Myofibroblast modulation of cardiac myocyte structure and function.

Area of Science:

• Cardiovascular biology
• Cellular and molecular cardiology
• Cardiac electrophysiology

Background:

• Following myocardial infarction, resident fibroblasts differentiate into myofibroblasts, forming scar tissue and causing interstitial fibrosis.
• The specific roles and interaction mechanisms of fibroblasts (Fb) and myofibroblasts (MyoFb) with cardiac myocytes (CMs) remain incompletely understood.

Purpose of the Study:

• To elucidate the phenotype-specific modulation of CMs by MyoFbs versus Fbs.
• To investigate the roles of direct cell-cell contact via gap junctions and soluble mediators in Fb-CM and MyoFb-CM interactions.

Main Methods:

• Primary porcine left ventricular Fbs and CMs were utilized.
• Fbs were differentiated into MyoFbs using TGF-β1 or maintained in an undifferentiated state with SD-208.
• Co-cultures were established with direct contact or separated by a Thincert membrane.

Main Results:

• Direct co-culture of both Fbs and MyoFbs with CMs reduced CM viability after 2 days.
• MyoFbs, but not Fbs, induced significant distal CM spreading in both direct and indirect co-cultures.
• MyoFbs formed gap junction connections with CMs, increased connexin 43 expression, reduced CM action potential duration, and hyperpolarized CMs; these effects were reversed upon uncoupling.

Conclusions:

• Myofibroblasts, unlike fibroblasts, alter the structural phenotype of cardiac myocytes.
• Myofibroblasts are likely to form electrical connections with cardiac myocytes, modulating their membrane potential.
• These findings support an active role for myofibroblasts in the arrhythmogenic substrate following cardiac remodeling.