(18a) A Nuclear Rheostat That Couples Microenvironment Rigidity to Cell Lineage

A solid tissue can be soft like fat or brain, stiff like striated muscle and heart, or rigid like bone.  Proteomic profiling of tissue nuclei shows that Lamin-A/C expression increases more than 30-fold and in near-proportion to micro-elasticity of adult tissue, while other nuclear envelope components such as Lamin-B exhibit small variations.  Lamin-A/C has been implicated in aging syndromes that affect muscle and fat but not brain, and we find nuclei in brain-derived cells are indeed dominated by Lamin-B and are much softer than nuclei derived from muscle cells with predominantly Lamin-A/C.  In vitro, matrix elasticity can affect expression of nuclear envelope components in adult stem cells and major changes in Lamin-A/C direct lineage: lower levels favor soft tissue and higher levels promote rigid tissue lineage.  Stress response elements in the Lamin-A/C promoter are just beginning to be elaborated, but tagging of cryptic sites while physically stressing isolated nuclei reveals stress-driven, mass spectrometry-mapped changes in various nuclear proteins including Lamin-A/C, consistent with cell and tissue evidence that the nucleus transduces physical stress.