Abstract
Hair follicle stem cells are extensively reprogrammed by the aging process, manifesting as diminished self-renewal and delayed responsiveness to activating cues, orchestrated by both intrinsic microenvironmental and extrinsic macroenvironmental regulators. Dermal white adipose tissue (dWAT) is one of the peripheral tissues directly adjacent to hair follicles (HFs) and acts as a critical macroenvironmental niche of HF. dWAT directly contributes to HF aging by paracrine signal secretion. However, the altered interrelationship between dWAT and HF with aging has not been thoroughly understood. Here, through microdissection, we separated dWAT from the skin of aged mice (18 months) and young mice (2 months) in telogen and depilation-induced anagen for transcriptome comparing. Notably, compared with young dWAT, aberrant inflammatory regulators were recapitulated in aging dWAT in telogen, including substantial overexpressed inflammatory cytokines, matrix metalloproteinases, and prostaglandin members. Nonetheless, with anagen initiation, inflammation programs were mostly abolished in aging dWAT, and instead of which, impaired collagen biosynthesis, angiogenesis, and melanin synthesis were identified. Furthermore, we confirmed the inhibitory effect on hair growth of CXCL1, one of the most significantly upregulated inflammation cytokines in aging dWAT. Besides this, we also identified the under-expressed genes related to Wnt signaling fibroblast growth factor family members and increased BMP signaling in aging dWAT, further unraveling the emerging role of dWAT in aging HFs malfunction. Finally, we proved that relieving inflammation of aging dWAT by injecting high-level veratric acid stimulated HF regenerative behavior in aged mice. Concomitantly, significantly decreased TNF-a, CCL2, IL-5, CSF2, and increased IL10 in dWAT was identified. Overall, the results elaborated on the complex physiological cycling changes of dWAT during aging, providing a basis for the potential regulatory effect of dWAT on aging HFs.
Highlights
Progressive deterioration in the regenerative potential of stem cells is a hallmark of aging, which results in the failure to maintain proper tissue homeostasis
Upon depilation stimuli, aged hair follicles (HFs) exhibit activation more synchronously, mimicking the response fashion of young mice, though over a longer period. This result indicated that the responsiveness of HFs to tissue-regenerating cues were still retained with aging and could be activated by exogenous stimulus
We found that CXCL1 was one of the top significant upregulated differentially-expressed genes (DEGs) in OTD, and its overexpression in aging Dermal white adipose tissue (dWAT) was further confirmed by immunofluorescence and cytokine array panel
Summary
Progressive deterioration in the regenerative potential of stem cells is a hallmark of aging, which results in the failure to maintain proper tissue homeostasis. Hair follicles (HFs) are independent autonomous stem cell niches and undergo continuous regenerative cycling during their lifespan. HF have diminished self-renewing capacity, manifesting as cycling defects and poor dWAT in Hair Follicle Aging responsiveness to activating stimuli. HF cycling slows down (Figure 1A) with aging and gradually turns into senescent alopecia. Proper homeostasis between inhibiting signals and activating signals underlies continued HF growth. Inhibitory signals transcend the activatory signals, becoming the dominant environmental factor for HFs (Lei and Chuong, 2016)
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