Cross-talk between the skeletal muscle stem cells and endothelial cells
2018-03
Loading...
View/Download File
Persistent link to this item
Statistics
View StatisticsJournal Title
Journal ISSN
Volume Title
Title
Cross-talk between the skeletal muscle stem cells and endothelial cells
Authors
Published Date
2018-03
Publisher
Type
Thesis or Dissertation
Abstract
Duchenne muscular dystrophy (DMD) is a progressive neurodegenerative muscle disease caused by the absence of the dystrophin protein. While the muscle develops normally, it is susceptible to contraction-induced damage resulting in segmental necrosis. The damaged muscle is repaired by the resident stem cell, the satellite cell. However, after continuous rounds of regeneration/degeneration, the satellite cell pool is exhausted and the muscle fiber is replaced with fatty infiltrate and fibrosis. Although dystrophin is commonly studied in the muscle cells, its role in the vasculature has only recently been appreciated. The overall goal of research conducted in this thesis is to elucidate the role of the vascular endothelial cell, satellite cell, and their interactions in normal and DMD muscle. We have previously shown that when performed in developmental, there was increased angiogenesis and capillary density in mdx mice with the deletion of one allele for the Vascular Endothelial Growth Factor (VEGF) receptor, Flt1 gene. Interestingly, this led to an increase in muscle stem cells (satellite cells) and improved histological and contractile function. These data suggest that increasing the vasculature can increase the satellite cell pool and ameliorate the dystrophic phenotype seen in DMD model mice. However, the mechanism behind this interaction remains unclear. This thesis will attempt to fill in this gap in knowledge. In the following chapters (Figure 1), we identified VEGF receptors expressed on satellite cells and show that VEGFA binds to FLT1 to protect the cells from apoptosis. We investigated the cell-cell crosstalk between satellite cells and endothelial cells using 3-dimentional imaging. We showed that satellite cells secrete VEGFA to pattern the capillaries and in turn the endothelial cells keep the satellite cells in a quiescent state through expression of the notch ligand Delta-like protein 4 (DLL4). From a disease context, we utilized conditional Flt1 knockout mice to examine whether post-natal abolishment of Flt1 results in increased capillary density in the skeletal muscle and an improvement in the dystrophic phenotype in the mdx mice. Lastly, we utilized several strategies for recapitulating this phenomenon in a therapeutic manner. This will serve as a proof of concept to see whether FLT1 can be used as a drug target for the treatment of DMD. This information has applications beyond DMD as VEGF and its receptors are also under investigation for the treatment of peripheral artery disease, ischemic injury, as well as anti-cancer therapy. Outcomes from these studies will not only broaden our understanding of the juxtavascular niche for satellite cells but will also lead to the development of angiogenesis-targeted treatment options for DMD.
Description
University of Minnesota Ph.D. dissertation. March 2018. Major: Integrative Biology and Physiology. Advisor: Atsushi Asakura. 1 computer file (PDF); ix, 271 pages.
Related to
Replaces
License
Collections
Series/Report Number
Funding information
Isbn identifier
Doi identifier
Previously Published Citation
Suggested citation
Verma, Mayank. (2018). Cross-talk between the skeletal muscle stem cells and endothelial cells. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/202120.
Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.