Muscle Stem Cells in Development, Regeneration, and Homeostasis
Muscle development, growth, and regeneration take place throughout vertebrate life. Muscle stem cells are critical for all of these processes. Our research has concentrated on the developmental origin of muscle stem cells, their function, and the extrinsic signals that regulate them. We have found that all muscle stem cells in the limb arise in the embryo from the somites, but there are related, although distinct populations of stem cells in the embryo, fetus, and adult (Kardon et al. 2002, Schienda et al. 2006, Hutcheson et al. 2009, Murphy et al. 2011). We also have established that muscle stem cells are critical for muscle development (Hutcheson et al. 2009) and satellite cells (the adult muscle stem cells) are necessary and sufficient for muscle regeneration (Murphy et al. 2011). Satellite cells also contribute to muscle homeostasis, but their requirement is still not clear (Keefe et al. 2015). Our current research concentrates on the molecular mechanisms and cellular interactions regulating satellite cells and regeneration.
Muscle Connective Tissue Regulation of Muscle and Fibrosis
Muscle connective tissue ensheathes muscles and maintains muscle architecture and transmits muscle contractile force to adjoining tendon and bone. In addition, the connective tissue is an important component of the niche regulating muscle stem cells. However, connective tissue must be precisely regulated as connective tissue fibrosis, which is a feature of chronic injury, aging, and disease, can seriously impair muscle strength and elasticity. We have found that the connective tissue regulates development of the diaphragm and limb muscles (Kardon et al. 2003; Mathew et al. 2011, Merrell et al. 2015) and expansion of satellite cells during muscle regeneration (Murphy et al. 2011). We are working to understand the molecular nature of this regulation. In addition, how the fibroblasts regulate fibrosis is an active area of our research.
Diaphragm: Development, CDH, and Evolution
The diaphragm is an essential mammalian skeletal muscle essential. It is vital for respiration and serves as a barrier between the abdomen the thorax (see our review Merrell et al. 2013). Unfortunately, defects in development of the diaphragm are common in humans and lead to Congenital Diaphragmatic Hernias (CDH). We study the genetic, molecular, and cellular mechanisms regulating development of the diaphragm and CDH. Our research uses mouse genetics, ex vivo two photon imaging of the developing diaphragm, cell culture, and human genetics data. We have found that the connective tissue critically regulates development of the diaphragm and mutations in this tissue are a source of CDH (Merrell et al. 2015). Currently we are trying to understand the molecular nature of the connective tissue signaling to muscle. We also study evolution of the diaphragm - as the diaphragm is a unique and defining character of all mammals.
Development of the Limb Musculoskeletal System and Congenital Limb Abnormalities
Development of the musculoskeletal system requires the coordinated development of muscle, muscle connective tissue, tendon, and skeleton. How these tissues, derived from different embryonic sources, are patterned and assembled had been largely unknown. Using the limb as a model system, we have established that reciprocal interactions between muscle and tendon are essential for delimiting the major groups of limb muscles (Kardon 1998) and that the connective tissue regulates the pattern of individual muscles (Kardon et al. 2003) and muscle fiber type (Mathew et al. 2011). We have also found that specification of particular muscles is tightly linked to the specification of their bone origin and insertion sites, and mutations in the transcription factor Tbx3 leads to limb muscle and bone defects in Ulnar Mammary Syndrome (Colasanto et al. 2016).