A major problem confronting craniofacial repair is the difficulty in restoring soft-tissue function and contour in patients with anomalies including hemifacial microsomia, unilateral clefts of lips and palate as well as defects in the TMJ. In particular, repair of skeletal muscle defects is limited by difficulty in its transplantation and survival. A logical approach is to use existing population of muscle satellite cells which are quiescent undifferentiated precursors found beneath the basement membrane of mature muscle fibers. Following injury, activated satellite cells regenerate muscle after initiating a differentiation program whereby they migrate along laminin-rich basement membrane, proliferate, differentiate, and integrate with preexisting myofibers. Recent evidence supports the notion that satellite cells are heterogeneous and have stem cell potential. We have shown that the laminin-binding alpha 7 integrin, which is important for myoblast migration, is expressed on a subset of satellite cells and is upregulated in terminally differentiated myotubes. In this application, we propose to examine the potential of using alpha 7-positive human satellite cells for direct repair of muscle defects. We will explore the hypothesis that alpha 7 expressing satellite cells are pluripotent stem cells capable of regenerating skeletal muscle and other tissue such as bone. The proposal represents three aims.
In aim 1 we will characterize human muscle-derived satellite cells and correlate expression of alpha 7 integrin with their differentiation potential for skeletal muscle and other tissue lineages.
Aim 2 will determine the expression and function of the alpha 7 integrin during human skeletal muscle development.
Aim 3 is focused on the use of alpha 7-expressing human skeletal muscle stem cells to engineer in vitro three-dimensional skeletal muscle myofibers. These studies will form the basis for strategies that target the mechanical reintegration of regenerating myotubes to repair orofacial muscle structures using adult skeletal muscle stem cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE015404-01
Application #
6687239
Study Section
Special Emphasis Panel (ZDE1-PZ (37))
Program Officer
Kousvelari, Eleni
Project Start
2003-08-01
Project End
2007-05-31
Budget Start
2003-08-01
Budget End
2004-05-31
Support Year
1
Fiscal Year
2003
Total Cost
$340,875
Indirect Cost
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Dentistry
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Pawlikowski, Bradley; Lee, Laimeng; Zuo, Jianhong et al. (2009) Analysis of human muscle stem cells reveals a differentiation-resistant progenitor cell population expressing Pax7 capable of self-renewal. Dev Dyn 238:138-49
Ozeki, Nobuaki; Jethanandani, Poonam; Nakamura, Hiroshi et al. (2007) Modulation of satellite cell adhesion and motility following BMP2-induced differentiation to osteoblast lineage. Biochem Biophys Res Commun 353:54-9
Ozeki, Nobuaki; Lim, Moon; Yao, Chung-Chen et al. (2006) alpha7 integrin expressing human fetal myogenic progenitors have stem cell-like properties and are capable of osteogenic differentiation. Exp Cell Res 312:4162-80
Jethanandani, Poonam; Kramer, Randall H (2005) Alpha7 integrin expression is negatively regulated by deltaEF1 during skeletal myogenesis. J Biol Chem 280:36037-46
Xiao, Jianqiao; Jethanandani, Poonam; Ziober, Barry L et al. (2003) Regulation of alpha7 integrin expression during muscle differentiation. J Biol Chem 278:49780-8