In Vivo Models for the Study of Fibrosis

Abstract

Significance: Fibrosis and scar formation pose a substantial physiological and psychological burden on patients and a significant public health burden on the economy, estimated to be up to $12 billion a year. Fibrosis research is heavily reliant on in vivo models, but variations in animal models and differences between animal and human fibrosis necessitates careful selection of animal models to study fibrosis. There is also an increased need for improved animal models that recapitulate human pathophysiology. Recent Advances: Several murine and porcine models, including xenograft, druginduced fibrosis, and mechanical load-induced fibrosis, for different types of fibrotic disease have been described in the literature. Recent findings have underscored the importance of mechanical forces in the pathophysiology of scarring. Critical Issues: Differences in skin, properties of subcutaneous tissue, and modes of fibrotic healing in animal models and humans provide challenges toward investigating fibrosis with in vivo models. While porcine models are typically better suited to study cutaneous fibrosis, murine models are preferred because of the ease of handling and availability of transgenic strains. Future Directions: There is a critical need to develop novel murine models that recapitulate the mechanical cues influencing fibrosis in humans, significantly increasing the translational value of fibrosis research. We advocate a translational pipeline that begins in mouse models with modified biomechanical environments for foundational molecular and cellular research before validation in porcine models that closely mimic the human condition.

Scars or Regeneration?—Dermal Fibroblasts as Drivers of Diverse Skin Wound Responses

“…This notion is supported by the observation that human skin wounds with greater tension often form more extensive scars than those experiencing minimal tension [46]. Studies on mechanotransduction indicate that fibroblasts sense microenvironmental tension and convert mechanical forces into biological signals, which in turn regulate the fibrotic responses [5]. For example, activation of focal adhesion kinase (FAK) in fibroblasts results in increased scar formation [47], whereas placing tape on wounded skin to reduce tension has been shown to lead to reduction in the severity of skin scars.…”

“…A multitude of therapies have been introduced to treat and/or prevent skin scars, but the efficacy of commercially available therapies remains limited [4], largely due to lack of a comprehensive understanding of the underlying cellular and molecular mechanisms that lead to scar formation. Scarring is most noticeable in the skin, but it affects almost all adult mammalian and human tissues and organs [5].…”

A New Animal Model for Pathological Subcutaneous Fibrosis: Surgical Technique and in vitro Analysis

“…This fibrotic “patch” response to injury restores tissue integrity but fails to recapitulate the form and function of the native tissue. Research is currently focusing on the processes of underlying fibrosis to curtail the mechanism and promote regenerative healing (Padmanabhan et al, 2019 ). Fibrosis in response to injury is not limited to the skin but occurs in almost all adult tissues, specifically idiopathic pulmonary fibrosis (IPF) may be a consequence of myocardial infarction Fibrosis is most apparent in the skin and in dysregulated form will lead to the generation of hypertrophic scars or keloids (Padmanabhan et al, 2019 ).…”

New Drugs for Scar Treatment

“…While scarring occurs in almost all tissues, it is most apparent in the skin. Cutaneous scarring poses a significant psychological and physiological burden on patients, and an estimated $12 billion are spent annually on scar treatments in the USA alone [2]. Additionally, dysfunctional healing and hypertrophic scarring often causes lifelong disability, which has a significant additional economic impact [1,2].…”

“…Cutaneous scarring poses a significant psychological and physiological burden on patients, and an estimated $12 billion are spent annually on scar treatments in the USA alone [2]. Additionally, dysfunctional healing and hypertrophic scarring often causes lifelong disability, which has a significant additional economic impact [1,2]. Over 40 million patients undergo surgical procedures annually, which often lead to the formation of hypertrophic scars (HTSs) resulting in substantial morbidity and disfigurement of the skin.…”