Novel Techniques Targeting Fibroblasts after Ischemic Heart Injury

Figures

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  Figure 1. Cardiac fibroblast subpopulations. Four main subpopulations of cardiac fibroblasts have been reported: resident fibroblasts; activated fibroblasts; myofibroblasts; and matrifibrocytes. Upon injury, the resident fibroblasts, identified by the lineage tracing marker Tcf21, differentiate in response to fibrogenic growth factors (FGF) usually stored within the matrix. These activated fibroblasts are phenotypically distinct, present increased adhesion molecules and overexpress several extracellular proteins, such as collagens and periostin (POSN), and matrix metalloproteinases (MMPs). These cells can further differentiate into myofibroblasts, identified by alpha smooth muscle actin (αSMA), upon continuous stress stimuli, such as transforming growth factor beta (TGFβ), angiotensin II (Ang II), cytokines, and increased substrate stiffness (mechanical stimulus). Myofibroblasts display an engorged reticulum endoplasmic (RE) to promote the secretion of extracellular matrix proteins to form the myocardial scar. Long-term remodeling leads to fiber alignment and scar maturation, at this point matrifibrocytes are observed, identified by protein Comp, to stabilize and maintain the mature scar.

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  Figure 2. Fibroblast-specific approaches. Cardiac fibroblasts can be specifically targeted via genetic models by combining the use of Cre recombinase and fibroblast-specific promoters (e.g., Tcf21, periostin, collagen 1a1, alpha smooth muscle actin, …). Another popular approach to target fibroblasts is through the use of several types of nanoparticles and liposomes that either encapsulate or are coated with fibroblast-specific antibodies, peptides, or miRNAs. Finally, adeno-associated viruses (AAV) carrying a small hairpin RNA targeting fibroblast-specific proteins have also been shown to be an effective delivery tool in cardiac research.