Fibrogenesis: Fibrogenic Cells, Their Origins, and a Site for Therapeutic Targeting

Fibrogenesis: Fibrogenic Cells, Their Origins, and a Site for Therapeutic Targeting

Our lab is interested in the cellular and molecular mechanisms that regulate fibrogenesis in tissue repair and fibrosis. Fibrogenesis is a specialized cell function; essential to the formation of connective tissue that supports the organs throughout the body. Two major types of fibrogenic cells, fibroblasts and myofibroblasts, synthesize the extracellular matrix proteins that constitute the connective tissue. The activity of fibroblasts/myofibroblasts can be altered by genetic and systemic factors, leading to a state of aberrant fibrogenic activity termed fibrosis. Fibrosis is characterized by excessive proliferation of fibroblasts/myofibroblasts with concomitant excess accumulation of extracellular matrix. Fibrosis negatively affects tissue function and ultimately leads to organ failure.

Fibrosis can also ensue as a consequence of tissue damage, when the mechanisms of tissue regeneration fail. In this case, fibroblasts proliferate and actively synthesize extracellular matrix components in what constitutes a transient phase of fibrogenic activity that supports tissue regeneration. In pathologies involving chronic tissue damage, the fibrogenic stage becomes permanent and is accompanied by persistent inflammation with elevated levels of inflammatory cytokines including as TNFα, IL6, or IL1β.

Given the central role of fibroblasts and myofibroblasts in both tissue damage and repair, there is great interest in understanding their origin and the signals that regulate their activity. In particular, both cell types constitute relevant therapeutic targets for the treatment of fibrosis in different pathological contexts and for the stimulation of regenerative processes

Using a variety of cutting-edge techniques, our laboratory focuses on important aspects of pericyte and fibroblast biology. We actively study signals triggered by tissue damage that activate pericytes and induce them to differentiate into fibroblasts. We are interested in the role of pericytes in inflammation and the mechanisms by which inflammatory signals can activate and epigenetically modify pericytes. We are also interested in the pro-fibrogenic signals that stimulate extracellular matrix production by fibroblasts and how those signals can affect the outcome of the regenerative process. We use transgenic mouse models to study the mechanisms of fibrosis and tissue regeneration in ischemic tissue injury, Alport syndrome, diabetes mellitus, and forms of idiopathic fibrosing diseases.