What is the significance of myofibroblast to fibroblast conversion in Ehlers-Danlos Syndrome (EDS)?

From the Guidelines

The conversion of myofibroblasts to fibroblasts in Ehlers-Danlos Syndrome (EDS) is crucial as it may help mitigate the excessive scarring and fibrosis associated with the condition, potentially improving tissue function and reducing morbidity. In EDS, the abnormal collagen synthesis and structure lead to connective tissue dysfunction, which can result in joint instability and tissue fragility 1. Myofibroblasts are specialized cells that produce excessive extracellular matrix components during wound healing and fibrotic processes, and their persistent activation contributes to pathological fibrosis and scarring. Promoting the conversion of these activated myofibroblasts back to their quiescent fibroblast state could potentially reduce abnormal scarring and improve tissue function. This process involves downregulating transforming growth factor-beta (TGF-β) signaling, which is often dysregulated in EDS.

The significance of this conversion is further emphasized by the fact that EDS, particularly vascular Ehlers-Danlos syndrome, is associated with life-threatening vascular complications, including dissections, aneurysms, arterial ruptures, and arteriovenous fistulas 1. The prognosis depends on the type of COL3A1 variant, with null variants showing a better outcome. Understanding the cellular transition of myofibroblasts to fibroblasts is essential for developing future treatments that could address the underlying connective tissue abnormalities in EDS rather than just managing symptoms.

Key aspects of EDS management include:

• Early identification and thorough family inquiry
• Avoidance of invasive procedures when possible
• Medical therapy, such as celiprolol, which has shown benefit in patients with vascular Ehlers-Danlos syndrome, although data are limited 1
• Surgical repair, which carries an increased risk due to vascular fragility and associated bleeding complications, and requires meticulous technique and shared decision-making 1.

Overall, the conversion of myofibroblasts to fibroblasts in EDS represents a potential therapeutic target for managing the condition and improving patient outcomes, particularly in terms of reducing morbidity and mortality associated with vascular complications.

From the Research

Myofibroblast to Fibroblast Conversion in Ehlers-Danlos Syndrome (EDS)

• The conversion of myofibroblasts to fibroblasts is a significant process in the context of Ehlers-Danlos Syndrome (EDS), as it may impact the pathogenesis of the disorder 2, 3.
• Studies have shown that fibroblasts from EDS patients exhibit a dysfunctional phenotype, including impairments in cell adhesion and cytoskeleton organization 4.
• The absence of dermal fibroblasts in patients with hypermobile EDS (hEDS) has been demonstrated, with αSMA negativity indicating a lack of myofibroblast presence in vivo 2.
• Research has also highlighted the importance of matrix metalloproteinases (MMPs) in the pathogenesis of hEDS, with MMPs dysfunction leading to excessive ECM degradation and myofibroblast differentiation 3.
• The inhibition of MMPs by doxycycline has been shown to rescue ECM organization and partially revert myofibroblast differentiation in hEDS dermal fibroblasts, offering a potential therapeutic target 3.

Key Findings

• The ultrastructural study of skin fibroblasts in EDS patients has revealed differences in ECM composition between classical and hypermobile forms of the disorder 2.
• The diameter of collagen fibrils has been found to be statistically significantly different between the classic and hypermobile forms of EDS 2.
• Gene expression changes related to cell-matrix interactions, inflammatory/pain responses, and acquisition of an in vitro pro-inflammatory myofibroblast-like phenotype may contribute to the complex pathogenesis of hEDS 5.

Molecular Mechanisms

• The molecular basis of hEDS is unknown, but research suggests that it may be related to defects in cell adhesion and cytoskeleton dynamics, as well as aberrations in ECM biology 4, 5.
• The latest nosology recognizes 13 types of EDS, caused by pathogenic variants in genes encoding collagens and other molecules involved in collagen processing and ECM biology 5.
• Emerging findings from miRNA profiling of hEDS fibroblasts may add novel biological aspects to the etiopathogenesis of the disorder 5.