Novel Techniques Targeting Fibroblasts after Ischemic Heart Injury

Abstract

The great plasticity of cardiac fibroblasts allows them to respond quickly to myocardial injury and to contribute to the subsequent cardiac remodeling. Being the most abundant cell type (in numbers) in the heart, and a key participant in the several phases of tissue healing, the cardiac fibroblast is an excellent target for treating cardiac diseases. The development of cardiac fibroblast-specific approaches have, however, been difficult due to the lack of cellular specific markers. The development of genetic lineage tracing tools and Cre-recombinant transgenics has led to a huge acceleration in cardiac fibroblast research. Additionally, the use of novel targeted delivery approaches like nanoparticles and modified adenoviruses, has allowed researchers to define the developmental origin of cardiac fibroblasts, elucidate their differentiation pathways, and functional mechanisms in cardiac injury and disease. In this review, we will first characterize the roles of fibroblasts in the different stages of cardiac repair and then examine novel techniques targeting fibroblasts post-ischemic heart injury.

Keywords: cardiac fibroblast; fibroblast-specific; myocardium; nanoparticles; novel delivery methods.

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.

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.