Time to Redefine Endometriosis Including Its Pro-fibrotic Nature

P. Vigano; M. Candiani; A. Monno; E. Giacomini; P. Vercellini; E. Somigliana

Disclosures

Hum Reprod. 2018;33(3):347-352. 

In This Article

The Biological Basis of Fibrosis Development: The Crucial Role of Myofibroblasts

Myofibroblasts are contractile non-muscle cells that are usually activated in response to injury with the intent to repair damaged extracellular matrix (ECM). These cells can differentiate from different cellular lineages including tissue resident fibroblasts, endothelial cells undergoing endothelial-to-mesenchymal transition, vascular smooth muscle cells and epithelial cells after epithelial-to-mesenchymal transition. A myofibroblast is activated when the α-smooth muscle isoform of actin (α-SMA) is neo-expressed and incorporated in stress fiber-like bundles which are pivotal to promote the specific myofibroblast function of contracting the ECM. Two factors seem critical to activate myofibroblasts from various precursor cells in the vast majority of organs studied: Transforming Growth Factor (TGF)-β and the stiffness of the tissue. Indeed, TGF-β1 is able to induce neo-expression of α-SMA by fibroblasts in vivo and in vitro and in cultures on stiff substrates (e.g. a fibrotic scar) can activate a variety of different progenitors to become myofibroblasts (Richter et al., 2015; Hinz, 2016a).

When activated, myofibroblasts display increased proliferation, migratory ability, production of cytokines and interstitial matrix with the consequence of disrupting the function of intact residual tissues and altering the biochemical and biophysical microenvironment. A persistent myofibroblast activity causes accumulation and contraction of collagenous ECM, a condition called fibrosis. Macroscopically, due to accumulation of ECM, contraction of myofibroblasts and reduced vasculature, fibrotic organs usually display an uneven surface, are pale and not elastic. This process ultimately results in disruption of the normal anatomical structure (Bochaton-Piallat et al., 2016). Myofibroblasts are present in all fibrotic diseases, such as scleroderma, as well as liver, kidney, and lung fibrosis and are prominent in heart failure and repair after myocardial infarction (Rockey et al., 2015; Chistiakov et al., 2016). Myofibroblast-produced tissue contractures can become life-threatening when fibrosis affects vital organs (Rockey et al., 2015).

Discriminating between myofibroblasts and smooth muscle cells may be demanding and is a matter of controversy (Hinz, 2016a). Neo-expression of α-SMA in stress fibers is the most commonly used molecular marker for myofibroblasts that also express mesenchymal marker proteins such as N-cadherin, vimentin and S1004A. However, these latter markers are also expressed in smooth muscle cells, at least during tissue repair. Smooth muscle cells conversely express a number of late differentiation markers, such as smooth muscle myosin heavy chain, h-caldesmon, smoothelin and the muscle intermediate filament protein desmin, that are absent from myofibroblasts in most organs. However, discriminating smooth muscle cells from myofibroblasts is quite difficult in pathological conditions, so their distinction is usually a rather semantic issue (Hinz, 2016a). It is noteworthy that a metaplastic transformation from stromal cells to smooth muscle cells via differentiation from fibroblasts to myofibroblasts has been suggested (Zhang et al., 2016).

Not surprisingly, the interest of researchers in various fields of medicine has recently focused on antifibrotic therapeutic strategies aimed at blocking cytokines and factors that directly control myofibroblast activation (Yang et al., 2014). The complex presentation and activation mechanisms of TGF-β1 have led to the development of various anti-TGF-β1 approaches to prevent myofibroblast formation and fibrosis development. Some initial findings were disappointing in terms of both efficacy and safety. However, clinical trials using different anti-TGF-β1 treatments are ongoing in various diseases. Interestingly, since all the αv integrins have been shown to be able to activate TGF-β1 and are expressed in a tissue- and cell-distinctive manner, inhibiting their TGF-β1 activating function may be biologically more specific compared to the global inhibition of TGF-β1 itself. Some anti-integrin molecules are currently under investigation in clinical trials to treat patients with lung fibrosis and initial findings seem promising (Hinz, 2016b).

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