Aging alters functionally human dermal papillary fibroblasts but not reticular fibroblasts: a new view of skin morphogenesis and aging - PubMed (original) (raw)
Aging alters functionally human dermal papillary fibroblasts but not reticular fibroblasts: a new view of skin morphogenesis and aging
Solène Mine et al. PLoS One. 2008.
Abstract
Understanding the contribution of the dermis in skin aging is a key question, since this tissue is particularly important for skin integrity, and because its properties can affect the epidermis. Characteristics of matched pairs of dermal papillary and reticular fibroblasts (Fp and Fr) were investigated throughout aging, comparing morphology, secretion of cytokines, MMPs/TIMPs, growth potential, and interaction with epidermal keratinocytes. We observed that Fp populations were characterized by a higher proportion of small cells with low granularity and a higher growth potential than Fr populations. However, these differences became less marked with increasing age of donors. Aging was also associated with changes in the secretion activity of both Fp and Fr. Using a reconstructed skin model, we evidenced that Fp and Fr cells do not possess equivalent capacities to sustain keratinopoiesis. Comparing Fp and Fr from young donors, we noticed that dermal equivalents containing Fp were more potent to promote epidermal morphogenesis than those containing Fr. These data emphasize the complexity of dermal fibroblast biology and document the specific functional properties of Fp and Fr. Our results suggest a new model of skin aging in which marked alterations of Fp may affect the histological characteristics of skin.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
Figure 1. Experimental definition of Fp and Fr cells.
(A) and (B), principle of papillary (Fp) and reticular (Fr) fibroblast isolation. (C) Histological preparation of a mammary skin sample after dermatome cutting at a depth of 0.3 mm to obtain the superficial dermis with the epidermis. (D) Full thickness histology of the same skin sample. (E) Histological preparation of the skin sample after dermatome cutting at a depth of 0.7 mm to reach the deep dermis. Scale bars = 50 µm. (F) and (G) Photographs of typical cultures of Fp and Fr in light microscopy. Scale bars = 10 µm. (H) and (I) Fluorescence photographs of Fp and Fr after actin and vinculin immuno-staining. Scale bars = 2.5 µm.
Figure 2. Histological characteristics of young and old human skin.
Photographs shown correspond to histological sections of mammary skin biopsies obtained from a 19 year old (A) and a 74 year old donor (B). Sections were stained with hematoxylin, eosin, and saffron (HES). Scale bars = 50 µm. Dp = papillary dermis. Dr = reticular dermis.
Figure 3. Secretion of KGF by Fp and Fr as a function of donor's age.
Evolution of secretion was estimated by linear regression in a cohort of 16 different pairs of Fp and Fr obtained from independent donors, ranging from 19 to 74 years old. Secretion of KGF was quantified. Values are expressed in pg/ml per 105 cells. (A) KGF secretion by Fp samples. (B) KGF secretion by Fr samples. (C) KGF secretion ratio [Fr/Fp].
Figure 4. Evolution with age of Fp and Fr morphology.
Fp and Fr samples from 3 young donors (19 yr, 21 yr, and 26 yr) and 3 old donors (57 yr, 62 yr, and 74 yr) were examined by flow cytometry according to the morphological parameters of size (forward scatter, FSC) and granularity (side scatter, SSC). FSC versus SSC dot plots corresponding to a typical pair of young [19 yr] Fp (A) and Fr (B), and a typical pair of old [74 yr] Fp (C) and Fr (D). Median FSC and SSC values were determined for the different samples. (E) Comparison of Fp and Fr FSC values in young and old donors (mean±SEM, n = 3). (F) Comparison of Fp and Fr SSC values in young and old donors (mean±SEM) (*p<0.05; n.s. = not significant). a.u. = arbitrary unit.
Figure 5. Age-related growth characteristics of Fp and Fr.
Fp and Fr samples from 3 young (19 yr, 19 yr, and 26 yr) and 3 old donors (57 yr, 58 yr, and 67 yr) were cultured for 21 days. Cellular growth rate was estimated every 7 days after culture initiation. Data are expressed as cumulative expansion curves (means±SEM, n = 3 independent samples). (A) Comparison of growth rates of Fp and Fr from young donors. (B) Comparison of growth rates of Fp and Fr from old donors (*p<0.05; n.s. = not significant).
Figure 6. Evolution with age of Fp and Fr clonogenic capacity.
The growth capacity of Fp and Fr samples from 4 young (19 yr, 21 yr, 23 yr, and 26 yr) and 4 old donors (57 yr, 60 yr, 63 yr, and 74 yr) was analyzed in term of colony-forming efficiency (CFE) and size of the colonies generated by these different fibroblast samples. (A) Comparison of the CFE of Fp and Fr from young and old donors. Data are expressed as number of colonies obtained from 100 plated fibroblasts (means±SEM, n = 4, independent samples). Colonies were classified according to their individual area (mm2). (B) Photographs of colonies of typical ‘small’, ‘intermediate’, and ‘large’ size. Scale bars = 50 µm. (C) Correspondence between colony area (mm2) and fibroblast number (means±SEM, n = 10 colonies per size category). (D) Comparison of the sizes of colonies generated by Fp and Fr from young and old donors. The histogram shown corresponds to the number of colonies obtained from 100 plated fibroblasts (means±SEM, n = 4, independent samples), (*p<0.05; n.s. = not significant).
Figure 7. Age-dependent capacity of Fp and Fr to contract a collagen gel.
Dermal equivalents were generated with Fp and Fr samples from 3 young (19 yr, 21 yr, and 26 yr) and 3 old donors (57 yr, 62 yr, and 74 yr). Diameter of lattices (cm) was measured at days 1, 2, 3, and 4. (A) Evolution of the diameter of lattices generated with Fp from young and old donors (means±SEM, n = 3, independent samples). (B) Evolution of the diameter of lattices generated with Fr from young and old donors (means±SEM, n = 3). (*p<0.05; n.s. = not significant).
Figure 8. Age-related impact of Fp and Fr on the epidermal compartment in three-dimensional reconstructed skin.
Keratinocytes from the same batch were seeded onto dermal equivalents containing Fp or Fr from young or old donors. Typical histological sections of reconstructed skin samples made with collagen contracted lattices containing: (A) young Fp; (B) young Fr; (C) old Fp; (D) old Fr. Measurements of the thicknesses of total nucleated (E), cornified (F), granular (G), and spinous (H) keratinocyte layers in reconstructed skins generated in the presence of Fp or Fr from young or old donors. (I) to (L) Typical expression pattern of filaggrin in reconstructed skin epidermis generated in the presence of Fp or Fr from young or old donors. Scale bars = 50 µm.
Figure 9. Age-dependent effects of Fp and Fr on the morphology of reconstructed skin after grafting into nude mice.
The histology of the different types of three-dimensional reconstructed skin samples was next observed 5 weeks after graft onto nude mice: (A) reconstructed skin containing young Fp; (B) young Fr; (C) old Fp; (D) old Fr. All histological sections were stained with hematoxylin, eosin, and saffron (HES). Scale bars = 50 µm.
Figure 10. Model of skin morphogenesis and aging.
Preferential modifications of Fp characteristics throughout aging may have structural and physiological consequences not only on the dermis, but also on the epidermis. Cellular differentiation of epidermal keratinocytes and dermal fibroblasts may be symmetrically organized including upward differentiation of keratinocytes associated with downward differentiation of fibroblasts. This cellular organization may be altered during skin aging.
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