contract lattices. We found that, whatever donor’s age, Fp were less efficient in lattice contraction than Fr, which is in agreement with previous reports [61]. The capacity of Fr to contract lattices remained unchanged throughout aging unlike that of Fp, which increased with age, leading to a reduction of the functional difference between Fp and Fr in old donors. An increased capacity of fetal fibroblast to contract lattices after successive passages in culture has been reported [62], but the specific properties of Fp and Fr were not investigated in is previous study. We have secondly analyzed the effect of Fp and Fr from young and old donors on the development of an epidermis. Lattices containing Fp from young donors promoted the formation of a more correctly stratified and differentiated epidermis than Fr of a similar age. Interestingly, when these reconstructed skin samples were grafted into nude mice, only those containing young Fp formed rete ridge- like structures at the dermal-epidermal interface. It is important to note that all these particularities of young Fp were markedly decreased in Fp from old donors. Based on these results, different hypotheses can be proposed to interpret the age-related changes of the dermal fibroblast populations in the context of skin aging. The Fp population may be progressively lost throughout aging, and be replaced by Fr. This hypothesis is comforted by previous results obtained in a reconstructed skin model, where fibroblast from the deeper dermis migrate to the upper dermis to replace superficial fibroblasts killed after UVA exposure [63]. Several lines of evidence suggest that Fr are in a more advanced state of differentiation than Fp, which leads to the alternative hypothesis that the observed decrease of Fp with age may result from a gradual transition of the Fp state to a Fr state. Thus, cellular aging may be related to a terminal differentiation process, as previously proposed [64,65]. Such a mechanism has been described for fibroblasts derived from the upper dermis during long-term culture. Authors have shown that, after serial cultivations, these cells acquire an expression profile of References 1. Guarente L, Kenyon C (2000) Genetic pathways that regulate ageing in model organisms. Nature 408: 255–262. 2. Martin GM, Oshima J (2000) Lessons from human progeroid syndromes. Nature 408: 263–266. 3. Capri M, Salvioli S, Sevini F, Valensin S, Celani L, et al. (2006) The genetics of human longevity. Ann New York Acad Sci 1067: 252–263. 4. Finch CE, Tanzi RE (1997) Genetics of aging. Science 278: 407–411. 5. 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Synthesis of chemokines and regulation of inflammation. Am J Pathol 151: 317–322. Fp and Fr in Skin Aging collagen chains similar to that of fibroblasts isolated from the deeper part of the dermis [34]. In conclusion, our results shed a new light on the distinct properties of Fp and Fr, their modifications during aging and possible implications on skin aging. In particular, our investiga- tions, performed at the cellular and tissue levels, revealed that the cell population defined as Fp is a central actor in this complex process. As summarized in the schema presented in Figure 10, we propose that the loss of Fp characteristics may have structural and physiological consequences not only on the dermis, but also on the epidermis. In the actual state-of-the-art, much remains to be done to understand the dynamic process leading to the specific evolution of fibroblast characteristics in particular dermal sub-localizations. The interfollicular epidermis is for long known to contain primitive subpopulations of keratinocyte with stem cell properties [66–70]. The more recent discovery of multipotent mesenchymal-like stem cells within the follicular [71] and non-follicular dermis [72–74] opens promising perspectives for future studies on dermal fibroblast origin and fate. Acknowledgments We thank N. Seugnet-Deshayes for her help in colony assays, and B. Buan for flow cytometry analyses. We are grateful to S. Ricois for technical assistance with reconstructed skins, and to P. Rossio and A. Jomard from Galderma for performing the grafting experiments. We are also indebted to E. Bessac, and M. Thomas for statistical analyses. Finally, we wish to thank R. Schmidt for critical reading of this manuscript. Author Contributions Conceived and designed the experiments: SM NOF HP DA. Performed the experiments: SM HP. Analyzed the data: SM NOF DA. Contributed reagents/materials/analysis tools: SM NOF HP DA. 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