The Michael Rudnicki laboratory 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.

Notably, the lab has identified Pax7 as a transcription factor required for the specification of satellite cells, identified Wnt signaling as playing an important role in muscle stem cell function, and identified satellite stem cells. More recently, the lab has characterized asymmetric satellite stem cell self-renewal and discovered that Wnt7a drives satellite stem cell expansion by activating the planar cell polarity pathway to stimulate symmetric stem cell divisions. Research has led to the publication of over 160 peer reviewed articles in scientific journals that include Cell, Nature, Nature Cell Biology, Cell Stem Cell, Genes & Development, and PLoS Biology.

The Rudnicki laboratory is interested in understanding the molecular mechanisms that regulate stem cell function. While our primary focus has been on satellite cells in adult skeletal muscle, our studies have also ranged from embryonic stem cells, to pancreas regeneration, to metabolic control. We have used cell and molecular approaches, genetics and animal studies, and the tools of genomics and proteomics to advance our knowledge of the molecular regulation of stem cell function.

We are a leading group in the study of myogenesis, and we have made many seminal contributions that have had wide impact. We discovered that satellite cells in skeletal muscle express the transcription factor Pax7 and that Pax7-deficient satellite cells are progressively lost in all muscle groups in the neonatal period due to survival deficits or precocious differentiation. We identified the molecular mechanism through which Pax7 directs myogenic specification by activating target genes via recruitment of the MLL1/Ash2L histone methyltransferase (HMT) trithorax complex. We discovered that satellite cells are a heterogeneous population of stem cells and committed cells based on the expression of two transcriptional factors Pax7 and Myf5. We showed using transplantation studies that satellite stem cells, expressing Pax7 but not Myf5, function to sustain the stem cell and committed progenitor pool within the satellite cell niche. We have made important and novel contributions in understanding the signals acting on the stem cell niche. We identified a role for Notch signaling in maintaining stem cell identity and that canonical Wnt signaling induces precocious differentiation and loss of stems cells. We discovered that Wnt7a acts at two levels to intrinsically regulate muscle homeostasis. First, Wnt7a signals through the planar-cell-polarity pathway to stimulate symmetric stem cell expansion and thus regulate the homeostatic levels of stem cells and progenitor cells. Second, Wnt7a signals through the PI3K/Akt/mTOR growth pathway to stimulate myofiber hypertrophy. In a collaborative study, we performed lineage tracing to demonstrate that brown fat is derived from muscle progenitors in the embryo. We identified a role of miR-133 in regulating a switch from myogenic to brown adipogenic lineage determination in satellite stem cells. We recently discovered that satellite cells remodel their niche during activation with fibronectin and that this is necessary for Wnt7a signaling as Fzd7 and Syn4 are co-receptors.