Editors' ChoiceStem Cells

Inflammation Ages Stem Cells

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Science Signaling  09 Oct 2012:
Vol. 5, Issue 245, pp. ec259
DOI: 10.1126/scisignal.2003672

The prominent age-related changes in the appearance, function, and healing properties of skin have been hypothesized to result from changes in epidermal stem cells. Using transgenic mice that harbor a green fluorescent protein–tagged Keratin-15 reporter (Krt-15-GFP), Doles et al. found that the number of Krt-15-GFP–positive (GFP+) hair follicle stem cells increased with age. However, the proliferative capacity of these stem cells, which contribute to sebaceous gland function, hair follicle cycling, and wound repair, decreased with age. When isolated from young mice, these GFP+ stem cells exhibited greater colony-forming capacity in vitro than those isolated from aged mice. Exposure to ionizing radiation or topical treatment with a chemical that induces epidermal hyperproliferation caused expansion of the GFP+ cell population in young mice but had no effect (radiation) or even reduced (chemical agent) the number of GFP+ stem cells in aged mice. Transcriptome analysis of GFP+ cells revealed age-related changes in the expression of genes associated with the Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling pathway, including an increase in stem cells from aged mice in the expression of suppressor of cytokine signaling 1 (Socs1) and Socs2 that participate in a negative feedback loop to limit inflammation-associated JAK-STAT signaling. The abundance of many proinflammatory cytokines was increased in the epidermis of aged mice compared to the epidermis of young mice, as was the abundance of phosphorylated (activated) Stat3, consistent with increased inflammatory signaling in epidermal stem cells. Two of these cytokines (IL-1α and ICAM-1) suppressed the growth of keratinocytes cultured from young mice. Treatment with any of three JAK inhibitors (pyridone-6, ruxolitinib, and tofacitinib) rescued the reduced colony-forming ability of epidermal stem cells isolated from aged mice, but this rescue was lost as the cells were propagated in vitro. In vivo, topical application of pyridine-6 stimulated hair follicle cycling in aged epidermis but also depleted the Krt-15–GFP+ stem cell pool. These results imply that age-related changes in the inflammatory milieu may account for age-related phenotypic changes in skin, such as reduced hair follicle cycling and impaired wound healing, and suggest that inflammation may play a role in stem cell aging in other contexts.

J. Doles, M. Storer, L. Cozzuto, G. Roma, W. M. Keyes, Age-associated inflammation inhibits epidermal stem cell function. Genes Dev. 26, 2144–2153 (2012). [Abstract] [Full Text]

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