BoneKEy Reports | BoneKEy Watch
Lamin-A in the cell nucleus regulates tissue stiffness, driving differentiation
DOI:10.1038/bonekey.2013.225
The mechanisms that dictate development into soft, non-stress-bearing tissues or stiff tissues are not well understood. Swift et al. performed a large-scale proteomic analysis to compare the impact of lamin-A protein levels on cultured stem cells exposed to different matrices with different levels of mechanosensitive stimuli.
Analysis revealed that the levels of lamin-A were 30 times greater in stiff tissues than in soft, whereas levels of lamin-B varied only 1–3-fold. Lamin-A, like collagen, scaled directly with the degree of tissue elasticity measured. In vivo experiments using nude mice showed that glioblastoma tumors grown in the animals' flank were stiffer than those grown in the brain, and the levels of lamin-A were correspondingly higher in flank-grown tumors.
Both the actual level of lamin-A protein and its conformation into an active state were mechanosensitive in cultured cells. Human bone-derived mesenchymal stem cells grown on a stiff matrix showed overexpression of lamin-A, and 80% were positive for alkaline phosphatase, an established osteogenesis marker. Although lamin-A is regulated by the retinoic acid (RA) pathway, the protein itself regulates levels of the receptor for RA (RAR).
Editor’s comment: Matrix stiffness determined by collagen directly influences nuclear lamin-A levels. Lamin-A transcription was regulated by the RA–RAR system, but nuclear entry of RAR was regulated by lamin-A. Thus, tissue stiffness determines lamin-A levels, which contributes to lineage determination.
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