P342Lamin A/C mutations associated with different laminopathies affect differentiation of mesenchimal stem cells

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Abstract

Nuclear lamins are the major proteins of nuclear envelope and provide the strength of nuclear membrane as well as the interaction of extra-nuclear structures with components of cell nucleus. Recently, it became clear that lamins not only play a structural role in the cell, but could also regulate cell fate, for example lamins could influence cell differentiation via interaction with components of Notch signaling pathway. The best known modification of lamin A/C is progerin. It causes a very rare and severe syndrome of premature aging, or progeria. More often human mutations in LMNA encoding lamin A/C lead to diseases commonly referred to as laminopathies. In these diseases different mutations cause tissue specific phenotypes that affect predominantly a tissue of mesenchimal origin such as myocardium, skeletal muscle, adipose and bone tissues. The nature of this phenomenon, as well as the mechanisms by which lamins A/C regulate cell differentiation remain poorly understood. The aim of this study was to investigate the effect of different mutations of LMNA on human mesenchimal stem cell (MSC) osteogenic differentiation, and to explore a possible interaction of lamins A/C and Notch signaling pathway. We modified human mesenchimal stem cells (MSC) with several variants of mutant LMNA bearing known mutations with tissue specific phenotype associated with different laminopathies and then analyzed effects of different mutations on the efficiency of osteogenic differentiation. Efficiency of differentiation was evaluated by the number of differentiated MSC through 21 days after the induction of differentiation and by assessing the level of expression of specific osteogenic markers: SPP1, IBSP, BGLAP. We have shown that mutations associated with different types of laminopathies have different effects on the efficiency of MSC osteogenic differentiation at the morphological level and at the level of the expression of specific osteogenic markers. Different LMNA mutations increased or reduced the efficiency of differentiation. Our results explain why different mutations in the same gene could lead to a broad spectrum of phenotypes seen in different laminopathies. Mutant LMNA impaired the function of Notch signaling pathway and also changed HDAC activity in modified MSC comparing to MSC bearing wt LMNA. Thus, we have shown that a mechanism involved in the regulation of MSC differentiation may be an interaction of lamins A/C with components of Notch signaling and also epigenetic mechanisms.

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