Molecular regulation of muscle-resident mesenchymal stem cells - Mueller, Alisa Anne; Rando, Thomas A; Brunet, Anne, 1972-; Chang, Howard Y. (Howard Yuan-Hao), 1972-; Fire, Andrew Zachary; Stanford University, Cancer Biology Program (2014)
The platelet-derived growth factor receptor alpha (PDGFR [alpha]) exhibits divergent effects in skeletal muscle. At physiological levels, signaling through this receptor promotes muscle development in growing embryos and proper angiogenesis in regenerating adult muscle. However, increased PDGF ligands and enhanced PDGFR [alpha] pathway cause pathological fibrosis. This excessive collagen deposition, which is seen in aged and diseased muscle, interferes with proper muscle contraction and limits the effectiveness of gene- and cell- based therapies for muscle disorders. Although compelling evidence exists for the role of PDGFR [alpha] in fibrosis, little is known about the cells through which this pathway acts. Here we show that PDGFR [alpha] signaling regulates a population of muscle-resident mesenchymal stem cells (MSCs) that play a supportive role in muscle regeneration but may also cause fibrotic buildup when aberrantly regulated. Unexpectedly, our investigation revealed that changes in alternative polyadenylation of PDGFR [alpha] control MSC activation and consequently tissue regenerative potential. MSCs produce multiple transcriptional variants of PDGFR alpha] with different polyadenylation sites including an intronic variant of PDGFR [alpha] that codes for a protein isoform containing a truncated kinase domain. This variant, upregulated during regeneration, inhibits PDGF signaling and prevents MSC over-activation. Increasing expression of this isoform through administration of specified morpholinos limits fibrosis in vivo. Furthermore, in our global analysis of polyadenylation patterns in MSCs, we show that intronic polyadenylation is not limited to PDGFR [alpha]. Rather, it is a widespread phenomenon, and the levels of intronic polyadenylation variants compared to their full-length counterparts increases with cell activation on a global level. Overall, our findings suggest both biological relevance and therapeutic potential of modulating polyadenylation patterns in stem cell populations.
Submitted to the Program in Cancer Biology.
Thesis (Ph.D.)--Stanford University, 2014.
Rights: (c) Copyright 2014 by Alisa Anne Mueller
Rights: This work is licensed under a Creative Commons Attribution Non Commercial No Derivatives 3.0 Unported license (CC BY-NC-ND).
Keywords: theses