Recent developments in myofibroblast biology: paradigms for connective tissue remodeling

Abstract

The discovery of the myofibroblast has opened new perspectives for the comprehension of the biological mechanisms involved in wound healing and fibrotic diseases. In recent years, many advances have been made in understanding important aspects of myofibroblast basic biological characteristics. This review summarizes such advances in several fields, such as the following: i) force production by the myofibroblast and mechanisms of connective tissue remodeling; ii) factors controlling the expression of α-smooth muscle actin, the most used marker of myofibroblastic phenotype and, more important, involved in force generation by the myofibroblast; and iii) factors affecting genesis of the myofibroblast and its differentiation from precursor cells, in particular epigenetic factors, such as DNA methylation, microRNAs, and histone modification. We also review the origin and the specific features of the myofibroblast in diverse fibrotic lesions, such as systemic sclerosis; kidney, liver, and lung fibrosis; and the stromal reaction to certain epithelial tumors. Finally, we summarize the emerging strategies for influencing myofibroblast behavior in vitro and in vivo, with the ultimate goal of an effective therapeutic approach for myofibroblast-dependent diseases.

Figure 1

Myofibroblast epigenetics. A: Transcriptional regulation of the ACTA gene in myofibroblast differentiation. Activating or repressing transcription factors are shown directed at the relative locations of their cognate binding elements in the ACTA gene promoter. The interaction of Kruppellike factor (KLF) 4 with Smad3 results in decreased Smad3 binding to the Smad-binding element (SBE). In contrast, MRTF enhances serum response factor binding to its cognate element to activate differentiation. PPARγ and NF-κB are also shown, but the location/nature of their direct interaction with the promoter is uncertain (indicated with a question mark). The activation of Notch signaling activates its downstream factor CSL. CArG, CC(A/T)6GG; C/EBP, CCAAT enhancer binding protein; CSL, from CBF1/RBP-J in mammals, suppressor of hairless [Su(H)] in drosophila and xenopus, and Lag-1 in Caenorhabditis elegans; IM-CAT, binding element with sequence CATCCT; LAP, liver activator protein; LIP, liver inhibitory protein; NKE, Nkx2.5 binding element; SRF, serum response factor; TEF, transcription enhancer factor; THR, TGF-β1 hypersensitivity region; TSS, transcription start site. B: DNA methylation and miRNAs in myofibroblast differentiation. Methylated CpG islands are shown in the ACTA gene promoter in the fibroblast, which are maintained by DNMT. The differentiated myofibroblast shows reduced methylation with activation of ACTA gene expression. The methylated DNA-binding protein MeCP2 promotes myofibroblast differentiation; however, multiple target genes are regulated by this protein. The indicated miRNA species regulate their target mRNAs with downstream consequences on myofibroblast differentiation, as indicated. Although ACTA is used as a hallmark gene of the myofibroblast, other fibrosis-relevant genes have been regulated by hypermethylation as well (see Myofibroblast DNA Methylation). C: Histone deacetylation and myofibroblast differentiation. The indicated HDAC isoforms modulate differentiation via multiple mechanisms. In addition, inhibition/depletion of HDAC4 suppresses TGFβ activation of Akt via 5′-TG-3′-interacting factor 1,2 (TGIF1,2) and protein phosphatase 2A/1 (PP2A/PP1).

Figure 2

Tumor myofibroblasts. A schematic view highlights the cross signaling (double arrows) within and between local and distant tumor ecosystems. Arrows indicate displacement of cells between ecosystems; dashed arrows, conversion from one cell type into another; positive arrows, stimulation; and bold arrows, importance of the signaling.

Figure 3

The myofibroblast in the center of attention. Anti-fibrotic therapies can be designed to interfere with the extracellular chemical and mechanical factors that lead to myofibroblast formation from a variety of different precursors. Alternatively, one might interfere with intracellular signaling pathways, transcription regulators, and epigenetic mechanisms that specifically modulate myofibroblast differentiation. Other potential anti-fibrotic targets are specific features of the differentiated myofibroblast, such as α-SMA in the contractile apparatus, specific integrins, and ECM proteins. Other strategies aim to induce myofibroblast regression and/or apoptosis