Adult stem cells are defined by their capacity to differentiate into a specific tissue type while maintaining their own population through a 'self-renewal'process. A precise balance of the cell fate choice between self-renewal and differentiation is critical for stem cell function, tissue homeostasis and prevention of tumor formation. However, the molecular mechanisms regulating this process are unclear. Satellite cells in the skeletal muscle represent one of the few systems in which stem self- renewal and differentiation can be elegantly dissected. Specifically, satellite cells can asymmetrically generate self-renewal and committed daughter cells upon apical-basal, but not planar, oriented cell divisions. Our long-term goal is to understand how signals within the muscle regulate satellite cell self-renewal and differentiation, and utilize this knowledge to enhance satellite cell function and improve the repair of diseased muscles. Here, we aim to investigate the role of 'Notch'signaling in the regulation of muscle stem cell fate. The Notch signaling will be visualized using a transgenic mouse in which Notch-activated cells exhibit green fluorescence. We will then examine whether Notch signaling regulates stem cell fate and self-renewal in undamaged and regenerating muscles, respectively. We will further genetically activate or inactivate key components of the Notch signaling pathway and ask how this perturbation shifts the balance between stem cell self-renewal and differentiation. Finally, we will investigate the molecular regulation of Notch signaling in satellite cells. These studies may lead to development of novel therapeutic approaches to improve muscle repair in the aged and diseased muscles that are characterized by loss of stem cells.

Public Health Relevance

Understanding how the developmental fate of muscle stem cells is regulated may lead to potential therapeutic approaches to enhance stem cell function and restore degenerated muscles caused by aging and muscle diseases, conditions that affect a quarter of Americans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR060652-05
Application #
8703013
Study Section
Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Purdue University
Department
Veterinary Sciences
Type
Earth Sciences/Resources
DUNS #
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Wang, Chao; Wang, Min; Arrington, Justine et al. (2017) Ascl2 inhibits myogenesis by antagonizing the transcriptional activity of myogenic regulatory factors. Development 144:235-247
Yang, Xin; Yang, Shiqi; Wang, Chao et al. (2017) The hypoxia-inducible factors HIF1? and HIF2? are dispensable for embryonic muscle development but essential for postnatal muscle regeneration. J Biol Chem 292:5981-5991
Yue, Feng; Bi, Pengpeng; Wang, Chao et al. (2017) Pten is necessary for the quiescence and maintenance of adult muscle stem cells. Nat Commun 8:14328
Wang, Chao; Liu, Weiyi; Nie, Yaohui et al. (2017) Loss of MyoD Promotes Fate Transdifferentiation of Myoblasts Into Brown Adipocytes. EBioMedicine 16:212-223
Yue, Feng; Bi, Pengpeng; Wang, Chao et al. (2016) Conditional Loss of Pten in Myogenic Progenitors Leads to Postnatal Skeletal Muscle Hypertrophy but Age-Dependent Exhaustion of Satellite Cells. Cell Rep 17:2340-2353
Shan, Tizhong; Xiong, Yan; Kuang, Shihuan (2016) Deletion of Lkb1 in adult mice results in body weight reduction and lethality. Sci Rep 6:36561
Nie, Yaohui; Sato, Yoriko; Wang, Chao et al. (2016) Impaired exercise tolerance, mitochondrial biogenesis, and muscle fiber maintenance in miR-133a-deficient mice. FASEB J 30:3745-3758
Shan, Tizhong; Xiong, Yan; Zhang, Pengpeng et al. (2016) Lkb1 controls brown adipose tissue growth and thermogenesis by regulating the intracellular localization of CRTC3. Nat Commun 7:12205
Bi, Pengpeng; Yue, Feng; Karki, Anju et al. (2016) Notch activation drives adipocyte dedifferentiation and tumorigenic transformation in mice. J Exp Med 213:2019-37
Shan, Tizhong; Zhang, Pengpeng; Xiong, Yan et al. (2016) Lkb1 deletion upregulates Pax7 expression through activating Notch signaling pathway in myoblasts. Int J Biochem Cell Biol 76:31-8

Showing the most recent 10 out of 45 publications