Nuclear lamins regulate osteogenic differentiation of mesenchymal stem cells

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 the Notch signaling pathway. Human mutations in LMNA, encoding lamin A/C lead to diseases commonly referred to as laminopathies. Different mutations cause tissue specific phenotypes that affect predominantly a tissue of mesenchymal origin. The nature of this phenomenon, as well as the mechanisms by which lamins regulate cell differentiation remain poorly understood. The aim of this study was to investigate the effect of different mutations of the LMNA on human mesenchymal stem cell (MSC) osteogenic differentiation, and to explore a possible interaction of lamins and Notch signaling pathway. We modified human MSC with mutant LMNA bearing known mutations with tissue specific phenotype associated with different laminopathies. We have shown that mutations associated with different diseases have different effects on the efficiency of MSC osteogenic differentiation and on the expression of specific osteogenic markers SPP1, IBSP and BGLAP. We have also shown that one of the mechanisms involved in the regulation of MSC differentiation may be an interaction of lamins A/C with components of Notch signaling.