Abstract
Fibrosis is involved in 45% of deaths in the United States, and no treatment exists to reverse progression of the disease. In order to find novel targets for fibrosis therapeutics, we developed a model for the differentiation of monocytes to myofibroblasts that allowed us to screen for proteins involved in myofibroblast differentiation. Inhibition of a novel protein target generated by our model, talin2, reduces myofibroblast morphology, α-smooth muscle actin content, collagen I content, and lowers the pro-fibrotic secretome of myofibroblasts. We find that knockdown of talin2 de-differentiates myofibroblasts, talin2 knockdown reverses bleomycin-induced lung fibrosis in mice, and Tln2 -/-mice are resistant to unilateral ureteral obstruction-induced kidney fibrosis and are resistant to bleomycin-induced lung fibrosis. Talin2 inhibition is a potential treatment for reversing lung and kidney fibroses.
One Sentence Summary Silencing the stress sensor Talin2 reverses myofibroblast differentiation and existing fibrosis.
Competing Interest Statement
MJVW and JH are authors on a patent regarding this work
Footnotes
This version of the manuscript has been updated to include the data from the talin2 -/- mouse, kidney fibrosis data, and to clean up some of the writing for clarity This latest update is the final version of the paper, with some additional knockout data, some minor editing, and removing Roy Zent and David Critchley from the authors. They developed the knockout mouse, but felt their contributions didn't merit authorship, since all they did was share the mouse with me.
Abbreviations
- (αSMA)
- alpha-smooth muscle actin
- (ALT)
- Alanine Transferase
- (AST)
- Aspartate Transferase
- (BAL)
- broncheo-alveolar lavaged
- (BUN)
- blood urea nitrogen
- (FCS)
- fetal calf serum
- (FAs)
- focal adhesions
- (FBs)
- Fibrillar adhesions
- (IPF)
- idiopathic pulmonary fibrosis
- (IHC)
- Immunohistochemistry
- (MRC-5)
- Human fibroblasts
- (kilopascals)
- kPa
- (MCP1)
- macrophage-chemotactic protein-1
- (NIH-3T3)
- mouse fibroblasts
- (PBMC)
- peripheral blood mononuclear cells
- (PBS)
- phosphate buffered saline
- (SFM)
- Silencing RNA
- (siRNA)
- serum-free media
- (TGFβ)
- Transforming growth factor β
- (Tln2)
- Talin2
- (TNFα)
- Tumor necrosis factor α
- (UUO)
- Unilateral Ureteral Obstruction