Human stem cell models for Marfan syndrome: a brief overview of the rising star in disease modelling

Abstract

The introduction of pluripotent stem cells into the field of disease modelling resulted in numerous opportunities to study and uncover disease mechanisms in a petri dish. This promising avenue has also been applied to model Marfan syndrome, a disease affecting multiple organ systems, including the skeletal and cardiovascular system. Marfan syndrome is caused by pathogenic variants in FBN1, the gene encoding for the extracellular matrix protein fibrillin-1 which ensembles into microfibrils. There is a poor genotype-phenotype correlation displayed by the diverse clinical manifestations of this disease in patients. Up to now, 52 different human pluripotent stem cells lines have been established and reported for Marfan syndrome. These stem cells have been employed to model aortopathy, skeletal abnormalities and cardiomyopathy in vitro. These models were able to recapitulate key features of the disease that are also observed in patients. The use of pluripotent stem cells will help to uncover disease mechanisms and to identify new therapeutic strategies in Marfan syndrome.

Keywords: Marfan syndrome; aortopathy; cardiomyopathy; disease modelling; human pluripotent stem cells; in vitro.

FIGURE 1

Established human pluripotent stem cell lines for Marfan syndrome. In total 52 human stem cell lines were identified in scientific literature or in online registries. (A) The distribution of generated stem cell lines, either human embryonic stem cells (ESC, orange) or induced pluripotent stem cells (iPSC, green) over the years. (B) Distribution of generated stem cell lines per country.

FIGURE 2

(A) Different pathogenic variants in FBN1 used for the modelling of Marfan syndrome in vitro. (B) Primary functions of fibrillin-1. FBN1 variants can have various effects which are illustrated in the context of heart function. Indirectly, by altering aortic characteristics which imposes abnormal haemodynamic loads on the heart. Or, directly, via structural, mechanosensing or biochemical pathways. For instance, by impaired elastin fibres, increased stiffness or disrupted interactions between cell and matrix or upregulation of TGFβ signalling. These direct and indirect effects on cardiomyocytes and cardiac fibroblasts could impair heart function and could induce arrhythmias. LTBP: latent TGFβ binding protein, EGF domain: epidermal growth factor-like domain, cbEGF domain: calcium binding epidermal growth factor-like domain.

FIGURE 3

Schematic of an in vitro disease model for Marfan aortopathy based on pathogenic variants in FBN1 (c.2638G > A and c.3725G > A) used in two different studies. (A) Comparing Marfan iPSC-derived vascular smooth muscle cells, with the isogenic control reveals abnormalities in the extracellular matrix (ECM), increased levels of apoptosis, proteolysis, and an abnormal response to stretching. GSK3β treatment could be promising to decrease proteolytic and apoptotic effects. Adapted from (Davaapil et al., 2020). (B) The proposed mechanism for abnormal behaviour of vascular smooth muscle cells in Marfan aortopathy through abnormal mechanosensing effects in smooth muscle cells (red arrows) and abnormal TGFβ signalling (blue arrows) resulting in increased ERK1/2, p38 and KLF4. Adapted from (Granata et al., 2017).

FIGURE 4

Functional abnormalities observed in the first in vitro model for Marfan-related cardiomyopathy using human induced pluripotent stem cell derived cardiomyocytes. These abnormalities included impaired extracellular matrix, decreased contraction amplitude, increased stiffness of cardiomyocytes and decreased heart rate variability (Aalders et al., 2020).

FIGURE 5

Novel disease mechanisms in Marfan-related cardiomyopathy uncovered by a 3D co-culture model with human induced pluripotent stem cell derived cardiomyocytes and cardiac fibroblasts shows a high percentage of nuclear blebbing in Marfan cardiac fibroblasts. Decreased binucleation and sarcomere length point to decreased development of cardiomyocytes as another disease mechanism at play in Marfan-related cardiomyopathy (Aalders et al., 2024).