Myofibroblast secretome and its auto-/paracrine signaling

Abstract

Myofibroblasts (myoFb) are phenotypically transformed, contractile fibroblast-like cells expressing α-smooth muscle actin microfilaments. They are integral to collagen fibrillogenesis with scar tissue formation at sites of repair irrespective of the etiologic origins of injury or tissue involved. MyoFb can persist long after healing is complete, where their ongoing turnover of collagen accounts for a progressive structural remodeling of an organ (a.k.a. fibrosis, sclerosis or cirrhosis). Such persistent metabolic activity is derived from a secretome consisting of requisite components in the de novo generation of angiotensin (Ang) II. Autocrine and paracrine signaling induced by tissue AngII is expressed via AT1 receptor ligand binding to respectively promote: i) regulation of myoFb collagen synthesis via the fibrogenic cytokine TGF-β1-Smad pathway; and ii) dedifferentiation and protein degradation of atrophic myocytes immobilized and ensnared by fibrillar collagen at sites of scarring. Several cardioprotective strategies in the prevention of fibrosis and involving myofibroblasts are considered. They include: inducing myoFb apoptosis through inactivation of antiapoptotic proteins; AT1 receptor antagonist to interfere with auto-/paracrine myoFb signaling or to induce counterregulatory expression of ACE2; and attacking the AngII-AT1R-TGF-β1-Smad pathway by antibody or the use of triplex-forming oligonucleotides.

Keywords: Cardiac fibrosis; angiotensin II; auto-/paracrine signaling; cardioprotection; myofibroblast secretome.

Figure 1

The myofibroblast secretory phenotype found at the site of healing. This myofibroblast secretome includes the de novo generation of angiotensin II and subsequent induction of collagen synthesis by these cells. Included in the secretome is the expression of renin, ACE and AT₁ receptors. Autocrine actions of angiotensin II, mediated via AT₁ receptor binding, results in expression of fibrogenic TGF-β₁ and CTGF to stimulate myofibroblast production of fibronectin, which forms a provisional scaffold for type I and type III collagen fibrillogenesis. Abbreviations: ACE, angiotensin-converting enzyme; AT₁, angiotensin II type 1; CTGF, connective tissue growth factor; MMPs, matrix metalloproteinases; TGF-β₁, transforming growth factor β₁. Adapted from Weber KT, Sun Y, Bhattacharya SK, Ahokas RA, Gerling IC. Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol. 2013;10:15-26.

Figure 2

Segmental myocyte atrophy along a myofiber composed of individual myocytes joined end-to-end to form an in-series syncytium. Left panel: longitudinal perspective of several myofiber syncytia as seen by light microscopy. Arrowheads indicate atrophied cells composing this syncytia while arrows identify myofibroblasts juxtaposed to these atrophied myocytes (hematoxylin and eosin, ×200). Right panel: a schematic representation of normal and atrophic myocytes of the myofiber syncytium and where collagen fibrils emanating from scar tissue encircle myocytes. Myocytes so ensnared are smaller and subject to disuse atrophy. An activated myofibroblast with a fibrogenic phenotype is seen in proximity to an atrophied myocyte. Reprinted with permission from Al Darazi F, Zhao W, Zhao T, Sun Y, Marion TN, Ahokas RA, Bhattacharya SK, Gerling IC, Weber KT. Small dedifferentiated cardiomyocytes bordering on microdomains of fibrosis: evidence for reverse remodeling with assisted recovery. J Cardiovasc Pharmacol. 2014;64:237-246.

Figure 3

Myofibroblast (myoFb) cross-talk with neighboring myocytes via paracrine signaling involving de novo angiotensin (Ang) II generation and AT₁ receptor binding. Ensuing IP₃ stimulation leads to the release from and subsequent fall in endoplasmic reticulum [Ca²⁺]_er whose Ca²⁺ sensor, STIM1, in turn, is then activated to promote store-operated Ca²⁺ channel entry (SOCE) to raise cytosolic [Ca²⁺]_i and mitochondrial [Ca²⁺]_m. Ensuing oxidative stress and reactive oxygen species (ROS) activate proteolytic UPS ligases (MuRF1 and atrogin-1) leading to myocyte protein degradation with resultant atrophy.