent cells.Key words: amphiphysin-1 • endocytosis • senescence • human diploid fibroblast ormal human diploid fibroblasts (HDFs) do not divide indefinitely and eventually lead to an arrest of cell division by a process termed cellular, or replicative, senescence (1, 2). Irreversible growth arrest of senescent cells is suggested to be strongly related to the attenuated response to growth factors (3,4). However, in the case of the epidermal growth factor (EGF), the kinetics for binding in senescent cells still remains active as in early-passaged presenescent cells (5,6). Recently, we reported that up-regulation of caveolin in the senescent cells is partly responsible for the attenuated response to growth factors through the regulation of the downstream signal pathway (7). However, for the receptor-mediated endocytosis, the clathrin-dependent endocytosis system plays the more active and dominant role over the caveolae system. Therefore, it would be worthwhile to monitor the efficiency of clathrindependent receptor-mediated endocytosis in the senescent cells in order to elucidate the exact mode of the attenuated response to growth factors in the senescent cells. N The functional capacity of clathrin-dependent receptor-mediated endocytosis in the senescent HDF can be illustrated by the transferrin uptake model system (8). To reveal the molecular mechanism for the altered endocytosis of the senescent cells, the expression of proteins related to the clathrin-mediated endocytosis was analyzed and the functional recovery of the receptormediated endocytosis in the senescent cells was attempted. MATERIALS AND METHODS AntibodiesMonoclonal antibodies against clathrin heavy chain (C68220), dynamin (D25520), α-adaptin (A43920), β-adaptin (A35620), and transferrin receptor (CD71: SC-7088) were purchased from Cell culture and induction of senescenceHuman foreskin fibroblasts were isolated from a 7-year-old Korean male (10) in our labor...

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“…As for the EGF-specific receptors, it is found that not only their number stays stable during cellular ageing but also their degradation process remains qualitatively and quantitatively unchanged throughout the cellular lifespan('). It is also reported that the internalization and the consequent acidification of the EGF is equally effective in skin fibroblasts of both early and late passage cultures (55).…”

Section: Growth Factor Receptors and Altered Responsivenessmentioning

confidence: 94%

Altered cellular responsiveness during ageing

Rattan

Derventzi

1991

BioEssays

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The capacity of cells and organisms to respond to external stimuli and to maintain stability in order to survive decreases progressively during ageing. The mitogenic and stimulatory effects of growth factors, hormones and other agents are reduced significantly during cellular ageing. The sensitivity of ageing cells to toxic agents including antibiotics, phorbol esters, radiations and heat shock increases. This failure of homeostasis during cellular ageing does not appear to be due to any quantitative and qualitative defects in the receptor systems. Instead, metabolic defects in the pathways of macromolecular synthesis may be the basis of altered cellular responsiveness during ageing.

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Internalization and processing of epidermal growth factor in aging human fibroblasts in culture

Cited by 12 publications

References 20 publications

Age-Related Changes in Pericellular Hyaluronan Organization Leads to Impaired Dermal Fibroblast to Myofibroblast Differentiation

Age-Related Changes in Pericellular Hyaluronan Organization Leads to Impaired Dermal Fibroblast to Myofibroblast Differentiation

Down‐regulation of amphiphysin‐1 is responsible for reduced receptor‐mediated endocytosis in the senescent cells

Altered cellular responsiveness during ageing

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