Defining the Cardiac Fibroblast Secretome in a Fibrotic Microenvironment
| Autor: | Leslie A. Leinwand, Tova L. Ceccato, Tobin E. Brown, Rachel B. Starbuck, Kristi S. Anseth, Jessica K. Hall, Cierra J. Walker, Jason P. Killgore |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_treatment
Cardiomegaly macromolecular substances 030204 cardiovascular system & hematology Mechanotransduction Cellular Molecular Cardiology Transforming Growth Factor beta1 03 medical and health sciences Paracrine signalling 0302 clinical medicine Paracrine Communication medicine Animals Myocyte Myocytes Cardiac Myofibroblasts Protein kinase B Cells Cultured hydrogels Original Research mechanotransduction 030304 developmental biology 0303 health sciences business.industry Growth factor fibrosis Cardiac myocyte Membrane Proteins Cell Differentiation Remodeling Rats Cell biology secretome Growth Factors/Cytokines Cytokine secretion Cardiology and Cardiovascular Medicine business Myofibroblast Basic Science Research Signal Transduction Transforming growth factor |
| Zdroj: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| ISSN: | 2047-9980 |
| DOI: | 10.1161/jaha.120.017025 |
| Popis: | Background Cardiac fibroblasts (CFs) have the ability to sense stiffness changes and respond to biochemical cues to modulate their states as either quiescent or activated myofibroblasts. Given the potential for secretion of bioactive molecules to modulate the cardiac microenvironment, we sought to determine how the CF secretome changes with matrix stiffness and biochemical cues and how this affects cardiac myocytes via paracrine signaling. Methods and Results Myofibroblast activation was modulated in vitro by combining stiffness cues with TGFβ1 (transforming growth factor β 1) treatment using engineered poly (ethylene glycol) hydrogels, and in vivo with isoproterenol treatment. Stiffness, TGFβ1, and isoproterenol treatment increased AKT (protein kinase B) phosphorylation, indicating that this pathway may be central to myofibroblast activation regardless of the treatment. Although activation of AKT was shared, different activating cues had distinct effects on downstream cytokine secretion, indicating that not all activated myofibroblasts share the same secretome. To test the effect of cytokines present in the CF secretome on paracrine signaling, neonatal rat ventricular cardiomyocytes were treated with CF conditioned media. Conditioned media from myofibroblasts cultured on stiff substrates and activated by TGFβ1 caused hypertrophy, and one of the cytokines in that media was insulin growth factor 1, which is a known mediator of cardiac myocyte hypertrophy. Conclusions Culturing CFs on stiff substrates, treating with TGFβ1, and in vivo treatment with isoproterenol all caused myofibroblast activation. Each cue had distinct effects on the secretome or genes encoding the secretome, but only the secretome of activated myofibroblasts on stiff substrates treated with TGFβ1 caused myocyte hypertrophy, most likely through insulin growth factor 1. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text