Transforming Growth Factor β1 Modulates Sex Differences in Cardiac Myofibroblast Activation on Hydrogel Biomaterials

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Biomaterials Science

Background:

• Cardiac fibrosis, characterized by myocardial stiffening from extracellular matrix (ECM) overproduction, is a key factor in heart disease.
• Biological sex significantly impacts cardiac fibrosis severity and outcomes, with males typically showing more pronounced scarring.
• Understanding sex-specific cellular mechanisms of cardiac fibroblast activation is crucial for targeted therapies.

Purpose of the Study:

• To investigate sex differences in cardiac myofibroblast activation mediated by transforming growth factor beta1 (TGF-β1).
• To determine how TGF-β1 influences the secretion of bioactive molecules in a sex-specific manner.
• To evaluate the utility of hydrogel biomaterials in recapitulating sex-specific cardiac fibrosis phenotypes.

Main Methods:

• Primary cardiac fibroblasts were isolated from male and female mice.
• Cells were cultured on hydrogel biomaterials mimicking myocardial ECM stiffness.
• Cultures were treated with TGF-β1 and/or a TGF-β1 receptor inhibitor (SD208) to assess myofibroblast activation and secreted factors.

Main Results:

• Male myofibroblasts showed increased alpha-smooth muscle actin (α-SMA) stress fiber formation and SMAD2/3 localization compared to females.
• Male myofibroblasts exhibited greater resistance to TGF-β1 receptor inhibition.
• Sex-specific cytokine secretion patterns were observed: males released more vascular endothelial growth factor (VEGF), while females produced more periostin and fibroblast growth factor 21.

Conclusions:

• TGF-β1 mediates distinct sex differences in cardiac myofibroblast activation and secreted factors on biomaterial platforms.
• These findings highlight the importance of considering biological sex in cardiac fibrosis research.
• Hydrogel platforms can effectively model sex-specific cardiac fibrosis, paving the way for sex-dependent therapeutic strategies.