Research Article: Robust nuclear lamina-based cell classification of aging and senescent cells

Date Published: December 24, 2011

Publisher: Impact Journals LLC

Author(s): Christiaan H. Righolt, Merel L.R. van ‘t Hoff, Bart J. Vermolen, Ian T. Young, Vered Raz.

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Abstract

Changes in the shape of the nuclear lamina are exhibited in senescent cells, as well as in cells expressing mutations in lamina genes. To identify cells with defects in the nuclear lamina we developed an imaging method that quantifies the intensity and curvature of the nuclear lamina. We show that this method accurately describes changes in the nuclear lamina. Spatial changes in nuclear lamina coincide with redistribution of lamin A proteins and local reduction in protein mobility in senescent cell. We suggest that local accumulation of lamin A in the nuclear envelope leads to bending of the structure. A quantitative distinction of the nuclear lamina shape in cell populations was found between fresh and senescent cells, and between primary myoblasts from young and old donors. Moreover, with this method mutations in lamina genes were significantly distinct from cells with wild-type genes. We suggest that this method can be applied to identify abnormal cells during aging, in in vitro propagation, and in lamina disorders.

Partial Text

Cellular senescence refers to a decline in cell proliferation, initially described during in vitro propagation [1]. In vivo senescent cells are suggested to promote biological processes that are associated with aging and cancer progression [2]. Cellular senescence is induced by numerous intra- and extra- cellular stimuli, which lead to changes in many cellular processes. A broad range of molecular markers is used to identify senescent cells [2]. Nevertheless, the identification of senescent cells is insufficient and cell-based methods for identification of those cells are not quantitative [3]. Cellular senescence in marrow stroma cells (MSCs) is associated with spatial changes of the nuclear lamina [4]. Deformed nuclear structure is also exhibited in aging and apoptosis [5, 6], as well as in aging-associated cellular processes like apoptosis [7, 8]. Thus spatial changes of the nuclear lamina could be used to identify aging, apoptotic and senescent cells.

Mutations in lamin A are known to trigger changes in the nuclear shape [9]. Deformed nuclear shape has also been found in cells undergoing senescence and aging cells [4, 8]. Quantification of the nuclear lamina structure could, therefore, be an objective tool to describe changes in the lamina structure and to identify mutant or unhealthy cells within a cell population. Here we report that based on the nuclear lamina robust and accurate cell classification can be obtained between fresh or young and senescent or aging cells. Statistical analysis of fluorescence intensity and curvature show that cell populations of fresh, senescent and apoptotic cells form separate clusters (Figure 6). Cells expressing mutations in lamina genes also cluster according to their biological definition (Figure 6). Moreover, primary myoblasts from a young and an old donor cluster together with fresh and senescent hMSCs, respectively (Figure 6). This indicates that changes in lamina shape are quantitative, robust and spatial changes of the nuclear lamina between young or fresh cells and aging or senescent cells are similar.

 

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