| Summary: | 博士 === 國立臺灣大學 === 醫學工程學研究所 === 105 === How organs deploy their stem cell (SC) pools during metamorphic remodeling is not only vital for homeostasis but also for regenerative potential after injury. Hair follicles (HFs) serve as an exceptional model to study this question because they undergo life-time cyclic growth with structural transformation between anagen (active growth), catagen (regression), and telogen (relative rest). Clinically, radiotherapy and chemotherapy are often inevitably accompanied by various side effects, such as hair loss, which causes great psychological distress in patients. Currently, there is no effective treatment for radiotherapy and chemotherapy-induced hair loss. Up to date, how the growing HFs respond and regenerate after radiotherapy and chemotherapy are not well understood. To investigate this, ionizing radiation (IR) and genotoxic cyclophosphamide (CYP) were employed to damage anagen HFs in mice. We aim to explore the following topics: (1) the cellular effects of IR and CYP injuries on anagen HFs, (2) the cell dynamics of distinct cell populations during HF regeneration from such injuries, (3) the molecular mechanisms of dystrophy and regeneration in anagen HFs. We found that both IR and CYP induced a dose-dependent DNA damage and apoptosis mainly in the proliferative matrix cells. Hair loss was observed after high-dose of IR and CYP injuries. Combining BrdU incorporation and lineage tracing, we found that, depending on the severity of IR injury, anagen HFs activated two distinct regenerative attempts to regenerate hair bulbs and to avoid regression through mobilization and dedifferentiation of two different populations of ectopic progenitor cells. After low-dose of IR, the K5+ basal hair bulb cells, rather than bulge stem cells (BgSCs), were quickly activated to replenish the germinative and matrix cells lost by apoptosis and regenerated concentric layers of various differentiations between 12 and 72 hrs. We named it “the early regenerative attempt”. After high-dose of IR, when all basal hair bulb, germinative, and matrix cells were depleted by apoptosis, the surviving radioresistant outer root sheath cells rapidly dedifferentiated toward the SC-like state and fueled HF regeneration between 72 and 120 hrs. We named it “the late regenerative attempt”. These dedifferentiated ectopic progenitor cells were functionally similar to the secondary hair germ stem cells (ShgSCs) in telogen HFs. BgSC activation was detected at day 5 when the hair bulb has been regenerated by the dedifferentiated ectopic progenitor cells. By immunostaining and RNA sequencing, we found that Wnt/β-catenin signaling was transiently suppressed in a p53-dependent manner, and Wnt/β-catenin signaling reactivation was a prerequisite for regenerative attempts from IR injury. Inhibiting Wnt/β-catenin signaling reactivation abolished the regenerative attempts. Finally, we demonstrated that both IR and CYP-induced alopecia could be largely prevented by enhancing the ectopic SC mobilization through augmenting Wnt/β-catenin signaling. These results demonstrate that the wide deployment of multipotent cells in anagen HFs confers flexible regenerative strategies upon them to enable prompt regeneration from genotoxic injury. Enhancing ectopic progenitor mobilization can be a potential strategy to prevent hair loss from radiotherapy and chemotherapy.
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