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Published on: December 26, 2019
Increased PDGFRalpha activation disrupts connective tissue development and drives systemic fibrosis
Lorin E Olson1, Philippe Soriano
1Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Developmental Cell
|February 17, 2009
Summary
Increased platelet-derived growth factor receptor alpha (PDGFRalpha) signaling drives connective tissue growth, leading to fibrosis in multiple organs. Tumor suppressors may attenuate this fibrotic disease progression.
Area of Science:
- Developmental biology
- Cell signaling
- Fibrosis research
Background:
- Platelet-derived growth factor receptor alpha (PDGFRalpha) signaling is crucial for mesenchymal cell development.
- The role of PDGFRalpha receptor activation in maintaining tissue homeostasis remains largely uninvestigated.
Purpose of the Study:
- To investigate the role of increased PDGFRalpha signaling in tissue homeostasis and fibrotic diseases.
- To generate and analyze conditional knockin mice with hyperactive PDGFRalpha mutations.
Main Methods:
- Generation of conditional knockin mice with PDGFRalpha mutations that enhance kinase activity.
- Analysis of embryonic and adult mouse models to assess tissue development and homeostasis.
- Investigation of PDGFRalpha signaling in an Ink4a/Arf-deficient genetic background.
Main Results:
- Embryonic overexpression of PDGFRalpha signaling caused stromal fibroblast hyperplasia and disrupted smooth muscle development in organs.
- Adult mice with elevated PDGFRalpha signaling exhibited increased connective tissue growth and progressive fibrosis across multiple organs.
- Accelerated fibrosis was observed in PDGFRalpha hyperactive mice with a deficient Ink4a/Arf background, implicating tumor suppressors.
Conclusions:
- PDGFRalpha signaling is essential for normal connective tissue development and homeostasis.
- Aberrant PDGFRalpha signaling plays a pivotal role in the pathogenesis of systemic fibrosis.
- Tumor suppressors may have a role in mitigating fibrotic disease progression.
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