Absract
Nuclear lamins are the main proteins of the nuclear envelope providing nuclear-membrane strength. Recently, it became clear that lamins in cells play not only a structural role, but are also involved in regulation of gene expression. The LMNA gene encodes lamin A or C depending on the synthesizing splicing variant. The best-known LMNA mutation causes severe disorders in development known as progeria (premature aging syndrome). The disease is of rare occurrence. More frequently, point mutations in LMNA gene encoding lamin A/C result in so-called laminopathies, these diseases manifesting as tissue damage, mostly in tissues of mesenchymal origin. The mutations manifest in a tissue-specific manner: particular mutations always display the same disease phenotype. 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 LMNA mutations on human mesenchimal stem cell (MSC) osteogenic differentiation and explore the possible interaction of lamins and Notch signaling pathway. We modified human MSCs with mutant LMNA bearing known mutations with tissue specific phenotype associated with different laminopathies. Differentiation was evaluated 21 days after its induction by number of differentiated cells, as well as by the expression level of specific osteogenic markers SPP, IBSP, and BGLAP. Some mutations enhance differentiation whereas others decrease its level. These findings support the notion that lamin A/C is involved in the regulation of MMSC differentiation. Introduction of mutant LMNA forms together with the activated Notch domain modified the expression of HEY1, a major target of Notch signaling. Thereby, one of the mechanisms involved in the regulation of MSC differentiation may be the interaction of lamins A/C with components of Notch signaling.
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Abbreviations
- MMSC:
-
multipotent mesenchymal stromal cell
- AT:
-
adipose tissue
- LMNA :
-
lamin A/C
- LMNAwt :
-
lamin A/C wild type
- SPP1 :
-
osteopontin
- IBSP :
-
sialoprotein
- BGLAP :
-
osteocalcin
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Original Russian Text © M.A. Bogdanova, A.Y. Gudkova, A.S. Zabirnik, E.V. Ignatieva, R.I. Dmitrieva, N.A. Smolina, A.A. Kostareva, A.B. Malashicheva, 2014, published in Tsitologiya, 2014, Vol. 56, No. 4, pp. 260–267.
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Bogdanova, M.A., Gudkova, A.Y., Zabirnik, A.S. et al. Nuclear lamins regulate osteogenic differentiation of mesenchymal stem cells. Cell Tiss. Biol. 8, 292–298 (2014). https://doi.org/10.1134/S1990519X14040026
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DOI: https://doi.org/10.1134/S1990519X14040026