Gabrielle Kardon

Overview

How does muscle develop, regenerate, maintain, age, and evolve? These are the questions that drive our research. We focus on muscle stem cells because they are the source of all muscle. We focus on the muscle connective tissue because it provides the niche for muscle stem cells and is critical for muscle form and function. We study how interactions between muscle stem cells and the connective tissue orchestrate development of limb muscles and the diaphragm, regulate muscle regeneration and aging, are the source of birth defects and fibrosis, and shape evolution of the musculoskeletal system.

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 and Kardon et al. 2017) . 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.