Abstract

Fibrosis is the abnormal accumulation of extracellular matrix
components and other morphological changes that accompany sustained tissue
microinjury. An aberrant wound healing response, fibrosis is a scarring that
contributes to and can even sustain dysfunction in many organs (kidney, lungs,
liver), and which can ultimately lead to progressive organ failure. As the
burden of fibrotic disease increases, so does the unmet medical need for
therapies that prevent, halt the progression of, or reverse fibrotic lesions:
currently, transplant is often the only option for late-stage disease. The
development of effective anti-fibrotic agents has historically been slow with
limited therapies approved to date. Excellent preclinical data have often
failed to translate into positive clinical outcomes, at least partly due to the
challenge of generating physiologically relevant in vitro models. But the incentive to do so remains: fibrosis
induction in in vivo models is complex, gradual, expensive, and sometimes
ambiguous. In this poster, we present a validated in vitro model of rat renal fibrosis as a basis for broader
tissue-specific fibrosis and related disease models. The model reports
high-content cell imaging of multiple endpoints (extracellular matrix
deposition, myofibroblast activation, tissue remodeling), and is available to
screen and triage anti-fibrotic drugs for progression into lower throughput and
much more resource-demanding in vivo models. Validated using anti-fibrotic tool compounds,
this model is the foundation of an ongoing technology programme that seeks to
establish a fully customizable and flexible assay platform for screening
multiple mechanisms of action in fibrosis and related indications. We are
actively developing co-culture strategies to better recapitulate the cellular
context of native tissue (exemplified in a lung fibroblast-epithelial cell
model of idiopathic pulmonary fibrosis), and are currently validating
iterations of this assay for primary human liver (purified hepatic stellate
cells and mixed parenchyma). Together, this family of models will enable more
sophisticated interrogations of disease pathologies across different organs, a recognition of disparate
aetiologies that will make fibrosis more tractable to drug discovery.