Molecular networks underlying myofibroblast fate and fibrosis

Abstract

Fibrotic remodeling is a hallmark of most forms of cardiovascular disease and a strong prognostic indicator of the advancement towards heart failure. Myofibroblasts, which are a heterogeneous cell-type specialized for extracellular matrix (ECM) secretion and tissue contraction, are the primary effectors of the heart's fibrotic response. This review is focused on defining myofibroblast physiology, its progenitor cell populations, and the core signaling network that orchestrates myofibroblast differentiation as a way of understanding the basic determinants of fibrotic disease in the heart and other tissues.

Keywords: Actin cytoskeleton; Differentiation; Fibrosis; Mitogen activated protein kinases; Myofibroblast; RNA binding proteins; TGFβ; TRP channels.

Figure 1

Cellular progenitors of cardiac myofibroblasts. Fate mapping approaches have identified that locally residing TCF21 positive epicardially derived fibroblasts are responsible for the majority of myofibroblasts that secrete collagen (Col1a) and periosten (Postn) and express αSMA. A majority of TCF21 fibroblasts are also positive for PDGFRα and can also express THY1 and/or WT1. Circulating fibrocytes that are hematopoietic (CD45+, CD34+, CD14+) and GLI1+ pericytes can also give rise to myofibroblasts in the heart, but their contribution to the myofibroblast population seems to be primarily associated with ischemic injury. Endothelial and epithial to mesenchymal transition has also been proposes as a mechanism for myofibroblast formation although recent studies suggest that less than 5% of Col1a+ myofibroblasts come from this population in response to aortic banding.

Figure 2

The signaling network orchestrating fibroblast to myofibroblast differentiation. Injury-induced chemical (TGFβ, AngII, ET-1 and others) and mechanical stimuli (tissue rigidity, shear and tensile forces, and matrix isotropy) activate 4 potent signaling axes: canonical TGFβ (red), non-canonical TGFβ-MAPK (orange), actin cytoskelal (green), and Ca²⁺-pathways (purple) to induce myofibroblast gene transcription. MBNL1 selectively matures transcripts of the myofibroblast differentiation transcriptome including most components of all 4 axes listed above. Several signaling arms converge on p38 and the transcription factor SRF, suggesting their nodal role in this differentiation process. The combinatorial activation of these regulators potentiate and reinforce the transition of a fibroblast into a myofibroblast. *Factors in gray have links to these pathways but have not been directly proven as regulators myofibroblast conversion.