The Rudnicki lab works to understand the molecular mechanisms that regulate the determination, proliferation, and differentiation of stem cells during embryonic development and during adult tissue regeneration. Located at the Sprott Centre for Stem Cell Research within the Regenerative Medicine Program at the Ottawa Hospital Research Institute, the lab has conducted extensive studies into both embryonic myogenesis and the function of myogenic satellite cells in adult skeletal muscle. Towards this end, the lab employs molecular genetic, genomic and proteomic approaches to determine the function and roles played by regulatory factors in stem cell function.
The lab is an internationally recognized leader in stem cell biology. With 238 publications, 14 patents, and an h-index of 100, their work has more than 47,600 citations. An elected Fellow of the Royal Society, Dr. Rudnicki has given 345 scholarly presentations and serves on scientific advisory panels, grant panels, and editorial boards of numerous national and international agencies. Their discovery and characterization of muscle stem cells transformed our understanding of myogenesis and opened the door to new therapeutic strategies to treat neuromuscular disease. His contributions stand out in a heavily researched field for their clarity and impact not only in muscle stem cell biology but in the larger field of stem cell biology.
The Rudnicki lab made the seminal discovery that Pax7 is expressed in muscle satellite cells and plays an essential role in satellite cell function (Cell 2000). We demonstrated that expression of Pax7 was necessary and sufficient to induce myogenic specification of non-satellite cells (PLoS Biol 2004). We performed an elegant study that unequivocally demonstrated that Pax7 is an absolute requirement for satellite cell function at all ages (PNAS 2013). We also identified that Pax7 associates with a histone methyltransferase (HMT) complex that activates transcription to activate transcription (Nat Cell Biol 2008).
Our lab discovered that satellite cells are a heterogeneous population primarily composed of committed progenitors together with a small subpopulation of muscle stem cells that self-renew through asymmetric stem cell divisions (Cell 2007). This insight has facilitated innovative advances in understanding the molecular mechanisms that regulate satellite cell homeostasis. We discovered the arginine methyltransferase Carm1 specifically methylates Pax7 to allow binding of a histone H3K4 methyltransferase and gene activation through asymmetric stem cell divisions (Cell Stem Cell 2012), and that Carm1 nuclear localization is negatively regulated by p38g MAPK localized to the basal cortex via interaction with b-syntrophin (Cell Stem Cell 2018).
We also discovered that Wnt7a/Fzd7 signaling activates the planar-cell-polarity (PCP) pathway to drive the symmetric expansion of satellite stem cells (Cell Stem Cell 2009), activates the Akt/mTOR to induce hypertrophy (Nat Cell Biol 2011), and stimulates directional migration (JCB 2014). We demonstrated that Wnt7a treatment significantly ameliorates the dystrophic phenotype in mdx mice (PNAS 2012). Sdc4 and Fzd7 form a co-receptor complex and the binding of Fibronectin to Sdc4 is required for Wnt7a/Fzd7 signaling (Cell Stem Cell 2013). Moreover, activating satellite cells remodel their niche through the autologous expression of FN that provides feedback to allow Wnt7a signaling.
The Rudnicki lab found that inhibition of JAK/STAT signaling increases as satellite cells age and that inhibition of Jak2/Stat3 rejuvenated the function of these stem cells by stimulating their capacity for symmetric expansion (Nat Med 2014). Importantly, we discovered that the disease gene of Duchenne Muscular Dystrophy (DMD), called dystrophin, is expressed in muscle stem cells where its loss results in perturbation of cell polarity, markedly reduced numbers of asymmetric divisions, and reduced generation of progenitors (Nat Med 2015). This work is paradigm-shifting, suggesting that DMD pathology originates in part from a defect in muscle stem cell function.
We were also the first to identify a unique role for p107 in regulating preadipocyte differentiation into white or brown fat through repression of PGC-1α (Cell Met 2005). We performed lineage tracing as part of a collaborative study with the Speigelman lab that demonstrated that brown fat is derived from muscle precursors during embryonic development (Nature 2008). We went on to discover that adult satellite cells also give rise to brown adipocytes and that microRNA-133 regulates the choice between myogenic and brown adipose determination by targeting the 3'UTR of Prdm16 (Cell Met 2013).