S-Space College of Natural Sciences (자연과학대학) Dept. of Biological Sciences (생명과학부) Theses (Ph.D. / Sc.D._생명과학부)
Studies on the establishment of adult muscle stem cells by sex hormones
성호르몬에 의한 성체 근육 줄기세포의 형성에 관한 연구
- 자연과학대학 생명과학부
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 생명과학부, 2017. 2. 공영윤.
- Quiescent satellite cells, known as adult muscle stem cells, possess a remarkable ability to regenerate skeletal muscle following injury throughout life. Active proliferation and differentiation of juvenile satellite cells contribute to myonuclear accretion in the pre-existing myofiber until puberty. Meanwhile, some of juvenile satellite cells preserve their stemness in order to comprise a reservoir of adult stem cells. Although it is known that they mainly originate from multipotent stem/progenitor cells of the somite, the mechanism underlying the establishment of quiescent satellite cell populations is unknown. Stem cells interact with their specialized microenvironment which refers to a stem cell niche. Since satellite cells reside within basal lamina and sarcolemma, myofibers have been considered as a niche component of muscle stem cells. Although a plethora of studies have suggested that myofibers compose a niche of muscle stem cells, the mechanism of muscle stem cell regulation by myofiber niche is not known.
Puberty is initiated via the hypothalamus-pituitary axis by diffusion of gonadotrophin-releasing hormone from hypothalamus. The increased secretion of gonadotropins such as luteinizing and follicular stimulating hormones primarily acts on the ovary and testis to stimulate production of androgens and estrogens. The function of sex hormones is coordinated by paracrine regulatory mechanisms and essential for establishing and promoting the secondary characteristics of reproductive organs at puberty.
Since the conversion of proliferating juvenile satellite cells into quiescent adult satellite cells occurs during puberty and both androgen receptor, and estrogen receptors α/β are highly expressed in skeletal muscles, the hypothalamic–pituitary–gonadal (HPG) axis might be related to the establishment of satellite cell populations.
In this study, I tested whether the HPG axis is responsible for the conversion of cycling juvenile SCs into quiescent adult SCs at puberty. I investigated how the HPG axis generates quiescent SC pools by activating Notch signaling at puberty. Using mouse genetic models (Gnrh1hpg/hpg, MCK-Cre
Arf/y (ARMF), MCK-Cre
Mib1f/f (Mib1MF), Pax7-CreER
Notch1f/f (N1SC) and Pax7-CreER
RosaN1 (N1OE/SC)), surgical (orchiectomy), and pharmacological (antide treatment) approaches, I revealed a novel mechanism that pubertal sex hormones capacitate myofiber niches to activate Notch signaling in the adjacent
juvenile SCs and to orchestrate the establishment of adult satellite cell populations. Myofibers under impaired HPG axis or myofibers lacking Mib1 fail to send Notch signals to juvenile satellite cells, leading to impaired cell cycle exit and depletion. Moreover, the same axis regulates the re-establishment of quiescent satellite cell populations following injury. These findings reveal an unknown link between the sex hormone and the skeletal muscle, which will provide a new insight to understand why sex hormones should be secreted at puberty and maintained throughout life.