Dr. Hadi Khalil, Heart Institute Cincinnati Children's Hospital Medical Center
“Identification of key regulator of cardiac fibrosis”
Mercredi 14 mars 2018 (15h30 - 17h00) - Bugnon 27 - Lipari
Identification of key regulator of cardiac fibrosis
Heart failure is a progressive disease characterized by cardiomyocyte loss, interstitial fibrosis and chamber remodeling. During physiological conditions, cardiac fibroblasts contribute to the homeostatic maintenance of myocardial structure as well as the maintenance of biochemical, mechanical, and electrical properties of the heart. Injury and cytokine stimulation activate fibroblasts which transdifferentiate into myofibroblasts. These newly generated contractile cells secrete extracellular matrix (ECM) proteins such as collagens and periostin for wound healing which eventually leads to fibrosis. After an acute injury such as myocardial infarction (MI), fibrosis can initially be a beneficial response that acutely scarifies and contracts areas with myocyte loss. However, during chronic disease states such as heart failure, persistent recruitment of myofibroblasts leads to excessive deposition of ECM which results in cardiomyopathy and heart failure. Tissue fibrosis is a common pathological feature of chronic inflammatory diseases affecting nearly every organ in the body. Importantly, at present, NO effective anti-fibrotic therapies exist. In the heart, fibrosis restricts normal cardiac function and promotes arrhythmia. Therefore, myofibroblasts implicated in regulating aspects of this deleterious profile in heart failure are a potential therapeutic target in treating or preventing progressive heart failure.
We generated a reliable genetic mouse model to identify the cellular origin, and to manipulate the function of cardiac fibroblasts. This led to the innovative finding that defined the origin of myofibroblasts as periostin-expressing cells (Fig. 1). This population of fibroblasts was identified as the principal mediator of fibrosis in the heart (Kanisicak, Khalil et al. 2016 Nat. Comm.), (Khalil et. al. 2017).
This fibroblast-specific tool (along with a few other genetic lines of highly characterized mice) are currently used to interrogate rigorously the relatively unknown biology of the cardiac fibroblast in vivo to elucidate the following fundamental principles:
How these cells exist and function in the adult heart with acute stress or chronic disease?
To define sub-stages in fibroblast to myofibroblast differentiation during cardiac injury and subsequent de-differentiation with injury resolution in the heart.
To define fibroblast lineage expansion in the adult heart after injury.
Prof. Dario Diviani