Investigating the mechanisms underlying age-related dysfunctions in skin and hair follicle regeneration

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Age-associated decline in overall skin function and impaired cutaneous wound healing are both direct consequences of the progressively weakening dermis and degeneration of necessary appendages such as glands, nerves and hair follicles (HFs). With a fresh perspective and access to new tools, I revisit aging skin phenotypes including hair loss and deficiency in wound healing from the perspective of the mesenchyme and its progenitors. In Chapter 2, I present a manuscript establishing the transcriptomic identities of bipotent hair follicle mesenchymal stem cells (hfDSCs) and its progeny dermal papilla (DP) via bulk RNA sequencing. Utilizing in vitro cell culture drug treatments, in vivo drug injections, and genetic deletion of Rspondin3 (Rspo3), my work define Rspo3 as an important modulator of epithelial-mesenchymal crosstalk in HF regeneration. In Chapter 3, I ask whether hfDSCs are lost with age and whether their dysfunction contributes to age-associated hair loss. Reporter mice experiments including long-term fate mapping and in vivo clonal analysis characterize the functional deficits of hfDSCs. Analysis of single-cell RNA sequencing (scRNAseq) data reveals that the driver of HF mesenchymal aging is senescence. In Chapter 4, I present on going work that describes the failure of aged mice to undergo wound induced hair neogenesis (WIHN). Using scRNAseq, I determine that mesenchymal fibroblasts in aged mice cannot acquire a regenerative phenotype after injury due to an overabundance of senescent fibroblasts. Senescent fibroblasts persist into late stages of wound healing, contributing to the loss of WIHN. In Chapter 5, I present a co-lead study investigating the impact of genomic instability on progenitor maintenance. I introduce a novel model of accelerated aging with skin deficiencies such as hair loss and hyper pigmentation. Genomic instability significantly impairs the HF regeneration cycle, and as a result, the HF degenerates in a process closely resembling natural HF aging. Characterizing the roles of aging dermal progenitors in skin deficiencies provides new insights into skin aging and aging stem cell research. Additionally, my work on defining functionally diverse fibroblast populations contribute to the growing appreciation for the importance of fibroblast heterogeneity in maintaining overall skin function.
Stem Cell, Hair follicle, Skin mesenchyme, Aging, Senescence, Tissue regeneration, Single cell RNA sequencing, Hair loss, Fibroblasts
Shin, W. (2020). Investigating the mechanisms underlying age-related dysfunctions in skin and hair follicle regeneration (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from