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Published on: February 15, 2019
Sequential Wnt Agonist Then Antagonist Treatment Accelerates Tissue Repair and Minimizes Fibrosis
Xiao-Jun Tian1, Dong Zhou2, Haiyan Fu3
1Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA; School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85287, USA.
Abstract:
Tissue fibrosis compromises organ function and occurs as a potential long-term outcome in response to acute tissue injuries. Currently, lack of mechanistic understanding prevents effective prevention and treatment of the progression from acute injury to fibrosis. Here, we combined quantitative experimental studies with a mouse kidney injury model and a computational approach to determine how the physiological consequences are determined by the severity of ischemia injury and to identify how to manipulate Wnt signaling to accelerate repair of ischemic tissue damage while minimizing fibrosis. The study reveals that memory of prior injury contributes to fibrosis progression and ischemic preconditioning reduces the risk of death but increases the risk of fibrosis. Furthermore, we validated the prediction that sequential combination therapy of initial treatment with a Wnt agonist followed by treatment with a Wnt antagonist can reduce both the risk of death and fibrosis in response to acute injuries.
Insights
Understanding tissue fibrosis progression after injury is key. This study reveals prior injury memory exacerbates fibrosis and identifies a Wnt signaling therapy to reduce death and fibrosis risk.
Area of Science:
- Nephrology
- Regenerative Medicine
- Computational Biology
Background:
- Tissue fibrosis impairs organ function following acute injury.
- Mechanistic understanding of fibrosis progression is limited, hindering effective treatment.
- Acute kidney injury (AKI) can lead to chronic kidney disease (CKD) through fibrosis.
Purpose of the Study:
- To investigate the impact of ischemia injury severity on physiological consequences.
- To identify strategies for manipulating Wnt signaling to promote repair and minimize fibrosis.
- To understand the role of prior injury and preconditioning in fibrosis development.
Main Methods:
- Utilized a mouse model of kidney ischemia-reperfusion injury.
- Employed quantitative experimental studies and computational modeling.
- Investigated the effects of Wnt signaling modulation on tissue repair and fibrosis.
Main Results:
- Prior injury contributes to fibrosis progression, a phenomenon termed 'memory of injury'.
- Ischemic preconditioning reduced mortality but increased fibrosis risk.
- A sequential Wnt agonist and Wnt antagonist therapy effectively reduced both death and fibrosis.
Conclusions:
- Wnt signaling is a critical target for managing acute kidney injury outcomes.
- Therapeutic strategies can be developed to accelerate repair while mitigating long-term fibrotic damage.
- Understanding injury memory is crucial for preventing chronic organ dysfunction.
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