Marfan syndrome; A connective tissue disease at the crossroads of mechanotransduction, TGFβ signaling and cell stemness

Abstract

Mutations in fibrillin-1 cause Marfan syndrome (MFS), the most common heritable disorder of connective tissue. Fibrillin-1 assemblies (microfibrils and elastic fibers) represent a unique dual-function component of the architectural matrix. The first role is structural for they endow tissues with tensile strength and elasticity, transmit forces across them and demarcate functionally discrete areas within them. The second role is instructive in that these macroaggregates modulate a large variety of sub-cellular processes by interacting with mechanosensors, and integrin and syndecan receptors, and by modulating the bioavailability of local TGFβ signals. The multifunctional, tissue-specific nature of fibrillin-1 assemblies is reflected in the variety of clinical manifestations and disease mechanisms associated with the MFS phenotype. Characterization of mice with ubiquitous or cell type-restricted fibrillin-1 deficiency has unraveled some pathophysiological mechanisms associated with the MFS phenotype, such as altered mechanotransduction in the heart, dysregulated TGFβ signaling in the ascending aorta and perturbed stem cell fate in the bone marrow. In each case, potential druggable targets have also been identified. However, the finding that distinct disease mechanisms underlie different organ abnormalities strongly argues for developing multi-drug strategies to mitigate or even prevent both life-threatening and morbid manifestations in pediatric and adult MFS patients.

Keywords: Cardiomyopathy; Fibrillin; Marfan syndrome; Mechanotransduction; Osteopenia; Stem cell niche; TGFβ; Thoracic aortic aneurysm.

Figure 1

(A) Original disease model of a linear relationship between AT1r activation and TGFβ signaling derived from the characterization of TAA in Fbn1^C1039G/+ mice (modified from Habashi et al, 2006 and Holm et al, 2011). (B) Revised model of TAA progression derived from studies of Fbn1^mgR/mgR mice (modified from Cook et al, 2015). (C) Model of medial degeneration during TAA progression derived from the analysis of MFS-iPSCs differentiated into vascular SMCs (modified from Granata et al, 2017).

Figure 2

(A) Schematic representation of the mechanotransducing role of fibrillin-1 assemblies in the myocardium as inferred from DMC characterization in Fbn1^mgR/mgR mice. In this model, fibrillin-1 assemblies influence cross talk between AT1r and integrin by participating in ECM loading on the mechanosensors (B) Proposed role of fibrillin-1 in stem cell fate regulation by modulating TGFβ bioavailability within the bone marrow niche, as implied from the characterization of progressive bone loss in Fbn1^Prx−/− mice. Arrows points to cellular processes of self-renewal, commitment and differentiation, while abbreviations signify mesenchyme stem cell (MSC), progenitor cell (PrC), osteoblast (Ob) and adipocyte (Ad).