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Impaired migration, integrin function, and actin cytoskeletal organization in dermal fibroblasts from a subset of
M J Reed1, N S Ferara, R B Vernon
1Division of Gerontology and Geriatric Medicine, Box 359755, Department of Medicine, University of Washington, Seattle, WA 98104, USA. mjr@u.washington.edu
Abstract:
Deficits in the motility of fibroblasts contribute to age-related impairment of wound healing. We analyzed 'young' fibroblasts from four healthy donors 22-30 years old and 'aged' fibroblasts from six healthy donors 81-92 years old for migratory ability on type I collagen, secretion of matrix metalloproteases (MMPs), attachment to matrices and, expression and function of integrin alpha2beta1. Cells from each donor were analyzed separately in each experiment. Whereas migration of young fibroblasts was uniformly robust, three aged lines migrated well and three migrated poorly. Synthesis of MMP1 and TIMP1, but not MMP2 or MMP9, was increased in the aged fibroblasts relative to the young fibroblast lines irrespective of their motility. All lines of young and aged fibroblasts attached to plastic or collagen with similar efficiency. Although young and aged fibroblasts expressed comparable levels of the alpha2 integrin; the lines of aged fibroblasts that were poor migrators exhibited a significant reduction in alpha2beta1 function relative to fibroblasts with normal migratory capacities. Moreover, the lines of aged fibroblasts that exhibited poor migration demonstrated a disordered actin cytoskeleton and a reduced ability to contract collagen gels. In conclusion, aged fibroblasts, unlike young fibroblasts, displayed variable migratory capacities. Deficient migration by specific lines of aged fibroblasts was not related to the capacity to attach, express alpha2 integrin, or secrete MMPs and TIMP1, but was characterized by disorganized cytoskeletal actin and reduced alpha2beta1 function.
Insights
Aging impairs fibroblast motility, crucial for wound healing. Poor migration in aged cells is linked to reduced integrin alpha2beta1 function and disorganized actin, not attachment or matrix metalloproteinase secretion.
Area of Science:
- Cell Biology
- Dermatology
- Gerontology
Background:
- Fibroblast motility is essential for effective wound healing.
- Aging is associated with impaired wound healing, partly due to reduced fibroblast function.
Purpose of the Study:
- To investigate age-related differences in fibroblast migratory ability.
- To identify the molecular mechanisms underlying impaired fibroblast migration in aged individuals.
Main Methods:
- Compared migratory capacity, matrix metalloproteinase (MMP) secretion, and integrin alpha2beta1 expression/function in young and aged fibroblasts.
- Assessed cell attachment to collagen and actin cytoskeleton organization.
Main Results:
- Aged fibroblasts showed variable migration; some migrated poorly.
- Poorly migrating aged fibroblasts had reduced integrin alpha2beta1 function and disorganized actin cytoskeleton.
- MMP1 and TIMP1 synthesis increased in aged fibroblasts, regardless of motility.
Conclusions:
- Fibroblast migration capacity varies with age.
- Reduced integrin alpha2beta1 function and cytoskeletal disorganization characterize deficient migration in aged fibroblasts.
- Impaired migration is not solely due to altered attachment or MMP/TIMP secretion.