Influences of lamin A levels on induction of pluripotent stem cells

Abstract

SummaryLamin A is an inner nuclear membrane protein that maintains nuclear structure integrity, is involved in transcription, DNA damage response and genomic stability, and also links to cell differentiation, senescence, premature aging and associated diseases. Induced pluripotent stem (iPS) cells have been successfully generated from various types of cells and used to model human diseases. It remains unclear whether levels of lamin A influence reprogramming of somatic cells to pluripotent states during iPS induction. Consistently, lamin A is expressed more in differentiated than in relatively undifferentiated somatic cells, and increases in expression levels with age. Somatic cells with various expression levels of lamin A differ in their dynamics and efficiency during iPS cell induction. Cells with higher levels of lamin A show slower reprogramming and decreased efficiency to iPS cells. Furthermore, depletion of lamin A by transient shRNA accelerates iPS cell induction from fibroblasts. Reduced levels of lamin A are associated with increased expression of pluripotent genes Oct4 and Nanog, and telomerase genes Tert and Terc. On the contrary, overexpression of lamin A retards somatic cell reprogramming to iPS-like colony formation. Our data suggest that levels of lamin A influence reprogramming of somatic cells to pluripotent stem cells and that artificial silencing of lamin A facilitates iPS cell induction. These findings may have implications in enhancing rejuvenation of senescent or older cells by iPS technology and manipulating lamin A levels.

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

“…Lamin A level influences the induction of iPSC, the higher lamin A level, the lower reprogramming efficiency of somatic cells into iPSC. Reduced levels of lamin A are associated with increased expression of pluripotent genes Oct4 and Nanog, and of telomerase genes Tert and Terc [464]. As progeroid syndromes affected mainly cells from mesenchymal lineage, HGPS iPSC have been differentiated into several derivates from mesenchymal stem cells [465], cardiomyocytes [466] and adipocytes, whose differentiation is impaired through the inhibition by progerin of two transcription factors, PPAR␥2 and C/EBP␣ active at late stage [467].…”

Mechanisms and models of somatic cell reprogramming

“…Consistent with this notion are the findings that general chromatin remodeling complexes such as BAF 45,97 , or global basal transcription machinery components like the transcription factor IID (TFIID) complex 98 , or exposure of cells to general DNA methyltransferase and histone deacetylase inhibitors like 5-azacytidine 13 and valporic acid 78 , can substantially enhance reprogramming in cooperation with OSKM. Also, in fibroblasts, down-regulation of the global chromatin organization modulator Lamin A, which is not expressed in ESCs 99 , has been reported to increase reprogramming efficiency 100 . Thus, although OSKM are highly efficient in inducing pluripotency, any chromatin remodeler or transcription factor - even those that do not normally function in ESCs - might be able to initiate the process leading to pluripotency, albeit with an efficiency that might be too low to be detected in standard reprogramming assays.…”

Causes and consequences of nuclear envelope alterations in tumour progression

“…Somatic cells treated to induce pluripotency show loss of lamin A/C expression, demonstrating that lamin levels are not static but scale reversibly with the degree of differentiation (Alberio et al, 2005; Bru et al, 2008). Conversely, somatic cells expressing higher levels of lamin A show decreased efficiency in reprogramming to induced pluripotent stem cells (iPSCs), and experimental manipulation to increase or decrease lamin A levels results in reduced or enhanced induction of iPSCs, respectively, suggesting that levels of lamin A in somatic cell populations reflect varying degrees of plasticity (Zuo et al, 2012). In addition, overexpression of lamin A in normal human fibroblasts results in decreased replicative lifespan (Candelario et al, 2008).…”