Dynamics of Hair Follicle Morphogenesis and Skin Homeostasis

[摘要] Mammalian skin and hair act as a protective barrier to protect our bodies from external damage while also regulating water loss. Hair follicles form in development and continue to produce new hairs throughout adult life. My thesis examined poorly understood aspects of hair follicle biology, including temporal features of terminal differentiation within the follicle, and the link between hair canal development and the severe human skin disease, harlequin ichthyosis. During hair growth, matrix progenitor cells housed at the bottom of the follicle undergo terminal differentiation to form the concentric layers of the hair follicle. These differentiation events are believed to require signals from the mesenchymal dermal papilla (DP), although it remains unclear how DP-progenitor cell interactions regulate specific cell fate decisions. I found that the matrix progenitor population can be separated into early and late phases based on distinct temporal, molecular and functional characteristics. Early matrix cells can undergo differentiation in the absence of sonic hedgehog (Shh), bone morphogenetic protein (BMP) signaling, and DP maturation. In contrast, later matrix cell populations require a mature DP and Shh and BMP signaling for differentiation to occur. The acquisition of epidermal barrier function occurs in conjunction with hair follicle morphogenesis, with the hair shaft extending out of an opening in the epidermis called the hair canal. The mechanisms underlying hair canal formation are poorly understood. Previous findings from our lab identified a novel population of hair follicle-derived cells marked by the expression of keratin 79 (K79), which may play a role in hair canal formation. I found that K79+ cells stream into the epidermis prior to barrier formation and remain there until late in development, when they are lost to apoptosis concurrent with initial canal specification. The early entry of K79+ cells into the epidermis sets the stage for canal formation and circumvents the complications associated with breaching a complete epidermal barrier.Epidermal barrier function is compromised in the severe skin disease harlequin ichthyosis (HI), which is caused by loss-of-function mutations in the lipid transporter gene ABCA12. HI patients are born with a thick plate-like outer skin layer and frequently die shortly after birth. Interestingly, case studies indicate that the HI phenotype appears in the hair canal, prior to the epidermis. These observations raise the possibility of a link between a barrier disease and hair follicle formation. I found that Abca12 is expressed in the hair canal, the same site affected in HI patients. The involvement of the hair follicle in HI has not been addressed due to limitations of the available genetic tools. I generated a new mouse model which facilitates spatial and temporal deletion of Abca12. Using this model, I can delete Abca12 in specific cell populations (e.g., hair follicle) at specific times (e.g., development, adult). This model will allow for critical evaluation of HI pathogenesis as well as the role of ABCA12 in normal skin and hair follicle development. In summary, my findings expand our understanding of key aspects of hair follicle biology, including terminal differentiation, and the mechanisms governing hair canal formation. Further, the conditional Abca12-knockout mouse model can be leveraged in future studies to address critical questions in skin biology and to understand the role of ABCA12 in diverse organ systems.

[发布机构] University of Michigan

[效力级别] epidermis

[关键词] hair follicle;epidermis;development;homeostasis;epithelial-mesenchymal interactions;harlequin ichthyosis;Molecular;Cellular and Developmental Biology;Science (General);Science;Cellular & Molecular Biology