Lamin A/C Acts as an Essential Factor in Mesenchymal Stem Cell Differentiation Through the Regulation of the Dynamics of the Wnt/β‐Catenin Pathway

Abstract

Changes in the expression of lamin A/C, a fibrilar protein of the nuclear envelope, are associated with the cellular features of age-related bone loss. Reduced expression of lamin A/C inhibits osteoblastogenesis while facilitating adipogenic differentiation of mesenchymal stem cells (MSC) in vitro and in vivo. In this study we investigated the regulatory role that lamin A/C plays on the essential elements of the Wnt/β-catenin pathway, which are pivotal in MSC differentiation. Initially, we assessed the effect of lamin A/C gene (LMNA) overexpression on MSC differentiation while compared it to lamin A/C depleted MSC. Osteogenesis and gene expression of osteogenic factors were higher in LMNA-transfected MSC as compared to control. Conversely, adipogenesis and expression of adipogenic factors were significantly lower in LMNA transfected cells. Nuclear β-catenin was significantly higher (∼two fold) in MSC expressing higher levels of LMNA as compared to control with nuclear β-catenin levels being significantly lower (∼ -42%) in siRNA-treated MSC. Luciferase activity for β-catenin-mediated transcriptional activation was significantly higher in cells overexpressing LMNA. These data indicate that MSC overexpressing LMNA have higher osteogenic and lower adipogenic differentiation potential. In conclusion, our studies demonstrate that lamin A/C plays a significant role in the differentiation of both osteoblasts and adipocytes by regulating some of the elements of Wnt/β-catenin signaling during early MSC differentiation.

N-cadherin is Key to Expression of the Nucleus Pulposus Cell Phenotype under Selective Substrate Culture Conditions

“…Apart from tethering to CDH2, β-catenin has also been shown to interact with lamin A/C (LMNA), a fibrillar protein of the nuclear envelope5152. In human mesenchymal stem cells (MSCs), overexpression of LMNA facilitated β-catenin entry into the cell nucleus and led to increased levels of nuclear β-catenin51 that impacted MSC differentiation.…”

Nuclear organization during in vitro differentiation of porcine mesenchymal stem cells (MSCs) into adipocytes

“…Beyond their structural function, lamins also participate in cell proliferation and differentiation through regulation of transcription and chromatin organization (Dechat et al 2008). It has been previously reported that reduced expression of lamin A/C facilitates adipogenic differentiation of mesenchymal stem cells by regulating the Wnt/β-catenin signaling pathway (Bermeo et al 2015). Reorganization of the nuclear lamina during adipocyte formation has been well described in the mouse and human model systems (Verstraeten et al 2011).…”

Cell Mechanosensitivity Is Enabled by the LINC Nuclear Complex

“…MSCs have a more robust lamin A/C network [53] and perhaps increased LINC connectivity compared to pluripotent cells. Lamin A/C increases when MSCs enter the osteogenic lineage [120], a change consistent with the increased cellular stiffness of osteoblasts [121, 122], and lamin A/C overexpression promotes osteogenic differentiation [123]. In contrast, lamin A/C decreases when MSCs undergo adipogenesis [48] and both partial and complete deletion of lamin A/C promotes an adipogenic program in MSCs [124–126].…”