Fibroblasts cultured from venous ulcers display cellular characteristics of senescence

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Abstract

Purpose:

A well-recognized characteristic of venous ulcers is impaired healing. Fibroblasts cultured from venous ulcers (wound-fb) have been shown to have reduced growth rates and are larger than normal fibroblasts (normal-fb) from the ipsilateral limb. Reduced growth capacity and morphologic changes are 2 well-known traits of cellular senescence. Other molecular changes are overexpression of matrix proteins, such as cellular fibronectin (cFN), and enhanced activity of β-galactosidase at pH of 6.0 (senescence associated β-Gal, or SA-β-Gal). Senescence, an irreversible arrest of cell proliferation with maintenance of metabolic functions, may represent in vivo aging and thus may be related to impaired healing.

Methods:

Cultured normal-fb and wound-fb from 7 venous ulcer patients (average age, 51 years) were obtained by taking punch biopsies of the perimeter of the ulcer and from the ipsilateral thigh of the same patient. Growth rates, SA-β-Gal activity, and level of cFN protein (immunoblot) and message (Northern blot) were measured.

Results:

In all patients, wound-fb growth rates were significantly lower than those of normal-fb (P = .006). A higher percentage of SA-β-Gal positive cells were found in all wound-fb (average, 6.3% vs. 0.21%; P = .016). The level of cFN, was consistently higher in all wound-fb tested. Also, in 4 patients, the level of cFN messenger RNA (mRNA) was increased.

Conclusion:

Fibroblasts cultured from venous ulcers exhibited characteristics associated with senescent cells. Accumulation of senescent cell in ulcer environment may be associated with impaired healing.

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