Defects in primary cilia can result in a wide range of diseases, referred to as “ciliopathies”. The majority of ciliopathies are embryonic lethal and can cause severe kidney and heart disease, obesity and diabetes. While cilia are present on many cells in the adult, we know relatively little what their function is in the adult.
One tissue, which has a remarkable ability to regenerate, is skeletal muscle. However, in chronic muscle diseases, such as Duchenne muscular dystrophy (DMD) and age-related muscle wasting, regeneration fails and healthy muscle is gradually replaced with fibrotic scar and fat tissue, a process called fatty fibrosis. We recently discovered (Kopinke et al., Cell, 2017) that cilia coordinate muscle repair by controlling the communication between a mesenchymal stem cell population, called fibro/adipogenic progenitors (FAPs), and the muscle stem cells (MuSCs). More specifically, we discovered that FAPs, the cell of origin of fatty fibrosis, are the main ciliated cell type in skeletal muscle and that removal of FAP cilia prevents their adipogenic conversion. We also found that FAP cilia transduce Hedgehog (Hh) signaling, and that ciliary Hh signaling prevents fatty fibrosis by modulating the extracellular matrix through induction of TIMP3, a secreted tissue inhibitor of matrix metalloproteinases. Excitingly, loss of FAP cilia also accelerated muscle regeneration and improved muscle function.
We are now building on this work by investigating how cilia influence muscle healing and whether the ciliary mechanism governing intramuscular fat formation also controls adipogenesis in other tissues. We have created novel tools and approaches, including mouse genetic models and a fatty fibrosis cell culture model, which allow us to manipulate and study cilia and ciliary signaling during fatty fibrosis initiation and progression in skeletal muscle. However, we are also interested if the ciliary mechanisms controlling fatty fibrosis in skeletal muscle are also active in other tissues (i.e., heart, kidney and pancreas). Thus, the long-term research goal of the Kopinke lab is to elucidate how primary cilia coordinate adult tissue repair and regeneration. More specifically, our future research program will investigate how ciliary signaling coordinates cellular communication between stem cells and their niche, on understanding how cilia-based communication goes awry in disease and on identifying novel pharmacological tools to combat cilia-controlled diseases such as fatty fibrosis.